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  • <h1>SNAPSHOT</h1>
  • <h4>Created at: 2020-08-28 21:09</h4>
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  • <!-- Title Section, includes id, name and short name -->
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  • <h2>AOP ID and Title:</h2>
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  • AOP 307: Decreased testosterone synthesis leading to short anogenital distance (AGD) in male (mammalian) offspring
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  • <div class="title">AOP 307: Decreased testosterone synthesis leading to short anogenital distance (AGD) in male (mammalian) offspring</div>
  • <strong>Short Title: Decreased testosterone synthesis leading to short AGD</strong>
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  • <h2>Graphical Representation</h2>
  • <img src="https://aopwiki.org/system/dragonfly/production/2019/08/30/504x5c7c22_AOP_Graphic_decrease_testosterone_synthesis_leading_to_short_male_AGD.jpg" , height="500" , width="700"> </img>
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  • <hr>
  • <h2>Graphical Representation</h2>
  • <img src="https://aopwiki.org/system/dragonfly/production/2019/08/30/504x5c7c22_AOP_Graphic_decrease_testosterone_synthesis_leading_to_short_male_AGD.jpg" height="500" width="700" alt=""/>
  • <!-- Author section, includes text of author names as they have been entered by the user -->
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  • <h2>Authors</h2>
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  • <p>Terje Svingen; National Food Institute, Technical University of Denmark, Kongens Lyngby, 2800 Denmark</p>
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  • <!-- Status Section, lists status of aop -->
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  • <h2>Status</h2>
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  • <th>Author status</th>
  • <th>OECD status</th>
  • <th>OECD project</th>
  • <th>SAAOP status</th>
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  • <th scope="col">Author status</th>
  • <th scope="col">OECD status</th>
  • <th scope="col">OECD project</th>
  • <th scope="col">SAAOP status</th>
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  • <td>Under development: Not open for comment. Do not cite</td>
  • <td></td>
  • <td></td>
  • <td></td>
  • <td>Under Development</td>
  • <td>1.90</td>
  • <td>Included in OECD Work Plan</td>
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  • <!-- Abstract Section, text as generated by author -->
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  • <h2>Abstract</h2>
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  • <p>This AOP links decreased testosterone synthesis by fetal Leydig cells with short anogenital distance (AGD) in male offspring. A short AGD around birth is a marker for feminization of male fetuses and is associated with male reproductive disorders, including reduced fertility in adulthood. Although a short AGD is not necessarily &lsquo;adverse&rsquo; from a human health perspective, it is considered an &lsquo;adverse outcome&rsquo; in OECD test guidelines; AGD measurements are mandatory in specific tests for developmental and reproductive toxicity in chemical risk assessment (TG 443, TG 421/422, TG 414).</p>
  • <h2>Abstract</h2>
  • <p>This AOP links decreased testosterone synthesis by fetal Leydig cells with short anogenital distance (AGD) in male offspring. A short AGD around birth is a marker for feminization of male fetuses and is associated with male reproductive disorders, including reduced fertility in adulthood. Although a short AGD is not necessarily &lsquo;adverse&rsquo; from a human health perspective, it is considered an &lsquo;adverse outcome&rsquo; in OECD test guidelines; AGD measurements are mandatory in specific tests for developmental and reproductive toxicity in chemical risk assessment (TG 443, TG 421/422, TG 414).</p>
  • <p>Testosterone is primarily synthesized by fetal Leydig cells of the fetal testes by the process of steroidogenesis. The precursor molecule cholesterol is converted to testosterone via several enzymatic steps and includes for instance key CYP enzymes, CYP11 and CYP17. Following synthesis, testosterone is released into the circulation and transported to target tissues and organs where it initiates masculinization processes. Under normal physiological conditions, testosterone produced by the testicles, is converted in peripheral tissues by 5&alpha;-reductase into DHT, which in turn binds AR and activates downstream target genes. AR signaling is necessary for masculinization of the developing fetus, including differentiation of the levator ani/bulbocavernosus (LABC) muscle complex in males. The LABC complex does not develop in the absence, or low levels of, androgen signaling, as in female fetuses.</p>
  • <p>The key events in this pathway is inhibition of testosterone synthesis in the fetal Leydig cells. In turn, this results in reduced circulating testosterone levels and less DHT (converted by 5&alpha;-reductase). Low DHT fails to properly activate AR in target tissues, including &nbsp;the developing perineal region, which leads to failure to properly masculinize the perineum/LABC complex and ultimately a short AGD.</p>
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  • <!-- AOP summary, includes summary of each of the events associated with this aop -->
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  • <h2>Summary of the AOP</h2>
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  • <h3>Events</h3>
  • <h3>Molecular Initiating Events (MIE), Key Events (KE), Adverse Outcomes (AO)</h3>
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  • <tr>
  • <th>Sequence</th>
  • <th>Type</th>
  • <th>Event ID</th>
  • <th>Title</th>
  • <th>Short name</th>
  • <h3>Molecular Initiating Events (MIE), Key Events (KE), Adverse Outcomes (AO)</h3>
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  • <th scope="col">Sequence</th>
  • <th scope="col">Type</th>
  • <th scope="col">Event ID</th>
  • <th scope="col">Title</th>
  • <th scope="col">Short name</th>
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  • <tbody>
  • <tr><td></td><td></td><td></td><td></td><td></td></tr>
  • <tr>
  • <td></td>
  • <td>KE</td>
  • <td>413</td>
  • <td><a href="/events/413">Reduction, Testosterone synthesis in Leydig cells</a></td>
  • <td>Reduction, Testosterone synthesis in Leydig cells</td>
  • </tr>
  • <tr>
  • <td></td>
  • <td>KE</td>
  • <td>1690</td>
  • <td><a href="/events/1690">Decrease, testosterone levels </a></td>
  • <td>Decrease, testosterone levels</td>
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  • <tr>
  • <td></td>
  • <td>KE</td>
  • <td>1613</td>
  • <td><a href="/events/1613">Decrease, dihydrotestosterone (DHT) level</a></td>
  • <td>Decrease, DHT level</td>
  • </tr>
  • <tr>
  • <td></td>
  • <td>KE</td>
  • <td>1614</td>
  • <td><a href="/events/1614">Decrease, androgen receptor activation</a></td>
  • <td>Decrease, AR activation</td>
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  • <tr>
  • <td></td>
  • <td>KE</td>
  • <td>286</td>
  • <td><a href="/events/286">Altered, Transcription of genes by the androgen receptor</a></td>
  • <td>Altered, Transcription of genes by the AR</td>
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  • <tr><td></td><td></td><td></td><td></td><td></td></tr>
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  • <td></td>
  • <td>KE</td>
  • <td>413</td>
  • <td><a href="/events/413">Reduction, Testosterone synthesis in Leydig cells</a></td>
  • <td>Reduction, Testosterone synthesis in Leydig cells</td>
  • </tr>
  • <tr>
  • <td></td>
  • <td>KE</td>
  • <td>1690</td>
  • <td><a href="/events/1690">reduction, testosterone levels </a></td>
  • <td>reduction, testosterone levels </td>
  • </tr>
  • <tr>
  • <td></td>
  • <td>KE</td>
  • <td>1613</td>
  • <td><a href="/events/1613">Decrease, dihydrotestosterone (DHT) level</a></td>
  • <td>Decrease, DHT level</td>
  • </tr>
  • <tr>
  • <td></td>
  • <td>KE</td>
  • <td>1614</td>
  • <td><a href="/events/1614">Decrease, androgen receptors (AR) activation</a></td>
  • <td>Decrease, AR activation</td>
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  • <td></td>
  • <td>KE</td>
  • <td>286</td>
  • <td><a href="/events/286">Decreased, Transcription of genes by AR</a></td>
  • <td>Decreased, Transcription of genes by AR</td>
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  • <tr><td></td><td></td><td></td><td></td><td></td></tr>
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  • <td></td>
  • <td>AO</td>
  • <td>1688</td>
  • <td><a href="/events/1688">decrease, male anogenital distance</a></td>
  • <td>short male AGD</td>
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  • <tr><td></td><td></td><td></td><td></td><td></td></tr>
  • <tr>
  • <td></td>
  • <td>AO</td>
  • <td>1688</td>
  • <td><a href="/events/1688">anogenital distance (AGD), decreased</a></td>
  • <td>AGD, decreased</td>
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  • <h3>Key Event Relationships</h3>
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  • <th>Upstream Event</th>
  • <th>Relationship Type</th>
  • <th>Downstream Event</th>
  • <th>Evidence</th>
  • <th>Quantitative Understanding</th>
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  • <th scope="col">Upstream Event</th>
  • <th scope="col">Relationship Type</th>
  • <th scope="col">Downstream Event</th>
  • <th scope="col">Evidence</th>
  • <th scope="col">Quantitative Understanding</th>
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  • <td><a href="/relationships/2125">Reduction, Testosterone synthesis in Leydig cells</a></td>
  • <td>adjacent</td>
  • <td>Decrease, testosterone levels </td>
  • <td>High</td>
  • <td>Moderate</td>
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  • <td><a href="/relationships/2125">Reduction, Testosterone synthesis in Leydig cells</a></td>
  • <td>adjacent</td>
  • <td>reduction, testosterone levels </td>
  • <td>High</td>
  • <td>Moderate</td>
  • </tr>
  • <tr>
  • <td><a href="/relationships/2126">reduction, testosterone levels </a></td>
  • <td>adjacent</td>
  • <td>Decrease, dihydrotestosterone (DHT) level</td>
  • <td>Moderate</td>
  • <td>Low</td>
  • </tr>
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  • <td><a href="/relationships/1935">Decrease, dihydrotestosterone (DHT) level</a></td>
  • <td>adjacent</td>
  • <td>Decrease, androgen receptors (AR) activation</td>
  • <td>High</td>
  • <td>Moderate</td>
  • </tr>
  • <tr>
  • <td><a href="/relationships/2124">Decrease, androgen receptors (AR) activation</a></td>
  • <td>adjacent</td>
  • <td>Decreased, Transcription of genes by AR</td>
  • <td>High</td>
  • <td>Moderate</td>
  • </tr>
  • <tr>
  • <td><a href="/relationships/2127">Decreased, Transcription of genes by AR</a></td>
  • <td>adjacent</td>
  • <td>decrease, male anogenital distance</td>
  • <td>Moderate</td>
  • <td>Moderate</td>
  • </tr>
  • <tr><td></td><td></td><td></td><td></td><td></td></tr>
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  • <td><a href="/relationships/2131">reduction, testosterone levels </a></td>
  • <td>non-adjacent</td>
  • <td>Decrease, androgen receptors (AR) activation</td>
  • <td>Moderate</td>
  • <td>Moderate</td>
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  • <!-- stressor table -->
  • <h3>Stressors</h3>
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  • <th>Name</th>
  • <th>Evidence</th>
  • <td><a href="/relationships/2126">Decrease, testosterone levels </a></td>
  • <td>adjacent</td>
  • <td>Decrease, dihydrotestosterone (DHT) level</td>
  • <td>Moderate</td>
  • <td>Low</td>
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  • <td>Dibutyl phthalate</td>
  • <td>High</td>
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  • <td>Bis(2-ethylhexyl) phthalate</td>
  • <td>High</td>
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  • <td><a href="/relationships/1935">Decrease, dihydrotestosterone (DHT) level</a></td>
  • <td>adjacent</td>
  • <td>Decrease, androgen receptor activation</td>
  • <td>High</td>
  • <td>Moderate</td>
  • </tr>
  • <tr>
  • <td><a href="/relationships/2124">Decrease, androgen receptor activation</a></td>
  • <td>adjacent</td>
  • <td>Altered, Transcription of genes by the androgen receptor</td>
  • <td>High</td>
  • <td>Moderate</td>
  • </tr>
  • <tr>
  • <td><a href="/relationships/2127">Altered, Transcription of genes by the androgen receptor</a></td>
  • <td>adjacent</td>
  • <td>anogenital distance (AGD), decreased</td>
  • <td>Moderate</td>
  • <td>Moderate</td>
  • </tr>
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  • <td></td>
  • <td></td>
  • <td></td>
  • <td></td>
  • <td></td>
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  • <td><a href="/relationships/2131">Decrease, testosterone levels </a></td>
  • <td>non-adjacent</td>
  • <td>Decrease, androgen receptor activation</td>
  • <td>Moderate</td>
  • <td>Moderate</td>
  • </tr>
  • <tr>
  • <td><a href="/relationships/2820">Decrease, androgen receptor activation</a></td>
  • <td>non-adjacent</td>
  • <td>anogenital distance (AGD), decreased</td>
  • <td></td>
  • <td></td>
  • </tr>
  • </tbody>
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  • <h3>Stressors</h3>
  • <div class="table-responsive">
  • <table class="table table-bordered table-fullwidth">
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  • <th scope="col">Name</th>
  • <th scope="col">Evidence</th>
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  • <td>Dibutyl phthalate</td>
  • <td>High</td>
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  • <td>Bis(2-ethylhexyl) phthalate</td>
  • <td>High</td>
  • </tr>
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  • </table>
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  • <!-- end summary -->
  • <!-- Overall assessment section, *** what is included here? *** -->
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  • <h2>Overall Assessment of the AOP</h2>
  • <hr>
  • <h3>Domain of Applicability</h3>
  • <strong>Life Stage Applicability</strong>
  • <div class="panel panel-default">
  • <table class="table table-bordered table-striped">
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  • <h3>Domain of Applicability</h3>
  • <strong>Life Stage Applicability</strong>
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  • <table class="table table-bordered table-fullwidth">
  • <thead class="thead-light">
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  • <th>Life Stage</th>
  • <th>Evidence</th>
  • <th scope="col">Life Stage</th>
  • <th scope="col">Evidence</th>
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  • <td>Foetal</td>
  • <td>High</td>
  • </tr>
  • <tr>
  • <td>Pregnancy</td>
  • <td>High</td>
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  • <tbody class="tbody-striped">
  • <tr>
  • <td>Foetal</td>
  • <td>High</td>
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  • <td>Pregnancy</td>
  • <td>High</td>
  • </tr>
  • </tbody>
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  • <strong>Taxonomic Applicability</strong>
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  • <table class="table table-bordered table-striped">
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  • <strong>Taxonomic Applicability</strong>
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  • <thead class="thead-light">
  • <tr>
  • <th>Term</th>
  • <th>Scientific Term</th>
  • <th>Evidence</th>
  • <th>Links</th>
  • <th scope="col">Term</th>
  • <th scope="col">Scientific Term</th>
  • <th scope="col">Evidence</th>
  • <th scope="col">Links</th>
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  • <td>human</td>
  • <td>Homo sapiens</td>
  • <td>Moderate</td>
  • <td>
  • <a href="http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&id=9606" , target="_blank">NCBI</a>
  • </td>
  • </tr>
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  • <td>rat</td>
  • <td>Rattus norvegicus</td>
  • <td>High</td>
  • <td>
  • <a href="http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&id=10116" , target="_blank">NCBI</a>
  • </td>
  • </tr>
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  • <td>mouse</td>
  • <td>Mus musculus</td>
  • <td>Moderate</td>
  • <td>
  • <a href="http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&id=10090" , target="_blank">NCBI</a>
  • </td>
  • </tr>
  • <tbody class="tbody-striped">
  • <tr>
  • <td>human</td>
  • <td>Homo sapiens</td>
  • <td>Moderate</td>
  • <td><a href="http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&id=9606" target="_blank">NCBI</a></td>
  • </tr>
  • <tr>
  • <td>rat</td>
  • <td>Rattus norvegicus</td>
  • <td>High</td>
  • <td><a href="http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&id=10116" target="_blank">NCBI</a></td>
  • </tr>
  • <tr>
  • <td>mouse</td>
  • <td>Mus musculus</td>
  • <td>Moderate</td>
  • <td><a href="http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&id=10090" target="_blank">NCBI</a></td>
  • </tr>
  • </tbody>
  • </table>
  • </div>
  • <strong>Sex Applicability</strong>
  • <div class="panel panel-default">
  • <table class="table table-bordered table-striped">
  • <thead>
  • <strong>Sex Applicability</strong>
  • <div class="table-responsive">
  • <table class="table table-bordered table-fullwidth">
  • <thead class="thead-light">
  • <tr>
  • <th>Sex</th>
  • <th>Evidence</th>
  • <th scope="col">Sex</th>
  • <th scope="col">Evidence</th>
  • </tr>
  • </thead>
  • <tbody>
  • <tr>
  • <td>Male</td>
  • <td>High</td>
  • </tr>
  • <tbody class="tbody-striped">
  • <tr>
  • <td>Male</td>
  • <td>High</td>
  • </tr>
  • </tbody>
  • </table>
  • </div>
  • </div>
  • <!-- potential consierations, text as entered by author -->
  • <div id="considerations_for_potential_applicaitons">
  • </div>
  • <!-- reference section, text as of right now but should be changed to be handled as table -->
  • <div id="references">
  • <h2>References</h2>
  • <hr>
  • <p><span style="font-family:calibri,sans-serif; font-size:11.0pt">1. Schwartz CL, Christiansen S, Vinggaard AM, Axelstad M, Hass U and <strong>Svingen T</strong> (2019), Anogenital distance as a toxicological or clinical marker for fetal androgen action and risk for reproductive disorders. <em>Arch Toxicol</em> 93: 253-272.</span></p>
  • <br>
  • </div>
  • <div id="appendicies">
  • <h2>Appendix 1</h2>
  • <h3>List of Key Events in the AOP</h3>
  • <div>
  • <div>
  • <h4><a href="/events/413">Event: 413: Reduction, Testosterone synthesis in Leydig cells</a><br></h4>
  • <h5>Short Name: Reduction, Testosterone synthesis in Leydig cells</h5>
  • </div>
  • <h4>Key Event Component</h4>
  • <div class="panel panel-default">
  • <table class="table table-bordered table-striped">
  • <thead>
  • <tr>
  • <th>Process</th>
  • <th>Object</th>
  • <th>Action</th>
  • </tr>
  • </thead>
  • <tbody>
  • <tr>
  • <td>testosterone biosynthetic process</td>
  • <td>testosterone</td>
  • <td>decreased</td>
  • </tr>
  • </tbody>
  • </table>
  • </div>
  • <div>
  • <!-- loop to find all aops that use this event -->
  • <h4>AOPs Including This Key Event</h4>
  • <div class="panel panel-default">
  • <table class="table table-bordered table-striped">
  • <thead>
  • <h4><a href="/events/413">Event: 413: Reduction, Testosterone synthesis in Leydig cells</a></h4>
  • <h5>Short Name: Reduction, Testosterone synthesis in Leydig cells</h5>
  • <h4>Key Event Component</h4>
  • <div class="table-responsive">
  • <table class="table table-bordered table-fullwidth">
  • <thead class="thead-light">
  • <tr>
  • <th scope="col">Process</th>
  • <th scope="col">Object</th>
  • <th scope="col">Action</th>
  • </tr>
  • </thead>
  • <tbody class="tbody-striped">
  • <tr>
  • <th>AOP ID and Name</th>
  • <th>Event Type</th>
  • <td>testosterone biosynthetic process</td>
  • <td>testosterone</td>
  • <td>decreased</td>
  • </tr>
  • </thead>
  • <tbody>
  • <tr>
  • <td><a href="/aops/51">Aop:51 - PPARα activation leading to impaired fertility in adult male rodents </a></td>
  • <td>KeyEvent</td>
  • </tr>
  • <tr>
  • <td><a href="/aops/18">Aop:18 - PPARα activation in utero leading to impaired fertility in males</a></td>
  • <td>KeyEvent</td>
  • </tr>
  • <tr>
  • <td><a href="/aops/64">Aop:64 - Glucocorticoid Receptor (GR) Mediated Adult Leydig Cell Dysfunction Leading to Decreased Male Fertility</a></td>
  • <td>KeyEvent</td>
  • </tr>
  • <tr>
  • <td><a href="/aops/307">Aop:307 - Decreased testosterone synthesis leading to short anogenital distance (AGD) in male (mammalian) offspring</a></td>
  • <td>KeyEvent</td>
  • </tr>
  • </tbody>
  • </table>
  • </div>
  • </div>
  • <!-- loop to find stressors under event -->
  • <div>
  • </div>
  • <br>
  • <!-- biological organization -->
  • <div>
  • <h4>Biological Context</h4>
  • <div class="panel panel-default">
  • <table class="table table-bordered table-striped">
  • <thead>
  • <tr>
  • <th>Level of Biological Organization</th>
  • </tr>
  • </thead>
  • <tbody>
  • <tr>
  • <td>Cellular</td>
  • </tr>
  • </tbody>
  • </table>
  • </div>
  • </tbody>
  • </table>
  • </div>
  • <!-- end of bio org -->
  • <!-- cell term -->
  • <div>
  • <h4>Cell term</h4>
  • <div class="panel panel-default">
  • <table class="table table-bordered table-striped">
  • <thead>
  • <tr>
  • <th>Cell term</th>
  • </tr>
  • </thead>
  • <tbody>
  • <tr>
  • <td>testosterone secreting cell</td>
  • </tr>
  • <h4>AOPs Including This Key Event</h4>
  • <div class="table-responsive">
  • <table class="table table-bordered table-fullwidth">
  • <thead class="thead-light">
  • <tr>
  • <th scope="col">AOP ID and Name</th>
  • <th scope="col">Event Type</th>
  • </tr>
  • </thead>
  • <tbody class="tbody-striped">
  • <tr>
  • <td><a href="/aops/51">Aop:51 - PPARα activation leading to impaired fertility in adult male rodents </a></td>
  • <td>KeyEvent</td>
  • </tr>
  • <tr>
  • <td><a href="/aops/18">Aop:18 - PPARα activation in utero leading to impaired fertility in males</a></td>
  • <td>KeyEvent</td>
  • </tr>
  • <tr>
  • <td><a href="/aops/64">Aop:64 - Glucocorticoid Receptor (GR) Mediated Adult Leydig Cell Dysfunction Leading to Decreased Male Fertility</a></td>
  • <td>KeyEvent</td>
  • </tr>
  • <tr>
  • <td><a href="/aops/307">Aop:307 - Decreased testosterone synthesis leading to short anogenital distance (AGD) in male (mammalian) offspring</a></td>
  • <td>KeyEvent</td>
  • </tr>
  • </tbody>
  • </table>
  • </div>
  • </tbody>
  • </table>
  • </div>
  • <h4>Biological Context</h4>
  • <div class="table-responsive">
  • <table class="table table-bordered table-fullwidth">
  • <thead class="thead-light">
  • <tr><th scope="col">Level of Biological Organization</th></tr>
  • </thead>
  • <tbody class="tbody-striped">
  • <tr><td>Cellular</td></tr>
  • </tbody>
  • </table>
  • </div>
  • <!-- end of cell term -->
  • <!-- organ term -->
  • <div>
  • <h4>Cell term</h4>
  • <div class="table-responsive">
  • <table class="table table-bordered table-fullwidth">
  • <thead class="thead-light">
  • <tr><th scope="col">Cell term</th></tr>
  • </thead>
  • <tbody class="tbody-striped">
  • <tr><td>testosterone secreting cell</td></tr>
  • </tbody>
  • </table>
  • </div>
  • <!-- end of organ term -->
  • <!-- Evidence for Perturbation of This Event by Stressors -->
  • <!-- end Evidence for Perturbation of This Event by Stressors -->
  • <h4>Domain of Applicability</h4>
  • <br>
  • <!-- loop to find taxonomic applicability under event -->
  • <div>
  • <strong>Taxonomic Applicability</strong>
  • <div class="panel panel-default">
  • <table class="table table-bordered table-striped">
  • <thead>
  • <h4>Domain of Applicability</h4>
  • <strong>Taxonomic Applicability</strong>
  • <div class="table-responsive">
  • <table class="table table-bordered table-fullwidth">
  • <thead class="thead-light">
  • <tr>
  • <th>Term</th>
  • <th>Scientific Term</th>
  • <th>Evidence</th>
  • <th>Links</th>
  • <th scope="col">Term</th>
  • <th scope="col">Scientific Term</th>
  • <th scope="col">Evidence</th>
  • <th scope="col">Links</th>
  • </tr>
  • </thead>
  • <tbody>
  • <tr>
  • <td>rat</td>
  • <td>Rattus norvegicus</td>
  • <td>High</td>
  • <td>
  • <a href="http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&id=10116" , target="_blank">NCBI</a>
  • </td>
  • </tr>
  • <tr>
  • <td>human</td>
  • <td>Homo sapiens</td>
  • <td>High</td>
  • <td>
  • <a href="http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&id=9606" , target="_blank">NCBI</a>
  • </td>
  • </tr>
  • <tr>
  • <td>mice</td>
  • <td>Mus sp.</td>
  • <td>Low</td>
  • <td>
  • <a href="http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&id=10095" , target="_blank">NCBI</a>
  • </td>
  • </tr>
  • <tbody class="tbody-striped">
  • <tr>
  • <td>rat</td>
  • <td>Rattus norvegicus</td>
  • <td>High</td>
  • <td><a href="http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&id=10116" target="_blank">NCBI</a></td>
  • </tr>
  • <tr>
  • <td>human</td>
  • <td>Homo sapiens</td>
  • <td>High</td>
  • <td><a href="http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&id=9606" target="_blank">NCBI</a></td>
  • </tr>
  • <tr>
  • <td>mice</td>
  • <td>Mus sp.</td>
  • <td>Low</td>
  • <td><a href="http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&id=10095" target="_blank">NCBI</a></td>
  • </tr>
  • </tbody>
  • </table>
  • </div>
  • </div>
  • <!-- end loop for taxons -->
  • <!-- life stages -->
  • <div>
  • </div>
  • <!-- end life stages -->
  • <!-- sex terms -->
  • <div>
  • </div>
  • <!-- end sex terms -->
  • <div>
  • <p>Key enzymes needed for testosterone production first appear in the common ancestor of amphioxus and vertebrates (Baker 2011). Consequently, this key event is applicable to most vertebrates, including humans.
  • <p>Key enzymes needed for testosterone production first appear in the common ancestor of amphioxus and vertebrates (Baker 2011). Consequently, this key event is applicable to most vertebrates, including humans.
  • </p>
  • <br>
  • </div>
  • <!-- event text -->
  • <h4>Key Event Description</h4>
  • <p><b>Biological state</b>
  • <h4>Key Event Description</h4>
  • <p><b>Biological state</b>
  • </p><p>Testosterone is a steroid hormone from the androgen group and is found in humans and other vertebrates.
  • </p><p><b>Biological compartments</b>
  • </p><p>In humans and other mammals, testosterone is secreted primarily by the testicles of males and, to a lesser extent, the ovaries of females and other steroidogenic tissues (e.g., brain, adipose). It either acts locally /or is transported to other tissues via blood circulation. Testosterone synthesis takes place within the mitochondria of Leydig cells, the testosterone-producing cells of the testis. It is produced upon stimulation of these cells by Luteinizing hormone (LH) that is secreted in pulses into the peripheral circulation by the pituitary gland in response to Gonadotropin-releasing hormone (GnRH) from the hypothalamus. Testosterone and its aromatized product, estradiol, feed back to the hypothalamus and pituitary gland to suppress transiently LH and thus testosterone production. In response to reduced testosterone levels, GnRH and LH are produced. This negative feedback cycle results in pulsatile secretion of LH followed by pulsatile production of testosterone (Ellis, Desjardins, and Fraser 1983), (Chandrashekar and Bartke 1998).
  • </p><p><b>General role in biology</b>
  • </p><p>Testosterone is the principal male sex hormone and an anabolic steroid. Male sexual differentiation depends on testosterone (T), dihydrotestosterone (DHT), and the expression of androgen receptors by target cells (Manson and Carr 2003). During the development secretion of androgens by Leydig cells is essential for masculinization of the foetus (Nef 2000).
  • The foetal Leydig cells develop in utero. These cells become competent to produce testosterone in rat by gestational day (GD) 15.5, with increasing production thereafter. Peak steroidogenic activity is reached just prior to birth, on GD19 (Chen, Ge, and Zirkin 2009). Testosterone secreted by foetal Leydig cells is required for the differentiation of the male urogenital system late in gestation (Huhtaniemi and Pelliniemi 1992). Foetal Leydig cells also play a role in the scrotal descent of the testis through their synthesis of insulin-like growth factor 3 (Insl3), for review see (Nef 2000).
  • </p><p>In humans, the first morphological sign of testicular differentiation is the formation of testicular cords, which can be seen between 6 and 7 weeks of gestation. Steroid-secreting Leydig cells can be seen in the testis at 8 weeks of gestation. At this period, the concentration of androgens in the testicular tissue and blood starts to rise, peaking at 14-16 weeks of gestation. This increase comes with an increase in the number of Leydig cells for review see (Rouiller-Fabre et al. 2009).
  • </p><p>Adult Leydig cells, which are distinct from the foetal Leydig cells, form during puberty and supply the testosterone required for the onset of spermatogenesis, among other functions. Distinct stages of adult Leydig cell development have been identified and characterized. The stem Leydig cells are undifferentiated cells that are capable of indefinite self-renewal but also of differentiation to steroidogenic cells. These cells give rise to progenitor Leydig cells, which proliferate, continue to differentiate, and give rise to the immature Leydig cells. Immature Leydig cells synthesize high levels of testosterone metabolites and develop into terminally differentiated adult Leydig cells, which produce high levels of testosterone. With aging, both serum and testicular testosterone concentrations progressively decline, for review see (Nef 2000).
  • </p><p>Androgens play a crucial role in the development and maintenance of male reproductive and sexual functions.
  • Low levels of circulating androgens can cause disturbances in male sexual development, resulting in congenital
  • abnormalities of the male reproductive tract. Later in life, this may cause reduced fertility, sexual dysfunction,
  • decreased muscle formation and bone mineralisation, disturbances of fat metabolism, and cognitive
  • dysfunction. Testosterone levels decrease as a process of ageing: signs and symptoms caused by this decline
  • can be considered a normal part of ageing.
  • </p>
  • <br>
  • <h4>How it is Measured or Detected</h4>
  • <p>OECD TG 456 <a rel="nofollow" target="_blank" class="external autonumber" href="http://www.oecd-ilibrary.org/environment/test-no-456-h295r-steroidogenesis-assay_9789264122642-en">[1]</a> is the validated test guideline for an in vitro screen for chemical effects on steroidogenesis, specifically the production of 17ß-estradiol (E2) and testosterone (T).
  • <h4>How it is Measured or Detected</h4>
  • <p>OECD TG 456 <a rel="nofollow" target="_blank" class="external autonumber" href="http://www.oecd-ilibrary.org/environment/test-no-456-h295r-steroidogenesis-assay_9789264122642-en">[1]</a> is the validated test guideline for an in vitro screen for chemical effects on steroidogenesis, specifically the production of 17ß-estradiol (E2) and testosterone (T).
  • The testosterone syntheis can be measured in vitro cultured Leydig cells. The methods for culturing Leydig cells can be found in the Database Service on Alternative Methods to animal experimentation (DB-ALM):
  • Leydig Cell-enriched Cultures <a rel="nofollow" target="_blank" class="external autonumber" href="http://ecvam-dbalm.jrc.ec.europa.eu/beta/index.cfm/methodsAndProtocols/index?id_met=232">[2]</a>,
  • Testicular Organ and Tissue Culture Systems <a rel="nofollow" target="_blank" class="external autonumber" href="http://ecvam-dbalm.jrc.ec.europa.eu/beta/index.cfm/methodsAndProtocols/index?id_met=515">[3]</a>.
  • </p><p>Testosterone synthesis in vitro cultured cells can be measured indirectly by testosterone radioimmunoassay or analytical methods such as LC-MS.
  • </p>
  • <br>
  • <h4>References</h4>
  • <p>Chandrashekar, V, and A Bartke. 1998. “The Role of Growth Hormone in the Control of Gonadotropin Secretion in Adult Male Rats.” Endocrinology 139 (3) (March): 1067–74. doi:10.1210/endo.139.3.5816.
  • <h4>References</h4>
  • <p>Chandrashekar, V, and A Bartke. 1998. “The Role of Growth Hormone in the Control of Gonadotropin Secretion in Adult Male Rats.” Endocrinology 139 (3) (March): 1067–74. doi:10.1210/endo.139.3.5816.
  • </p><p>Ellis, G B, C Desjardins, and H M Fraser. 1983. “Control of Pulsatile LH Release in Male Rats.” Neuroendocrinology 37 (3) (September): 177–83.
  • Huhtaniemi, I, and L J Pelliniemi. 1992. “Fetal Leydig Cells: Cellular Origin, Morphology, Life Span, and Special Functional Features.” Proceedings of the Society for Experimental Biology and Medicine. Society for Experimental Biology and Medicine (New York, N.Y.) 201 (2) (November): 125–40.
  • </p><p>Manson, Jeanne M, and Michael C Carr. 2003. “Molecular Epidemiology of Hypospadias: Review of Genetic and Environmental Risk Factors.” Birth Defects Research. Part A, Clinical and Molecular Teratology 67 (10) (October): 825–36. doi:10.1002/bdra.10084.
  • </p><p>Nef, S. 2000. “Hormones in Male Sexual Development.” Genes &amp; Development 14 (24) (December 15): 3075–3086. doi:10.1101/gad.843800.
  • </p><p>Rouiller-Fabre, Virginie, Vincent Muczynski, Romain Lambrot, Charlotte Lécureuil, Hervé Coffigny, Catherine Pairault, Delphine Moison, et al. 2009. “Ontogenesis of Testicular Function in Humans.” Folia Histochemica et Cytobiologica / Polish Academy of Sciences, Polish Histochemical and Cytochemical Society 47 (5) (January): S19–24. doi:10.2478/v10042-009-0065-4.
  • </p>
  • <br>
  • <!-- end event text -->
  • </div>
  • <div>
  • <div>
  • <h4><a href="/events/1690">Event: 1690: reduction, testosterone levels </a><br></h4>
  • <h5>Short Name: reduction, testosterone levels </h5>
  • </div>
  • <h4><a href="/events/1690">Event: 1690: Decrease, testosterone levels </a></h4>
  • <h5>Short Name: Decrease, testosterone levels</h5>
  • <div>
  • <!-- loop to find all aops that use this event -->
  • <h4>AOPs Including This Key Event</h4>
  • <div class="panel panel-default">
  • <table class="table table-bordered table-striped">
  • <thead>
  • <tr>
  • <th>AOP ID and Name</th>
  • <th>Event Type</th>
  • </tr>
  • </thead>
  • <tbody>
  • <tr>
  • <td><a href="/aops/307">Aop:307 - Decreased testosterone synthesis leading to short anogenital distance (AGD) in male (mammalian) offspring</a></td>
  • <td>KeyEvent</td>
  • </tr>
  • </tbody>
  • </table>
  • </div>
  • </div>
  • <h4>AOPs Including This Key Event</h4>
  • <div class="table-responsive">
  • <table class="table table-bordered table-fullwidth">
  • <thead class="thead-light">
  • <tr>
  • <th scope="col">AOP ID and Name</th>
  • <th scope="col">Event Type</th>
  • </tr>
  • </thead>
  • <tbody class="tbody-striped">
  • <tr>
  • <td><a href="/aops/307">Aop:307 - Decreased testosterone synthesis leading to short anogenital distance (AGD) in male (mammalian) offspring</a></td>
  • <td>KeyEvent</td>
  • </tr>
  • <tr>
  • <td><a href="/aops/526">Aop:526 - Decreased Chicken Ovalbumin Upstream Promoter Transcription Factor II (COUP-TFII) stem Leydig cells leads to Impaired, Spermatogenesis</a></td>
  • <td>KeyEvent</td>
  • </tr>
  • </tbody>
  • </table>
  • </div>
  • <!-- loop to find stressors under event -->
  • <div>
  • <h4>Biological Context</h4>
  • <div class="table-responsive">
  • <table class="table table-bordered table-fullwidth">
  • <thead class="thead-light">
  • <tr><th scope="col">Level of Biological Organization</th></tr>
  • </thead>
  • <tbody class="tbody-striped">
  • <tr><td>Tissue</td></tr>
  • </tbody>
  • </table>
  • </div>
  • <br>
  • <!-- biological organization -->
  • <div>
  • <h4>Biological Context</h4>
  • <div class="panel panel-default">
  • <table class="table table-bordered table-striped">
  • <thead>
  • <tr>
  • <th>Level of Biological Organization</th>
  • </tr>
  • </thead>
  • <tbody>
  • <h4>Domain of Applicability</h4>
  • <strong>Taxonomic Applicability</strong>
  • <div class="table-responsive">
  • <table class="table table-bordered table-fullwidth">
  • <thead class="thead-light">
  • <tr>
  • <th scope="col">Term</th>
  • <th scope="col">Scientific Term</th>
  • <th scope="col">Evidence</th>
  • <th scope="col">Links</th>
  • </tr>
  • </thead>
  • <tbody class="tbody-striped">
  • <tr>
  • <td>Vertebrates</td>
  • <td>Vertebrates</td>
  • <td>High</td>
  • <td><a href="http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&id=0" target="_blank">NCBI</a></td>
  • </tr>
  • </tbody>
  • </table>
  • </div>
  • <strong>Life Stage Applicability</strong>
  • <div class="table-responsive">
  • <table class="table table-bordered table-fullwidth">
  • <thead class="thead-light">
  • <tr>
  • <th scope="col">Life Stage</th>
  • <th scope="col">Evidence</th>
  • </tr>
  • </thead>
  • <tbody class="tbody-striped">
  • <tr>
  • <td>During development and at adulthood</td>
  • <td>High</td>
  • </tr>
  • </tbody>
  • </table>
  • </div>
  • <strong>Sex Applicability</strong>
  • <div class="table-responsive">
  • <table class="table table-bordered table-fullwidth">
  • <thead class="thead-light">
  • <tr>
  • <th scope="col">Sex</th>
  • <th scope="col">Evidence</th>
  • </tr>
  • </thead>
  • <tbody class="tbody-striped">
  • <tr>
  • <td>Mixed</td>
  • <td>High</td>
  • </tr>
  • </tbody>
  • </table>
  • </div>
  • <p style="text-align:justify"><span style="font-size:12pt"><span style="font-size:11.0pt">Key enzymes needed for testosterone production first appear in the common ancestor of amphioxus and vertebrates <span style="color:black">(Baker, 2011)</span>. Consequently, this KE is applicable to vertebrates, including humans. This KE is also applicable to both sexes and throughout different life stages, from development to adulthood.</span></span></p>
  • <tr>
  • <td>Tissue</td>
  • </tr>
  • <h4>Key Event Description</h4>
  • <p style="text-align:justify"><span style="font-size:11pt">Testosterone is an endogenous steroid hormone and a potent androgen. Androgens act by binding androgen receptors in androgen-responsive tissues <span style="color:black">(Murashima et al., 2015)</span>. Testosterone and other androgens such as dihydrotestosterone (DHT) are important for reproductive development and masculinization of the fetus, but apart from their effects on reproduction, androgens affect a wide variety of non-reproductive tissues such as skin, bone, muscle, and brain <span style="color:black">(Heemers et al., 2006)</span>. Testosterone is secreted primarily by the testicles of males and, to a lesser extent, the ovaries of females, and the adrenal glands, acting locally and/or is transported to other tissues via blood circulation. Testosterone is synthesized through a series of enzymatic steps that convert cholesterol to androgens, the process is known as steroidogenesis. In steroidogenesis, androstenedione or androstenediol is converted to testosterone by the enzymes 17&beta;-hydroxysteroid dehydrogenase (HSD) or 3&beta;-HSD, respectively. Testosterone can then be converted to the more potent androgen, DHT, by 5&alpha;-reductase, or aromatized by aromatase (CYP19A1) into estrogens (see KEGG reference pathway 00140 for details; www.genome.jp/kegg;). </span></p>
  • <p style="text-align:justify"><span style="font-size:11pt">In males, testosterone synthesis primarily takes place within the mitochondria of testicular Leydig cells. In mature animals (and humans), testosterone production is stimulated by Luteinizing hormone (LH) that is secreted in pulses into the peripheral circulation by the pituitary gland in response to Gonadotropin-releasing hormone (GnRH) from the hypothalamus. In e.g. fetal mouse and rat testes, de novo testosterone production is independent of LH, whereas in humans and other primates human choriogonadotropin (hCG) may act as an LH-like stimulus. In response to reduced testosterone levels, GnRH and LH are produced. This negative feedback cycle results in pulsatile secretion of LH followed by pulsatile production of testosterone (Chandrashekar &amp; Bartke, 1998; Ellis et al., 1983).</span></p>
  • <p style="text-align:justify"><span style="font-size:11pt">Disruption of any of the aforementioned processes may result in reduced testosterone levels, such as inhibition of steroidogenic enzyme activity thereby inhibiting production of testosterone. </span></p>
  • </tbody>
  • </table>
  • </div>
  • </div>
  • <!-- end of bio org -->
  • <h4>How it is Measured or Detected</h4>
  • <p style="text-align:justify"><span style="font-size:11pt">Quantification of testosterone levels can be performed in many different ways. Traditional immunoassay methods (ELISA or RIA), and advanced instrumental techniques (e.g. LC-MS/MS) or liquid scintillation spectrometry (after radiolabeling) can be used <span style="color:black">(Shiraishi et al., 2008)</span>.</span></p>
  • <p style="text-align:justify"><span style="font-size:11pt">OECD test guideline 456 (H295R Steroidogenesis Assay) is the validated test guideline for an in vitro screen for chemical effects on steroidogenesis, including the production of testosterone. It uses adrenal H295R cells and hormone levels are then measured in the cell medium (OECD 2011).</span></p>
  • <!-- cell term -->
  • <div>
  • </div>
  • <!-- end of cell term -->
  • <!-- organ term -->
  • <div>
  • </div>
  • <!-- end of organ term -->
  • <!-- Evidence for Perturbation of This Event by Stressors -->
  • <!-- end Evidence for Perturbation of This Event by Stressors -->
  • <!-- event text -->
  • <!-- end event text -->
  • </div>
  • <div>
  • <div>
  • <h4><a href="/events/1613">Event: 1613: Decrease, dihydrotestosterone (DHT) level</a><br></h4>
  • <h5>Short Name: Decrease, DHT level</h5>
  • </div>
  • <div>
  • <!-- loop to find all aops that use this event -->
  • <h4>AOPs Including This Key Event</h4>
  • <div class="panel panel-default">
  • <table class="table table-bordered table-striped">
  • <thead>
  • <tr>
  • <th>AOP ID and Name</th>
  • <th>Event Type</th>
  • </tr>
  • </thead>
  • <tbody>
  • <tr>
  • <td><a href="/aops/288">Aop:288 - Inhibition of 17α-hydrolase/C 10,20-lyase (Cyp17A1) activity leads to birth reproductive defects (cryptorchidism) in male (mammals)</a></td>
  • <td>KeyEvent</td>
  • </tr>
  • <tr>
  • <td><a href="/aops/289">Aop:289 - Inhibition of 5α-reductase leading to impaired fecundity in female fish</a></td>
  • <td>KeyEvent</td>
  • </tr>
  • <tr>
  • <td><a href="/aops/305">Aop:305 - 5α-reductase inhibition leading to short anogenital distance (AGD) in male (mammalian) offspring</a></td>
  • <td>KeyEvent</td>
  • </tr>
  • <tr>
  • <td><a href="/aops/307">Aop:307 - Decreased testosterone synthesis leading to short anogenital distance (AGD) in male (mammalian) offspring</a></td>
  • <td>KeyEvent</td>
  • </tr>
  • </tbody>
  • </table>
  • </div>
  • </div>
  • <!-- loop to find stressors under event -->
  • <div>
  • </div>
  • <br>
  • <!-- biological organization -->
  • <div>
  • <h4>Biological Context</h4>
  • <div class="panel panel-default">
  • <table class="table table-bordered table-striped">
  • <thead>
  • <tr>
  • <th>Level of Biological Organization</th>
  • </tr>
  • </thead>
  • <tbody>
  • <tr>
  • <td>Cellular</td>
  • </tr>
  • </tbody>
  • </table>
  • </div>
  • </div>
  • <!-- end of bio org -->
  • <!-- cell term -->
  • <div>
  • </div>
  • <!-- end of cell term -->
  • <!-- organ term -->
  • <div>
  • </div>
  • <!-- end of organ term -->
  • <!-- Evidence for Perturbation of This Event by Stressors -->
  • <!-- end Evidence for Perturbation of This Event by Stressors -->
  • <!-- event text -->
  • <h4>Key Event Description</h4>
  • <p style="text-align: justify;"><span style="font-size:14px"><span style="font-family:times new roman,times,serif">Reduction in DHT synthesis leads to a reduction in DHT circulating levels.&nbsp;<sup>12</sup></span></span></p>
  • <br>
  • <h4>How it is Measured or Detected</h4>
  • <p style="text-align: justify;"><span style="font-size:14px"><span style="font-family:times new roman,times,serif">DHT levels in a sample can be measured by (High Performance) Liquid Chromatography. After sample fractionation, DHT can be identify by comparison with internal standards spectrum. Quantification of DHT levels can be performed using hormones measurements kits (ELISA), instrumental techniques (LC-MS) or liquid scintillation spectrometry (after radiolabeling).<sup>3</sup></span></span></p>
  • <br>
  • <h4>References</h4>
  • <table>
  • <tbody>
  • <tr>
  • <td colspan="1" rowspan="1">
  • <p style="text-align: justify;"><span style="font-size:14px"><span style="font-family:times new roman,times,serif"><sup>1&nbsp;</sup>Miller Walter L. (1988) Molecular Biology of Steroid Hormone Synthesis. Endocrine Reviews, 9(3): 295-318.<a href="https://www.google.com/url?q=https://doi.org/10.1210/edrv-9-3-295&amp;sa=D&amp;ust=1554891396614000">https://doi.org/10.1210/edrv-9-3-295</a>&nbsp;</span></span></p>
  • <h4>References</h4>
  • <p><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif">Baker, M. E. (2011). Origin and diversification of steroids: Co-evolution of enzymes and nuclear receptors. <em>Molecular and Cellular Endocrinology</em>, <em>334</em>(1&ndash;2), 14&ndash;20. https://doi.org/10.1016/j.mce.2010.07.013</span></span></p>
  • <p style="text-align: justify;">&nbsp;</p>
  • <p><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif">Benninghoff, A. D., &amp; Thomas, P. (2006). Gonadotropin regulation of testosterone production by primary cultured theca and granulosa cells of Atlantic croaker: I. Novel role of CaMKs and interactions between calcium- and adenylyl cyclase-dependent pathways. <em>General and Comparative Endocrinology</em>, <em>147</em>(3), 276&ndash;287. https://doi.org/10.1016/j.ygcen.2006.01.014</span></span></p>
  • <p style="text-align: justify;"><span style="font-size:14px"><span style="font-family:times new roman,times,serif"><sup>2&nbsp;</sup>Miller W.L. and Auchus R.J. (2011) The Molecular Biology, Biochemistry, and Physiology of Human Steroidogenesis and Its Disorders. Endocrine Reviews, 32(1): 81-151.<a href="https://www.google.com/url?q=https://doi.org/10.1210/er.2010-0013&amp;sa=D&amp;ust=1554891396616000">https://doi.org/10.1210/er.2010-0013</a>&nbsp;</span></span></p>
  • <p><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif">Campbell, B. K., Baird, D. T., &amp; Webb, R. (1998). Effects of dose of LH on androgen production and luteinization of ovine theca cells cultured in a serum-free system. <em>Reproduction</em>, <em>112</em>(1), 69&ndash;77. https://doi.org/10.1530/jrf.0.1120069</span></span></p>
  • <p style="text-align: justify;">&nbsp;</p>
  • <p><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif">Chandrashekar, V., &amp; Bartke, A. (1998). The Role of Growth Hormone in the Control of Gonadotropin Secretion in Adult Male Rats*. <em>Endocrinology</em>, <em>139</em>(3), 1067&ndash;1074. https://doi.org/10.1210/endo.139.3.5816</span></span></p>
  • <p style="text-align: justify;"><span style="font-size:14px"><span style="font-family:times new roman,times,serif"><sup>3</sup>&nbsp;Shiraishi S., Lee P.W., Leung A., Goh V.H., Swerdloff R.S. and Wang C. (2008) Simultaneous measurement of serum testosterone and dihydrotestosterone by liquid chromatography-tandem mass spectrometry. Clinical chemistry, 54(11): 1855-63.<a href="https://www.google.com/url?q=https://doi.org/10.1373/clinchem.2008.103846&amp;sa=D&amp;ust=1554891396617000">https://doi.org/10.1373/clinchem.2008.103846</a></span></span></p>
  • </td>
  • </tr>
  • </tbody>
  • </table>
  • <br>
  • <!-- end event text -->
  • </div>
  • <div>
  • <div>
  • <h4><a href="/events/1614">Event: 1614: Decrease, androgen receptors (AR) activation</a><br></h4>
  • <h5>Short Name: Decrease, AR activation</h5>
  • </div>
  • <div>
  • <!-- loop to find all aops that use this event -->
  • <h4>AOPs Including This Key Event</h4>
  • <div class="panel panel-default">
  • <table class="table table-bordered table-striped">
  • <thead>
  • <tr>
  • <th>AOP ID and Name</th>
  • <th>Event Type</th>
  • </tr>
  • </thead>
  • <tbody>
  • <tr>
  • <td><a href="/aops/288">Aop:288 - Inhibition of 17α-hydrolase/C 10,20-lyase (Cyp17A1) activity leads to birth reproductive defects (cryptorchidism) in male (mammals)</a></td>
  • <td>KeyEvent</td>
  • </tr>
  • <tr>
  • <td><a href="/aops/305">Aop:305 - 5α-reductase inhibition leading to short anogenital distance (AGD) in male (mammalian) offspring</a></td>
  • <td>KeyEvent</td>
  • </tr>
  • <tr>
  • <td><a href="/aops/306">Aop:306 - Androgen receptor (AR) antagonism leading to short anogenital distance (AGD) in male (mammalian) offspring</a></td>
  • <td>KeyEvent</td>
  • </tr>
  • <tr>
  • <td><a href="/aops/307">Aop:307 - Decreased testosterone synthesis leading to short anogenital distance (AGD) in male (mammalian) offspring</a></td>
  • <td>KeyEvent</td>
  • </tr>
  • <tr>
  • <td><a href="/aops/344">Aop:344 - Androgen receptor (AR) antagonism leading to nipple retention (NR) in male (mammalian) offspring</a></td>
  • <td>KeyEvent</td>
  • </tr>
  • </tbody>
  • </table>
  • </div>
  • </div>
  • <!-- loop to find stressors under event -->
  • <div>
  • </div>
  • <br>
  • <!-- biological organization -->
  • <div>
  • <h4>Biological Context</h4>
  • <div class="panel panel-default">
  • <table class="table table-bordered table-striped">
  • <thead>
  • <tr>
  • <th>Level of Biological Organization</th>
  • </tr>
  • </thead>
  • <tbody>
  • <tr>
  • <td>Cellular</td>
  • </tr>
  • </tbody>
  • </table>
  • </div>
  • </div>
  • <!-- end of bio org -->
  • <!-- cell term -->
  • <div>
  • </div>
  • <!-- end of cell term -->
  • <!-- organ term -->
  • <div>
  • </div>
  • <!-- end of organ term -->
  • <!-- Evidence for Perturbation of This Event by Stressors -->
  • <!-- end Evidence for Perturbation of This Event by Stressors -->
  • <!-- event text -->
  • <h4>Key Event Description</h4>
  • <p style="text-align: justify;"><span style="font-size:14px"><span style="font-family:times new roman,times,serif">Androgen receptor activation is regulated by the binding of androgens. AR activity can be decreased by either a lack of steroidal ligands (testosterone, DHT) or the presence of antagonist compounds.&nbsp;<sup>12</sup></span></span></p>
  • <br>
  • <h4>How it is Measured or Detected</h4>
  • <p style="text-align: justify;"><span style="font-size:14px"><span style="font-family:times new roman,times,serif">Significance of AR signaling in fetal development can be studied through&nbsp;a conditional&nbsp;deletion of the androgen receptor using a Cre/loxP approach. The recommended animal model for reproductive study is the mouse.<sup>3</sup></span></span></p>
  • <p><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif">Chen, H., Ge, R.-S., &amp; Zirkin, B. R. (2009). Leydig cells: From stem cells to aging. <em>Molecular and Cellular Endocrinology</em>, <em>306</em>(1&ndash;2), 9&ndash;16. https://doi.org/10.1016/j.mce.2009.01.023</span></span></p>
  • <p style="text-align: justify;"><span style="font-size:14px"><span style="font-family:times new roman,times,serif">Also, epidemiological case-studies following&nbsp;mouse or humans expressing a complete androgen insensitivity allow to directly assess the effects of a lack of AR activation on the development.<sup>4</sup></span></span></p>
  • <p><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif">Ellis, G. B., Desjardins, C., &amp; Fraser, H. M. (1983). Control of Pulsatile LH Release in Male Rats. <em>Neuroendocrinology</em>, <em>37</em>(3), 177&ndash;183. https://doi.org/10.1159/000123540</span></span></p>
  • <p style="text-align: justify;"><span style="font-size:14px"><span style="font-family:times new roman,times,serif">Enzyme immunoassay (ELISA) kits for&nbsp;in vitro&nbsp;quantitative measurement of AR activity are available. Androgen receptors activity can be measured using bioassay such as the (Anti-)Androgen Receptor CALUX reporter gene assay.<sup>5</sup></span></span></p>
  • <br>
  • <h4>References</h4>
  • <table>
  • <tbody>
  • <tr>
  • <td colspan="1" rowspan="1">
  • <p>&nbsp;</p>
  • </td>
  • <td colspan="1" rowspan="1">
  • <p><sup>1</sup> Davey R.A and Grossmann M. (2016) Androgen Receptor Structure, Function and Biology: From Bench to Bedside. Clinical Biochemist Reviews, 37(1): 3-15. PCM4810760</p>
  • <p><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif">Havelock, J. C., Rainey, W. E., &amp; Carr, B. R. (2004). Ovarian granulosa cell lines. <em>Molecular and Cellular Endocrinology</em>, <em>228</em>(1&ndash;2), 67&ndash;78. https://doi.org/10.1016/j.mce.2004.04.018</span></span></p>
  • <p><sup>2&nbsp;</sup>Gao W., Bohl C.E. and Dalton J.T. (2005) Chemistry and Structural Biology of Androgen Receptor. Chemical Reviews 105(9): 3352-3370<a href="https://www.google.com/url?q=https://doi.org/10.1021/cr020456u&amp;sa=D&amp;ust=1554891396627000">https://doi.org/10.1021/cr020456u</a>&nbsp;</p>
  • <p><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif">Heemers, H. V., Verhoeven, G., &amp; Swinnen, J. V. (2006). Androgen Activation of the Sterol Regulatory Element-Binding Protein Pathway: Current Insights. <em>Molecular Endocrinology</em>, <em>20</em>(10), 2265&ndash;2277. https://doi.org/10.1210/me.2005-0479</span></span></p>
  • <p><sup>3</sup>&nbsp;Kaftanovskaya E.M., Huang Z., Barbara A.M., De Gendt K., Verhoeven G., Ivan P. Gorlov, and Agoulnik A.I. (2012) Cryptorchidism in Mice with an Androgen Receptor Ablation in Gubernaculum Testis. Molecular Endocrinology, 26(4): 598-607.<a href="https://www.google.com/url?q=https://doi.org/10.1210/me.2011-1283&amp;sa=D&amp;ust=1554891396628000">https://doi.org/10.1210/me.2011-1283</a>&nbsp;</p>
  • <p><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif">Huhtaniemi, I., &amp; Pelliniemi, L. J. (1992). Fetal Leydig Cells: Cellular Origin, Morphology, Life Span, and Special Functional Features. <em>Experimental Biology and Medicine</em>, <em>201</em>(2), 125&ndash;140. https://doi.org/10.3181/00379727-201-43493</span></span></p>
  • <p><sup>4</sup>&nbsp;Hutson J.M. (1985) A biphasic model for the hormonal control of testicular descent. Lancet, 24;2(8452): 419-21<a href="https://www.google.com/url?q=http://dx.doi.org/10.1016/S0140-6736(85)92739-4&amp;sa=D&amp;ust=1554891396629000">http://dx.doi.org/10.1016/S0140-6736(85)92739-4</a>&nbsp;</p>
  • <p><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif">Murashima, A., Kishigami, S., Thomson, A., &amp; Yamada, G. (2015). Androgens and mammalian male reproductive tract development. <em>Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanisms</em>, <em>1849</em>(2), 163&ndash;170. https://doi.org/10.1016/j.bbagrm.2014.05.020</span></span></p>
  • <p><sup>5</sup>&nbsp;van der Burg B., Winter R., Man HY., Vangenechten C., Berckmans P., Weimer M., Witters M. and van der Linden S. (2010) Optimization and prevalidation of the in vitro AR CALUX method to test androgenic and antiandrogenic activity of compounds. Reproductive Toxicology, 30(1):18-24&nbsp;<a href="https://www.google.com/url?q=https://doi.org/0.1016/j.reprotox.2010.04.012&amp;sa=D&amp;ust=1554891396630000">https://doi.org/0.1016/j.reprotox.2010.04.012</a>&nbsp;</p>
  • </td>
  • </tr>
  • </tbody>
  • </table>
  • <p><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif">Nef, S., &amp; Parada, L. F. (2000). Hormones in male sexual development. <em>Genes &amp; Development</em>, <em>14</em>(24), 3075&ndash;3086. <a href="https://doi.org/10.1101/gad.843800" style="color:#0563c1; text-decoration:underline">https://doi.org/10.1101/gad.843800</a></span></span></p>
  • <p><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif">OECD (2011). Test No. 456: H295R Steroidogenesis Assay. OECD Guide. Paris: OECD Publishing doi:10.1787/9789264122642-en.</span></span></p>
  • <p><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif">Rouiller-Fabre, V., Muczynski, V., Lambrot, R., LĂ&Scaron;cureuil, C., Coffigny, H., Pairault, C., Moison, D., Angenard, G., Bakalska, M., Courtot, A. M., Frydman, R., &amp; Habert, R. (2010). Ontogenesis of testicular function in humans. <em>Folia Histochemica et Cytobiologica</em>, <em>47</em>(5). https://doi.org/10.2478/v10042-009-0065-4</span></span></p>
  • <p><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif">Shiraishi, S., Lee, P. W. N., Leung, A., Goh, V. H. H., Swerdloff, R. S., &amp; Wang, C. (2008). Simultaneous Measurement of Serum Testosterone and Dihydrotestosterone by Liquid Chromatography&ndash;Tandem Mass Spectrometry. <em>Clinical Chemistry</em>, <em>54</em>(11), 1855&ndash;1863. https://doi.org/10.1373/clinchem.2008.103846</span></span></p>
  • <br>
  • <!-- end event text -->
  • </div>
  • <div>
  • <div>
  • <h4><a href="/events/286">Event: 286: Decreased, Transcription of genes by AR</a><br></h4>
  • <h5>Short Name: Decreased, Transcription of genes by AR</h5>
  • </div>
  • <h4><a href="/events/1613">Event: 1613: Decrease, dihydrotestosterone (DHT) level</a></h4>
  • <h5>Short Name: Decrease, DHT level</h5>
  • <h4>Key Event Component</h4>
  • <h4>AOPs Including This Key Event</h4>
  • <div class="table-responsive">
  • <table class="table table-bordered table-fullwidth">
  • <thead class="thead-light">
  • <tr>
  • <th scope="col">AOP ID and Name</th>
  • <th scope="col">Event Type</th>
  • </tr>
  • </thead>
  • <tbody class="tbody-striped">
  • <tr>
  • <td><a href="/aops/288">Aop:288 - Inhibition of 17α-hydrolase/C 10,20-lyase (Cyp17A1) activity leads to birth reproductive defects (cryptorchidism) in male (mammals)</a></td>
  • <td>KeyEvent</td>
  • </tr>
  • <tr>
  • <td><a href="/aops/289">Aop:289 - Inhibition of 5α-reductase leading to impaired fecundity in female fish</a></td>
  • <td>KeyEvent</td>
  • </tr>
  • <tr>
  • <td><a href="/aops/305">Aop:305 - 5α-reductase inhibition leading to short anogenital distance (AGD) in male (mammalian) offspring</a></td>
  • <td>KeyEvent</td>
  • </tr>
  • <tr>
  • <td><a href="/aops/307">Aop:307 - Decreased testosterone synthesis leading to short anogenital distance (AGD) in male (mammalian) offspring</a></td>
  • <td>KeyEvent</td>
  • </tr>
  • <tr>
  • <td><a href="/aops/527">Aop:527 - Decreased Chicken Ovalbumin Upstream Promoter Transcription Factor II (COUP-TFII) stem Leydig cells leads to Hypospadias, increased</a></td>
  • <td>KeyEvent</td>
  • </tr>
  • </tbody>
  • </table>
  • </div>
  • <div class="panel panel-default">
  • <table class="table table-bordered table-striped">
  • <thead>
  • <tr>
  • <th>Process</th>
  • <th>Object</th>
  • <th>Action</th>
  • </tr>
  • </thead>
  • <tbody>
  • <tr>
  • <td>regulation of gene expression</td>
  • <td>androgen receptor</td>
  • <td>decreased</td>
  • </tr>
  • </tbody>
  • </table>
  • </div>
  • <div>
  • <!-- loop to find all aops that use this event -->
  • <h4>AOPs Including This Key Event</h4>
  • <div class="panel panel-default">
  • <table class="table table-bordered table-striped">
  • <thead>
  • <tr>
  • <th>AOP ID and Name</th>
  • <th>Event Type</th>
  • </tr>
  • </thead>
  • <tbody>
  • <tr>
  • <td><a href="/aops/19">Aop:19 - Androgen receptor antagonism leading to adverse effects in the male foetus (mammals)</a></td>
  • <td>KeyEvent</td>
  • </tr>
  • <tr>
  • <td><a href="/aops/307">Aop:307 - Decreased testosterone synthesis leading to short anogenital distance (AGD) in male (mammalian) offspring</a></td>
  • <td>KeyEvent</td>
  • </tr>
  • <tr>
  • <td><a href="/aops/344">Aop:344 - Androgen receptor (AR) antagonism leading to nipple retention (NR) in male (mammalian) offspring</a></td>
  • <td>KeyEvent</td>
  • </tr>
  • <tr>
  • <td><a href="/aops/345">Aop:345 - Androgen receptor (AR) antagonism leading to decreased fertility in females</a></td>
  • <td>KeyEvent</td>
  • </tr>
  • </tbody>
  • </table>
  • </div>
  • <h4>Biological Context</h4>
  • <div class="table-responsive">
  • <table class="table table-bordered table-fullwidth">
  • <thead class="thead-light">
  • <tr><th scope="col">Level of Biological Organization</th></tr>
  • </thead>
  • <tbody class="tbody-striped">
  • <tr><td>Tissue</td></tr>
  • </tbody>
  • </table>
  • </div>
  • <!-- loop to find stressors under event -->
  • <div>
  • <h4>Stressors</h4>
  • <div class="panel panel-default">
  • <table class="table table-bordered table-striped">
  • <thead>
  • <tr>
  • <th>Name</th>
  • </tr>
  • </thead>
  • <tbody>
  • <tr>
  • <td>Bicalutamide</td>
  • </tr>
  • <tr>
  • <td>Cyproterone acetate</td>
  • </tr>
  • <tr>
  • <td>Epoxiconazole</td>
  • </tr>
  • <tr>
  • <td>Flutamide</td>
  • </tr>
  • <tr>
  • <td>Flusilazole</td>
  • </tr>
  • <tr>
  • <td>Prochloraz</td>
  • </tr>
  • <tr>
  • <td>Propiconazole</td>
  • </tr>
  • <tr>
  • <td>Stressor:286 Tebuconazole</td>
  • </tr>
  • <tr>
  • <td>Triticonazole</td>
  • </tr>
  • <tr>
  • <td>Vinclozalin</td>
  • </tr>
  • </tbody>
  • </table>
  • </div>
  • </div>
  • <br>
  • <!-- biological organization -->
  • <div>
  • <h4>Biological Context</h4>
  • <div class="panel panel-default">
  • <table class="table table-bordered table-striped">
  • <thead>
  • <tr>
  • <th>Level of Biological Organization</th>
  • </tr>
  • </thead>
  • <tbody>
  • <tr>
  • <td>Cellular</td>
  • </tr>
  • </tbody>
  • </table>
  • </div>
  • </div>
  • <!-- end of bio org -->
  • <!-- cell term -->
  • <div>
  • <h4>Cell term</h4>
  • <div class="panel panel-default">
  • <table class="table table-bordered table-striped">
  • <thead>
  • <tr>
  • <th>Cell term</th>
  • </tr>
  • </thead>
  • <tbody>
  • <tr>
  • <td>eukaryotic cell</td>
  • </tr>
  • </tbody>
  • </table>
  • </div>
  • </div>
  • <!-- end of cell term -->
  • <!-- organ term -->
  • <div>
  • </div>
  • <!-- end of organ term -->
  • <!-- Evidence for Perturbation of This Event by Stressors -->
  • <h3>Evidence for Perturbation by Stressor</h3>
  • <hr>
  • <br>
  • <h4>Bicalutamide</h4>
  • <p><p>Using analysis of androgen-regulated gene expression in the LNCaP prostate cancer cell line (Ngan et al. 2009).</p>
  • </p>
  • <br>
  • <h4>Cyproterone acetate</h4>
  • <p><p style="margin-left:18.0pt">Using analysis of androgen-regulated gene expression in the LNCaP prostate cancer cell line (Ngan et al. 2009) and using the AR-CALUX reporter assay in antagonism mode, cyproterone acetate showed an IC50 of 7.1 nM (Sonneveld et al. 2005).</p>
  • </p>
  • <br>
  • <h4>Epoxiconazole</h4>
  • <p><p>Using transiently AR-transfected CHO cells, epoxiconazole showed a LOEC of 1.6 mM and an IC50 of 10 mM (Kj&aelig;rstad et al. 2010).</p>
  • </p>
  • <br>
  • <h4>Flutamide</h4>
  • <p><p>Analysis of androgen-regulated gene expression in the LNCaP prostate cancer cell line (Ngan et al. 2009) and using the AR-CALUX reporter assay in antagonism mode, flutamide showed an IC50 of 1.3 uM (Sonneveld et al. 2005).</p>
  • </p>
  • <br>
  • <h4>Flusilazole</h4>
  • <p><p>Using hAR-EcoScreen Assay, triticonazole showed a LOEC for antagonisms of 0.8 mM and an IC50 of 2.8 (&plusmn;0.1) mM (Draskau et al. 2019)</p>
  • </p>
  • <br>
  • <h4>Prochloraz</h4>
  • <p><p>Using gene expression analysis of the androgen-regulated genes ornithine decarboxylase, prostatic binding protein C3 as well as insulin-like growth factor I. Gene expression levels were reduced in ventral prostates of male Wistar pups at postnatal day 16 following <em>in utero</em> and lactational exposure from maternal perinatal dosing with prochloraz (50 and 150 mg/kg/day) from gestational day 7 to postnatal day 16 (Laier et al. 2006). Also, using transiently AR-transfected CHO cells, prochloraz showed a LOEC of 6.3 mM and an IC50 of 13 mM (Kj&aelig;rstad et al. 2010).</p>
  • </p>
  • <br>
  • <h4>Propiconazole</h4>
  • <p><p>Using transiently AR-transfected CHO cells, propiconazole showed a LOEC of 12.5 mM and an IC50 of 18 mM (Kj&aelig;rstad et al. 2010).</p>
  • </p>
  • <br>
  • <h4>Stressor:286 Tebuconazole</h4>
  • <p><p>Using transiently AR-transfected CHO cells, tebuconazole showed a LOEC of 3.1 mM and an IC50 of 8.1 mM (Kj&aelig;rstad et al. 2010).</p>
  • </p>
  • <br>
  • <h4>Triticonazole</h4>
  • <p><p>Using hAR-EcoScreen Assay, triticonazole showed a LOEC for antagonisms of 0.2 mM and an IC50 of 0.3 (&plusmn;0.01) mM (Draskau et al. 2019).</p>
  • </p>
  • <br>
  • <h4>Vinclozalin</h4>
  • <p><p>Using the AR-CALUX reporter assay in antagonism mode, vinclozolin showed an IC50of 1.0 uM (Sonneveld et al. 2005).</p>
  • </p>
  • <br>
  • <!-- end Evidence for Perturbation of This Event by Stressors -->
  • <h4>Domain of Applicability</h4>
  • <br>
  • <!-- loop to find taxonomic applicability under event -->
  • <div>
  • <strong>Taxonomic Applicability</strong>
  • <div class="panel panel-default">
  • <table class="table table-bordered table-striped">
  • <thead>
  • <tr>
  • <th>Term</th>
  • <th>Scientific Term</th>
  • <th>Evidence</th>
  • <th>Links</th>
  • <h4>Cell term</h4>
  • <div class="table-responsive">
  • <table class="table table-bordered table-fullwidth">
  • <thead class="thead-light">
  • <tr><th scope="col">Cell term</th></tr>
  • </thead>
  • <tbody class="tbody-striped">
  • <tr><td>eukaryotic cell</td></tr>
  • </tbody>
  • </table>
  • </div>
  • <h4>Domain of Applicability</h4>
  • <strong>Taxonomic Applicability</strong>
  • <div class="table-responsive">
  • <table class="table table-bordered table-fullwidth">
  • <thead class="thead-light">
  • <tr>
  • <th scope="col">Term</th>
  • <th scope="col">Scientific Term</th>
  • <th scope="col">Evidence</th>
  • <th scope="col">Links</th>
  • </tr>
  • </thead>
  • <tbody>
  • <tr>
  • <td>human</td>
  • <td>Homo sapiens</td>
  • <td>High</td>
  • <td>
  • <a href="http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&id=9606" , target="_blank">NCBI</a>
  • </td>
  • </tr>
  • <tr>
  • <td>rat</td>
  • <td>Rattus norvegicus</td>
  • <td>High</td>
  • <td>
  • <a href="http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&id=10116" , target="_blank">NCBI</a>
  • </td>
  • </tr>
  • <tr>
  • <td>mouse</td>
  • <td>Mus musculus</td>
  • <td>High</td>
  • <td>
  • <a href="http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&id=10090" , target="_blank">NCBI</a>
  • </td>
  • </tr>
  • <tbody class="tbody-striped">
  • <tr>
  • <td>Vertebrates</td>
  • <td>Vertebrates</td>
  • <td>High</td>
  • <td><a href="http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&id=0" target="_blank">NCBI</a></td>
  • </tr>
  • </tbody>
  • </table>
  • </div>
  • </div>
  • <!-- end loop for taxons -->
  • <!-- life stages -->
  • <div>
  • <strong>Life Stage Applicability</strong>
  • <div class="panel panel-default">
  • <table class="table table-bordered table-striped">
  • <thead>
  • <strong>Life Stage Applicability</strong>
  • <div class="table-responsive">
  • <table class="table table-bordered table-fullwidth">
  • <thead class="thead-light">
  • <tr>
  • <th>Life Stage</th>
  • <th>Evidence</th>
  • <th scope="col">Life Stage</th>
  • <th scope="col">Evidence</th>
  • </tr>
  • </thead>
  • <tbody>
  • <tr>
  • <td>Foetal</td>
  • <td>High</td>
  • </tr>
  • <tr>
  • <td>Adult, reproductively mature</td>
  • <td>High</td>
  • </tr>
  • <tbody class="tbody-striped">
  • <tr>
  • <td>During development and at adulthood</td>
  • <td>High</td>
  • </tr>
  • </tbody>
  • </table>
  • </div>
  • </div>
  • <!-- end life stages -->
  • <!-- sex terms -->
  • <div>
  • <strong>Sex Applicability</strong>
  • <div class="panel panel-default">
  • <table class="table table-bordered table-striped">
  • <thead>
  • <strong>Sex Applicability</strong>
  • <div class="table-responsive">
  • <table class="table table-bordered table-fullwidth">
  • <thead class="thead-light">
  • <tr>
  • <th>Sex</th>
  • <th>Evidence</th>
  • <th scope="col">Sex</th>
  • <th scope="col">Evidence</th>
  • </tr>
  • </thead>
  • <tbody>
  • <tr>
  • <td>Mixed</td>
  • <td>High</td>
  • </tr>
  • <tbody class="tbody-striped">
  • <tr>
  • <td>Mixed</td>
  • <td>High</td>
  • </tr>
  • </tbody>
  • </table>
  • </div>
  • </div>
  • <!-- end sex terms -->
  • <div>
  • <p>Both the DNA-binding and ligand-binding domains of the AR are highly evolutionary conserved, whereas the transactivation domain show more divergence, which may affect AR-mediated gene regulation across species (Davey and Grossmann 2016).&nbsp; Despite certain inter-species differences, AR function mediated through gene expression is highly conserved, with mutation studies from both humans and rodents showing strong correlation for AR-dependent development and function (Walters et al. 2010).</p>
  • <p><span style="font-size:11pt">This KE is applicable to both sexes, across developmental stages and adulthood, in many different tissues and across vertebrate taxa.</span></p>
  • <p>This KE is applicable for both sexes, across developmental stages into adulthood, in numerous cells and tissues and across taxa.</p>
  • <br>
  • </div>
  • <p><span style="font-size:11pt">In both humans and rodents, DHT is important for the <em>in utero</em> differentiation and growth of the prostate and male external genitalia (Azzouni et al., 2012; Gerald &amp; Raj, 2022). Besides its critical role in development, DHT also induces growth of facial and body hair during puberty in humans <span style="color:black">(Azzouni et al., 2012)</span>.</span></p>
  • <p><span style="font-size:11pt">In mammals, the role of DHT in females is less established <span style="color:black">(Swerdloff et al., 2017), however studies suggest that androgens are important in e.g. bone metabolism and growth, as well as female reproduction from follicle development to parturition (Hammes &amp; Levin, 2019).</span></span></p>
  • <!-- event text -->
  • <h4>Key Event Description</h4>
  • <p><u>The Androgen Receptor and its function</u></p>
  • <h4>Key Event Description</h4>
  • <p style="text-align:justify"><span style="font-size:11pt"><span style="background-color:white"><span style="color:black">Dihydrotestosterone (DHT) is an endogenous steroid hormone and a potent androgen. The level of DHT in tissue or blood is dependent on several factors, such as the synthesis, uptake/release, metabolism, and elimination from the system, which again can be dependent on biological compartment and developmental stage.</span></span></span></p>
  • <p>Androgens act by binding to the Androgen receptor (AR) in androgen-responsive tissues (Davey and Grossmann 2016). Human AR mutations and mouse knockout models have established the fundamental role of AR in masculinization and spermatogenesis (Maclean et al.; Walters et al. 2010; Rana et al. 2014). The AR is also expressed in many other tissues such as bone, muscles, ovaries and within the immune system (Rana et al. 2014).</p>
  • <p><span style="font-size:11pt"><span style="background-color:white"><span style="color:black">DHT is primarily synthesized from testosterone (T) via the irreversible enzymatic reaction facilitated by 5&alpha;</span></span><span style="background-color:white"><span style="color:black">-Reductases (5</span></span><span style="background-color:white"><span style="color:black">&alpha;-REDs) (Swerdloff et al., 2017). Different isoforms of this enzyme are differentially expressed in specific tissues (e.g. prostate, skin, liver, and hair follicles) at different developmental stages, and depending on disease status (Azzouni et al., 2012; Uhl&eacute;n et al., 2015), which ultimately affects the local production of DHT. </span></span></span></p>
  • <p>&nbsp;</p>
  • <p><span style="font-size:11pt"><span style="background-color:white"><span style="color:black">An alternative (&ldquo;backdoor&rdquo;) pathway , exists for DHT formation that is independent of T and androstenedione as precursors. This pathway relies on the conversion of progesterone (P) or 17-OH-P to androsterone and then androstanediol through several enzymatic reactions and finally, the conversion of androstanediol into DHT probably by HSD17B6 (Miller &amp; Auchus, 2019; Naamneh Elzenaty et al., 2022). The &ldquo;backdoor&rdquo; synthesis pathway is a result of an interplay between placenta, adrenal gland, and liver during fetal life (Miller &amp; Auchus, 2019).</span></span></span></p>
  • <p><u>Decreased transcription of genes by the AR as a Key Event</u></p>
  • <p><span style="font-size:11pt"><span style="background-color:white"><span style="color:black">The conversion of T to DHT by 5&alpha;-RED in peripheral tissue is mainly responsible for the circulating levels of DHT, though some tissues express enzymes needed for further metabolism of DHT consequently leading to little release and contribution to circulating levels (Swerdloff et al.). </span></span></span></p>
  • <p>The AR belongs to the steroid hormone nuclear receptor family. It is a ligand-activated transcription factor with three domains; the N-terminal domain, the DNA-binding domain, and the ligand-binding domain with the latter being the most evolutionary conserved (Davey and Grossmann 2016). Upon activation by ligand-binding, the AR translocate from the cytoplasm to the cell nucleus, dimerizes, binds to androgen response elements in the DNA to modulate gene transcription (Davey and Grossmann 2016). The transcriptional targets varies between different cells and tissues, as well as with developmental stages and is, for instance, dependent on available co-regulators (Bevan and Parker 1999; Heemers and Tindall 2007).</p>
  • <p><span style="font-size:11pt"><span style="background-color:white"><span style="color:black">The initial conversion of DHT into inactive steroids is primarily through 3&alpha;</span></span><span style="background-color:white"><span style="color:black">-hydroxysteroid dehydrogenase (3</span></span><span style="background-color:white"><span style="color:black">&alpha;</span></span><span style="background-color:white"><span style="color:black">-HSD) and 3</span></span><span style="background-color:white"><span style="color:black">&beta;-HSD in liver, intestine, skin, and androgen-sensitive tissues. The subsequent conjugation is mainly mediated by uridine 5&acute;-diphospho (UDP)-glucuronyltransferase 2 (UGT2) leading to biliary and urinary elimination from the system. Conjugation also occurs locally to control levels of highly potent androgens (Swerdloff et al., 2017).</span></span></span></p>
  • <p>Several known and proposed target genes of AR canonical signaling have been identified by analysis of gene expression following treatments with AR agonists (Bolton et al. 2007; Ngan et al. 2009) and can for instance be found in the Androgen-Responsive Gene Database (Jiang et al. 2009).</p>
  • <br>
  • <p><span style="font-size:11pt"><span style="background-color:white"><span style="color:black">Disruption of any of the aforementioned processes may lead to decreased DHT levels, either systemically or at tissue level.</span></span></span></p>
  • <h4>How it is Measured or Detected</h4>
  • <p><em>In vitro</em></p>
  • <p>Decreased transcription of genes by the AR can be measured by measuring the transcription level of known downstream target genes by RT-qPCR or other transcription analyses approaches, eg transcriptomics.</p>
  • <p>Indirect approaches include the use of transient or stable transactivation assays including the validated OECD test guideline assay, Test No. 458: <em>Stably Transfected Human Androgen Receptor Transcriptional Activation Assay for Detection of Androgenic Agonist and Antagonist Activity of Chemicals </em>(OECD 2016). The stably transfected AR-EcoScreenTM cell line is freely available for the Japanese Collection of Research Bioresources (JCRB) Cell Bank under reference number JCRB1328. These cell-based transcriptional activation assays are typically used to detect AR agonists and antagonists. However, these types of assays are well suited to measure this KE as what they measure is exactly AR transcriptional activity. Other assays along this line include the AR-CALUX reporter gene assay that is derived from human U2-OS cells stably transfected with the human AR and an AR responsive reporter gene (van der Burg et al. 2010).</p>
  • <h4>How it is Measured or Detected</h4>
  • <p><span style="font-size:11pt"><span style="font-size:10.5pt"><span style="background-color:white"><span style="color:black">Several methods exist for DHT identification and quantification, such as conventional immunoassay methods (ELISA or RIA) and advanced analytical methods as liquid chromatography tandem mass spectrometry (LC-MS/MS). The methods can have differences in detection and quantification limits, which should be considered depending on the DHT levels in the sample of interest. Further, the origin of the sample (e.g. cell culture, tissue, or blood) will have implications for the sample preparation. </span></span></span></span></p>
  • <p><em>In vivo</em></p>
  • <p>Known downstream target gene transcription level can be measured in tissues by RT-qPCR or other gene expression analyses approaches.</p>
  • <br>
  • <p><span style="font-size:11pt"><span style="font-size:10.5pt"><span style="background-color:white"><span style="color:black">Conventional immunoassays have limitations in that they can overestimate the levels of DHT compared to levels determined by gas chromatography mass spectrometry and liquid chromatography tandem mass spectrometry (Hsing et al., 2007; Shiraishi et al., 2008). This overestimation may be explained by lack of specificity of the DHT antibody used in the RIA and cross-reactivity with T in samples (Swerdloff et al., 2017).</span></span></span></span></p>
  • <h4>References</h4>
  • <p>Bevan C, Parker M (1999) The role of coactivators in steroid hormone action. Exp. Cell Res. 253:349&ndash;356</p>
  • <p>Bolton EC, So AY, Chaivorapol C, et al (2007) Cell- and gene-specific regulation of primary target genes by the androgen receptor. Genes Dev 21:2005&ndash;2017. doi: 10.1101/gad.1564207</p>
  • <p>Davey RA, Grossmann M (2016) Androgen Receptor Structure, Function and Biology: From Bench to Bedside. Clin Biochem Rev 37:3&ndash;15</p>
  • <p>Draskau MK, Boberg J, Taxvig C, et al (2019) In&nbsp;vitro and in&nbsp;vivo endocrine disrupting effects of the azole fungicides triticonazole and flusilazole. Environ Pollut 255:113309. doi: 10.1016/j.envpol.2019.113309</p>
  • <p>Estrada M, Espinosa A, M&uuml;ller M, Jaimovich E (2003) Testosterone Stimulates Intracellular Calcium Release and Mitogen-Activated Protein Kinases Via a G Protein-Coupled Receptor in Skeletal Muscle Cells. Endocrinology 144:3586&ndash;3597. doi: 10.1210/en.2002-0164</p>
  • <p>Heemers H V., Tindall DJ (2007) Androgen receptor (AR) coregulators: A diversity of functions converging on and regulating the AR transcriptional complex. Endocr. Rev. 28:778&ndash;808</p>
  • <h4>References</h4>
  • <p><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif">Azzouni, F., Godoy, A., Li, Y., &amp; Mohler, J. (2012). The 5 alpha-reductase isozyme family: A review of basic biology and their role in human diseases. In <em>Advances in Urology</em>. https://doi.org/10.1155/2012/530121</span></span></p>
  • <p>Jiang M, Ma Y, Chen C, et al (2009) Androgen-Responsive Gene Database: Integrated Knowledge on Androgen-Responsive Genes. Mol Endocrinol 23:1927&ndash;1933. doi: 10.1210/me.2009-0103</p>
  • <p><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif">Gerald, T., &amp; Raj, G. (2022). Testosterone and the Androgen Receptor. In <em>Urologic Clinics of North America</em> (Vol. 49, Issue 4, pp. 603&ndash;614). W.B. Saunders. https://doi.org/10.1016/j.ucl.2022.07.004</span></span></p>
  • <p>Kj&aelig;rstad MB, Taxvig C, Nellemann C, et al (2010) Endocrine disrupting effects in vitro of conazole antifungals used as pesticides and pharmaceuticals. Reprod Toxicol 30:573&ndash;582. doi: 10.1016/J.REPROTOX.2010.07.009</p>
  • <p><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif">Hammes, S. R., &amp; Levin, E. R. (2019). Impact of estrogens in males and androgens in females. In <em>Journal of Clinical Investigation</em> (Vol. 129, Issue 5, pp. 1818&ndash;1826). American Society for Clinical Investigation. https://doi.org/10.1172/JCI125755</span></span></p>
  • <p>Laier P, Metzdorff SB, Borch J, et al (2006) Mechanisms of action underlying the antiandrogenic effects of the fungicide prochloraz. Toxicol Appl Pharmacol 213:160&ndash;71. doi: 10.1016/j.taap.2005.10.013</p>
  • <p><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif">Hsing, A. W., Stanczyk, F. Z., B&eacute;langer, A., Schroeder, P., Chang, L., Falk, R. T., &amp; Fears, T. R. (2007). Reproducibility of serum sex steroid assays in men by RIA and mass spectrometry. <em>Cancer Epidemiology Biomarkers and Prevention</em>, <em>16</em>(5), 1004&ndash;1008. https://doi.org/10.1158/1055-9965.EPI-06-0792</span></span></p>
  • <p>Maclean HE, Chu S, Warne GL, Zajact JD Related Individuals with Different Androgen Receptor Gene Deletions</p>
  • <p>MacLeod DJ, Sharpe RM, Welsh M, et al (2010) Androgen action in the masculinization programming window and development of male reproductive organs. In: International Journal of Andrology. Blackwell Publishing Ltd, pp 279&ndash;287</p>
  • <p>Ngan S, Stronach EA, Photiou A, et al (2009) Microarray coupled to quantitative RT&amp;ndash;PCR analysis of androgen-regulated genes in human LNCaP prostate cancer cells. Oncogene 28:2051&ndash;2063. doi: 10.1038/onc.2009.68</p>
  • <p><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif">Miller, W. L., &amp; Auchus, R. J. (2019). The &ldquo;backdoor pathway&rdquo; of androgen synthesis in human male sexual development. <em>PLoS Biology</em>, <em>17</em>(4). https://doi.org/10.1371/journal.pbio.3000198</span></span></p>
  • <p>OECD (2016) Test No. 458: Stably Transfected Human Androgen Receptor Transcriptional Activation Assay for Detection of Androgenic Agonist and Antagonist Activity of Chemicals, OECD Guide. OECD Publishing</p>
  • <p><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif">Naamneh Elzenaty, R., du Toit, T., &amp; Fl&uuml;ck, C. E. (2022). Basics of androgen synthesis and action. In <em>Best Practice and Research: Clinical Endocrinology and Metabolism</em> (Vol. 36, Issue 4). Bailliere Tindall Ltd. https://doi.org/10.1016/j.beem.2022.101665</span></span></p>
  • <p>Rana K, Davey RA, Zajac JD (2014) Human androgen deficiency: Insights gained from androgen receptor knockout mouse models. Asian J. Androl. 16:169&ndash;177</p>
  • <p>Sonneveld E, Jansen HJ, Riteco JAC, et al (2005) Development of Androgen-and Estrogen-Responsive Bioassays, Members of a Panel of Human Cell Line-Based Highly Selective Steroid-Responsive Bioassays. Toxicol Sci 83:136&ndash;148. doi: 10.1093/toxsci/kfi005</p>
  • <p><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif">Shiraishi, S., Lee, P. W. N., Leung, A., Goh, V. H. H., Swerdloff, R. S., &amp; Wang, C. (2008). Simultaneous measurement of serum testosterone and dihydrotestosterone by liquid chromatography-tandem mass spectrometry. <em>Clinical Chemistry</em>, <em>54</em>(11), 1855&ndash;1863. https://doi.org/10.1373/clinchem.2008.103846</span></span></p>
  • <p>van der Burg B, Winter R, Man H yen, et al (2010) Optimization and prevalidation of the in vitro AR CALUX method to test androgenic and antiandrogenic activity of compounds. Reprod Toxicol 30:18&ndash;24. doi: 10.1016/j.reprotox.2010.04.012</p>
  • <p><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif">Swerdloff, R. S., Dudley, R. E., Page, S. T., Wang, C., &amp; Salameh, W. A. (2017). Dihydrotestosterone: Biochemistry, physiology, and clinical implications of elevated blood levels. In <em>Endocrine Reviews</em> (Vol. 38, Issue 3, pp. 220&ndash;254). Endocrine Society. https://doi.org/10.1210/er.2016-1067</span></span></p>
  • <p>Walters KA, Simanainen U, Handelsman DJ (2010) Molecular insights into androgen actions in male and female reproductive function from androgen receptor knockout models. Hum Reprod Update 16:543&ndash;558. doi: 10.1093/humupd/dmq003</p>
  • <br>
  • <!-- end event text -->
  • </div>
  • <p><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif">Uhl&eacute;n, M., Fagerberg, L., Hallstr&ouml;m, B. M., Lindskog, C., Oksvold, P., Mardinoglu, A., Sivertsson, &Aring;., Kampf, C., Sj&ouml;stedt, E., Asplund, A., Olsson, I. M., Edlund, K., Lundberg, E., Navani, S., Szigyarto, C. A. K., Odeberg, J., Djureinovic, D., Takanen, J. O., Hober, S., &hellip; Pont&eacute;n, F. (2015). Tissue-based map of the human proteome. <em>Science</em>, <em>347</em>(6220). https://doi.org/10.1126/science.1260419</span></span></p>
  • <h3>List of Adverse Outcomes in this AOP</h3>
  • <div>
  • <div>
  • <h4><a href="/events/1688">Event: 1688: decrease, male anogenital distance</a><br></h4>
  • <h5>Short Name: short male AGD</h5>
  • </div>
  • <h4><a href="/events/1614">Event: 1614: Decrease, androgen receptor activation</a></h4>
  • <h5>Short Name: Decrease, AR activation</h5>
  • <h4>Key Event Component</h4>
  • <h4>AOPs Including This Key Event</h4>
  • <div class="table-responsive">
  • <table class="table table-bordered table-fullwidth">
  • <thead class="thead-light">
  • <tr>
  • <th scope="col">AOP ID and Name</th>
  • <th scope="col">Event Type</th>
  • </tr>
  • </thead>
  • <tbody class="tbody-striped">
  • <tr>
  • <td><a href="/aops/288">Aop:288 - Inhibition of 17α-hydrolase/C 10,20-lyase (Cyp17A1) activity leads to birth reproductive defects (cryptorchidism) in male (mammals)</a></td>
  • <td>KeyEvent</td>
  • </tr>
  • <tr>
  • <td><a href="/aops/305">Aop:305 - 5α-reductase inhibition leading to short anogenital distance (AGD) in male (mammalian) offspring</a></td>
  • <td>KeyEvent</td>
  • </tr>
  • <tr>
  • <td><a href="/aops/306">Aop:306 - Androgen receptor (AR) antagonism leading to short anogenital distance (AGD) in male (mammalian) offspring</a></td>
  • <td>KeyEvent</td>
  • </tr>
  • <tr>
  • <td><a href="/aops/307">Aop:307 - Decreased testosterone synthesis leading to short anogenital distance (AGD) in male (mammalian) offspring</a></td>
  • <td>KeyEvent</td>
  • </tr>
  • <tr>
  • <td><a href="/aops/344">Aop:344 - Androgen receptor (AR) antagonism leading to nipple retention (NR) in male (mammalian) offspring</a></td>
  • <td>KeyEvent</td>
  • </tr>
  • <tr>
  • <td><a href="/aops/372">Aop:372 - Androgen receptor antagonism leading to testicular cancer </a></td>
  • <td>KeyEvent</td>
  • </tr>
  • <tr>
  • <td><a href="/aops/477">Aop:477 - Androgen receptor (AR) antagonism leading to hypospadias in male offspring</a></td>
  • <td>KeyEvent</td>
  • </tr>
  • </tbody>
  • </table>
  • </div>
  • <div class="panel panel-default">
  • <table class="table table-bordered table-striped">
  • <thead>
  • <tr>
  • <th>Process</th>
  • <th>Object</th>
  • <th>Action</th>
  • </tr>
  • </thead>
  • <tbody>
  • <tr>
  • <td>androgen receptor signaling pathway</td>
  • <td>Musculature of male perineum</td>
  • <td>disrupted</td>
  • </tr>
  • </tbody>
  • </table>
  • </div>
  • <div>
  • <!-- loop to find all aops that use this event -->
  • <h4>AOPs Including This Key Event</h4>
  • <div class="panel panel-default">
  • <table class="table table-bordered table-striped">
  • <thead>
  • <tr>
  • <th>AOP ID and Name</th>
  • <th>Event Type</th>
  • </tr>
  • </thead>
  • <tbody>
  • <tr>
  • <td><a href="/aops/305">Aop:305 - 5α-reductase inhibition leading to short anogenital distance (AGD) in male (mammalian) offspring</a></td>
  • <td>AdverseOutcome</td>
  • </tr>
  • <tr>
  • <td><a href="/aops/306">Aop:306 - Androgen receptor (AR) antagonism leading to short anogenital distance (AGD) in male (mammalian) offspring</a></td>
  • <td>AdverseOutcome</td>
  • </tr>
  • <tr>
  • <td><a href="/aops/307">Aop:307 - Decreased testosterone synthesis leading to short anogenital distance (AGD) in male (mammalian) offspring</a></td>
  • <td>AdverseOutcome</td>
  • </tr>
  • </tbody>
  • </table>
  • </div>
  • <h4>Biological Context</h4>
  • <div class="table-responsive">
  • <table class="table table-bordered table-fullwidth">
  • <thead class="thead-light">
  • <tr><th scope="col">Level of Biological Organization</th></tr>
  • </thead>
  • <tbody class="tbody-striped">
  • <tr><td>Tissue</td></tr>
  • </tbody>
  • </table>
  • </div>
  • <!-- loop to find stressors under event -->
  • <div>
  • <h4>Stressors</h4>
  • <div class="panel panel-default">
  • <table class="table table-bordered table-striped">
  • <thead>
  • <tr>
  • <th>Name</th>
  • </tr>
  • </thead>
  • <tbody>
  • <tr>
  • <td>Butylparaben</td>
  • </tr>
  • <tr>
  • <td>p,p&#39;-DDE</td>
  • </tr>
  • <tr>
  • <td>Bis(2-ethylhexyl) phthalate</td>
  • </tr>
  • <tr>
  • <td>Dexamethasone</td>
  • </tr>
  • <tr>
  • <td>Fenitrothion</td>
  • </tr>
  • <tr>
  • <td>Finasteride</td>
  • </tr>
  • <tr>
  • <td>Flutamide</td>
  • </tr>
  • <tr>
  • <td>Ketoconazole</td>
  • </tr>
  • <tr>
  • <td>Linuron</td>
  • </tr>
  • <tr>
  • <td>Prochloraz</td>
  • </tr>
  • <tr>
  • <td>Procymidone</td>
  • </tr>
  • <tr>
  • <td>Triticonazole</td>
  • </tr>
  • <tr>
  • <td>Vinclozolin</td>
  • </tr>
  • <tr>
  • <td>di-n-hexyl phthalate</td>
  • </tr>
  • <tr>
  • <td>Dicyclohexyl phthalate</td>
  • </tr>
  • <tr>
  • <td>butyl benzyl phthalate</td>
  • </tr>
  • <tr>
  • <td>monobenzyl phthalate</td>
  • </tr>
  • <tr>
  • <td>di-n-heptyl phthalate</td>
  • </tr>
  • </tbody>
  • </table>
  • </div>
  • </div>
  • <br>
  • <!-- biological organization -->
  • <div>
  • <h4>Biological Context</h4>
  • <div class="panel panel-default">
  • <table class="table table-bordered table-striped">
  • <thead>
  • <tr>
  • <th>Level of Biological Organization</th>
  • </tr>
  • </thead>
  • <tbody>
  • <tr>
  • <td>Tissue</td>
  • </tr>
  • </tbody>
  • </table>
  • </div>
  • </div>
  • <!-- end of bio org -->
  • <!-- cell term -->
  • <div>
  • </div>
  • <!-- end of cell term -->
  • <!-- organ term -->
  • <div>
  • <h4>Organ term</h4>
  • <div class="panel panel-default">
  • <table class="table table-bordered table-striped">
  • <thead>
  • <tr>
  • <th>Organ term</th>
  • </tr>
  • </thead>
  • <tbody>
  • <tr>
  • <td>perineum</td>
  • </tr>
  • </tbody>
  • </table>
  • </div>
  • </div>
  • <!-- end of organ term -->
  • <!-- Evidence for Perturbation of This Event by Stressors -->
  • <h3>Evidence for Perturbation by Stressor</h3>
  • <hr>
  • <br>
  • <h4>Butylparaben</h4>
  • <p><p>Butylparaben has been shown to cause decreased male AGD in rats following intrauterine exposure to 500 and 1000 mg/kg bw/day (<a href="#_ENREF_1" title="Boberg, 2016 #12">Boberg et al, 2016</a>; <a href="#_ENREF_39" title="Zhang, 2014 #148">Zhang et al, 2014</a>). A separate study using 600 mg/kg bw/day did not see an effect on male AGD (<a href="#_ENREF_2" title="Boberg, 2008 #45">Boberg et al, 2008</a>).</p>
  • </p>
  • <br>
  • <h4>p,p'-DDE</h4>
  • <p><p>p,p,DDE has been shown to cause decreased male AGD in rats following intrauterine exposure to 100-200 mg/kg bw/day (<a href="#_ENREF_20" title="Loeffler, 1999 #60">Loeffler &amp; Peterson, 1999</a>; <a href="#_ENREF_38" title="Wolf, 1999 #146">Wolf et al, 1999</a>).</p>
  • </p>
  • <br>
  • <h4>Bis(2-ethylhexyl) phthalate</h4>
  • <p><p>DEHP has been shown to cause decreased male AGD in rats following intrauterine exposure to 300-1500 mg/kg bw/day (<a href="#_ENREF_4" title="Christiansen, 2010 #13">Christiansen et al, 2010</a>; <a href="#_ENREF_8" title="Gray, 2000 #110">Gray et al, 2000</a>; <a href="#_ENREF_13" title="Howdeshell, 2007 #111">Howdeshell et al, 2007</a>; <a href="#_ENREF_15" title="Jarfelt, 2005 #113">Jarfelt et al, 2005</a>; <a href="#_ENREF_16" title="Kita, 2016 #34">Kita et al, 2016</a>; <a href="#_ENREF_18" title="Li, 2013 #71">Li et al, 2013</a>; <a href="#_ENREF_19" title="Lin, 2009 #120">Lin et al, 2009</a>; <a href="#_ENREF_25" title="Moore, 2001 #124">Moore et al, 2001</a>; <a href="#_ENREF_27" title="Nardelli, 2017 #149">Nardelli et al, 2017</a>; <a href="#_ENREF_30" title="Saillenfait, 2009 #134">Saillenfait et al, 2009</a>; <a href="#_ENREF_38" title="Wolf, 1999 #146">Wolf et al, 1999</a>).</p>
  • </p>
  • <br>
  • <h4>Dexamethasone</h4>
  • <p><p>Dexamethasone has been shown to cause decreased male AGD in rats following intrauterine exposure to 0.1 mg/kg bw/day (<a href="#_ENREF_35" title="Van den Driesche, 2012 #144">Van den Driesche et al, 2012</a>).</p>
  • </p>
  • <br>
  • <h4>Fenitrothion</h4>
  • <p><p>Fenitrothion has been shown to cause decreased male AGD in rats following intrauterine exposure to 25 mg/kg bw/day (<a href="#_ENREF_34" title="Turner, 2002 #213">Turner et al, 2002</a>).</p>
  • </p>
  • <br>
  • <h4>Finasteride</h4>
  • <p><p>Finasteride has been shown to cause decreased male AGD in rats following intrauterine exposure to 100 mg/kg bw/day (<a href="#_ENREF_3" title="Bowman, 2003 #29">Bowman et al, 2003</a>).</p>
  • </p>
  • <br>
  • <h4>Flutamide</h4>
  • <p><p>Flutamide has been shown to cause decreased male AGD in rats following intrauterine exposure to doses between 16-100 mg/kg bw/day (<a href="#_ENREF_7" title="Foster, 2005 #53">Foster &amp; Harris, 2005</a>; <a href="#_ENREF_11" title="Hass, 2007 #76">Hass et al, 2007</a>; <a href="#_ENREF_16" title="Kita, 2016 #34">Kita et al, 2016</a>; <a href="#_ENREF_23" title="McIntyre, 2001 #36">McIntyre et al, 2001</a>; <a href="#_ENREF_26" title="Mylchreest, 1999 #126">Mylchreest et al, 1999</a>; <a href="#_ENREF_32" title="Scott, 2007 #139">Scott et al, 2007</a>; <a href="#_ENREF_36" title="Welsh, 2007 #56">Welsh et al, 2007</a>).</p>
  • </p>
  • <br>
  • <h4>Ketoconazole</h4>
  • <p><p>Ketoconazole has been shown to cause decreased male AGD in rats following intrauterine exposure to 50 mg/kg bw/day in one study (<a href="#_ENREF_33" title="Taxvig, 2008 #184">Taxvig et al, 2008</a>), but no effect in another study using same dose (<a href="#_ENREF_38" title="Wolf, 1999 #146">Wolf et al, 1999</a>).</p>
  • </p>
  • <br>
  • <h4>Linuron</h4>
  • <p><p>Linuron has been shown to cause decreased male AGD in rats following intrauterine exposure to 50-100 mg/kg bw/day (<a href="#_ENREF_12" title="Hotchkiss, 2004 #40">Hotchkiss et al, 2004</a>; <a href="#_ENREF_24" title="McIntyre, 2002 #38">McIntyre et al, 2002</a>; <a href="#_ENREF_38" title="Wolf, 1999 #146">Wolf et al, 1999</a>).</p>
  • </p>
  • <br>
  • <h4>Prochloraz</h4>
  • <p><p>Prochloraz has been shown to cause decreased male AGD in rats following intrauterine exposure to 150-250 mg/kg bw/day (<a href="#_ENREF_17" title="Laier, 2006 #15">Laier et al, 2006</a>; <a href="#_ENREF_28" title="Noriega, 2005 #54">Noriega et al, 2005</a>).</p>
  • </p>
  • <br>
  • <h4>Procymidone</h4>
  • <p><p style="margin-left:18.0pt">Procymidone has been shown to cause decreased male AGD in rats following intrauterine exposure to doses between 50-150 mg/kg bw/day (<a href="#_ENREF_10" title="Hass, 2012 #220">Hass et al, 2012</a>; <a href="#_ENREF_11" title="Hass, 2007 #76">Hass et al, 2007</a>; <a href="#_ENREF_38" title="Wolf, 1999 #146">Wolf et al, 1999</a>).</p>
  • </p>
  • <br>
  • <h4>Triticonazole</h4>
  • <p><p>Triticonazole has been shown to cause decreased male AGD in rats following intrauterine exposure to 150 and 450 mg/kg bw/day (<a href="#_ENREF_6" title="Draskau, 2019 #258">Draskau et al, 2019</a>).</p>
  • </p>
  • <br>
  • <h4>Vinclozolin</h4>
  • <p><p>Vinclozolin has been shown to cause decreased male AGD in rats following intrauterine exposure to doses between 50-200 mg/kg bw/day (<a href="#_ENREF_5" title="Christiansen, 2009 #14">Christiansen et al, 2009</a>; <a href="#_ENREF_9" title="Gray, 1994 #109">Gray et al, 1994</a>; <a href="#_ENREF_11" title="Hass, 2007 #76">Hass et al, 2007</a>; <a href="#_ENREF_22" title="Matsuura, 2005 #243">Matsuura et al, 2005</a>; <a href="#_ENREF_29" title="Ostby, 1999 #78">Ostby et al, 1999</a>; <a href="#_ENREF_31" title="Schneider, 2011 #245">Schneider et al, 2011</a>; <a href="#_ENREF_37" title="Wolf, 2004 #51">Wolf et al, 2004</a>).</p>
  • </p>
  • <br>
  • <h4>di-n-hexyl phthalate</h4>
  • <p><p>DnHP has been shown to cause decreased male AGD in rats following intrauterine exposure to 500-750 mg/kg bw/day (<a href="#_ENREF_35" title="Saillenfait, 2009 #133">Saillenfait et al, 2009a</a>; <a href="#_ENREF_36" title="Saillenfait, 2009 #134">Saillenfait et al, 2009b</a>).</p>
  • </p>
  • <br>
  • <h4>Dicyclohexyl phthalate</h4>
  • <p><p>DCHP has been shown to cause decreased male AGD in rats following intrauterine exposure to 350-750 mg/kg bw/day (<a href="#_ENREF_1" title="Aydoğan Ahbab, 2015 #95">Aydoğan Ahbab &amp; Barlas, 2015</a>; <a href="#_ENREF_13" title="Hoshino, 2005 #239">Hoshino et al, 2005</a>; <a href="#_ENREF_32" title="Saillenfait, 2009 #133">Saillenfait et al, 2009a</a>).</p>
  • </p>
  • <br>
  • <h4>butyl benzyl phthalate</h4>
  • <p><p>BBP has been shown to cause decreased male AGD in rats following intrauterine exposure to 500-1000 mg/kg bw/day (<a href="#_ENREF_8" title="Ema, 2002 #104">Ema &amp; Miyawaki, 2002</a>; <a href="#_ENREF_10" title="Gray, 2000 #110">Gray et al, 2000</a>; <a href="#_ENREF_15" title="Hotchkiss, 2004 #40">Hotchkiss et al, 2004</a>; <a href="#_ENREF_30" title="Nagao, 2000 #128">Nagao et al, 2000</a>; <a href="#_ENREF_41" title="Tyl, 2004 #240">Tyl et al, 2004</a>).</p>
  • </p>
  • <br>
  • <h4>monobenzyl phthalate</h4>
  • <p><p>MBeP has been shown to cause decreased male AGD in rats following intrauterine exposure to 375 mg/kg bw/day (<a href="#_ENREF_9" title="Ema, 2003 #107">Ema et al, 2003</a>).</p>
  • </p>
  • <br>
  • <h4>di-n-heptyl phthalate</h4>
  • <p><p>DHPP has been shown to cause decreased male AGD in rats following intrauterine exposure to 1000 mg/kg bw/day (<a href="#_ENREF_36" title="Saillenfait, 2011 #135">Saillenfait et al, 2011</a>).</p>
  • </p>
  • <br>
  • <!-- end Evidence for Perturbation of This Event by Stressors -->
  • <h4>Domain of Applicability</h4>
  • <br>
  • <!-- loop to find taxonomic applicability under event -->
  • <div>
  • <strong>Taxonomic Applicability</strong>
  • <div class="panel panel-default">
  • <table class="table table-bordered table-striped">
  • <thead>
  • <tr>
  • <th>Term</th>
  • <th>Scientific Term</th>
  • <th>Evidence</th>
  • <th>Links</th>
  • <h4>Domain of Applicability</h4>
  • <strong>Taxonomic Applicability</strong>
  • <div class="table-responsive">
  • <table class="table table-bordered table-fullwidth">
  • <thead class="thead-light">
  • <tr>
  • <th scope="col">Term</th>
  • <th scope="col">Scientific Term</th>
  • <th scope="col">Evidence</th>
  • <th scope="col">Links</th>
  • </tr>
  • </thead>
  • <tbody>
  • <tr>
  • <td>human</td>
  • <td>Homo sapiens</td>
  • <td>Moderate</td>
  • <td>
  • <a href="http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&id=9606" , target="_blank">NCBI</a>
  • </td>
  • </tr>
  • <tr>
  • <td>rat</td>
  • <td>Rattus norvegicus</td>
  • <td>High</td>
  • <td>
  • <a href="http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&id=10116" , target="_blank">NCBI</a>
  • </td>
  • </tr>
  • <tr>
  • <td>mouse</td>
  • <td>Mus musculus</td>
  • <td>High</td>
  • <td>
  • <a href="http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&id=10090" , target="_blank">NCBI</a>
  • </td>
  • </tr>
  • <tbody class="tbody-striped">
  • <tr>
  • <td>Vertebrates</td>
  • <td>Vertebrates</td>
  • <td>High</td>
  • <td><a href="http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&id=0" target="_blank">NCBI</a></td>
  • </tr>
  • </tbody>
  • </table>
  • </div>
  • </div>
  • <!-- end loop for taxons -->
  • <!-- life stages -->
  • <div>
  • <strong>Life Stage Applicability</strong>
  • <div class="panel panel-default">
  • <table class="table table-bordered table-striped">
  • <thead>
  • <strong>Life Stage Applicability</strong>
  • <div class="table-responsive">
  • <table class="table table-bordered table-fullwidth">
  • <thead class="thead-light">
  • <tr>
  • <th>Life Stage</th>
  • <th>Evidence</th>
  • <th scope="col">Life Stage</th>
  • <th scope="col">Evidence</th>
  • </tr>
  • </thead>
  • <tbody>
  • <tr>
  • <td>Foetal</td>
  • <td>High</td>
  • </tr>
  • <tbody class="tbody-striped">
  • <tr>
  • <td>During development and at adulthood</td>
  • <td>High</td>
  • </tr>
  • </tbody>
  • </table>
  • </div>
  • </div>
  • <!-- end life stages -->
  • <!-- sex terms -->
  • <div>
  • <strong>Sex Applicability</strong>
  • <div class="panel panel-default">
  • <table class="table table-bordered table-striped">
  • <thead>
  • <strong>Sex Applicability</strong>
  • <div class="table-responsive">
  • <table class="table table-bordered table-fullwidth">
  • <thead class="thead-light">
  • <tr>
  • <th>Sex</th>
  • <th>Evidence</th>
  • <th scope="col">Sex</th>
  • <th scope="col">Evidence</th>
  • </tr>
  • </thead>
  • <tbody>
  • <tr>
  • <td>Male</td>
  • <td>High</td>
  • </tr>
  • <tbody class="tbody-striped">
  • <tr>
  • <td>Mixed</td>
  • <td>High</td>
  • </tr>
  • </tbody>
  • </table>
  • </div>
  • </div>
  • <!-- end sex terms -->
  • <p><span style="font-size:11pt">This KE is considered broadly applicable across vertebrate taxa as all vertebrate animals express the AR in numerous cells and tissues where it regulates gene transcription required for developmental processes and functions. </span></p>
  • <div>
  • <p>A short AGD in male offspring is a marker of insufficient androgen action during critical fetal developmental stages (<a href="#_ENREF_42" title="Schwartz, 2019 #252">Schwartz et al, 2019</a>; <a href="#_ENREF_49" title="Welsh, 2008 #23">Welsh et al, 2008</a>). A short AGD is thus a sign of undervirilization, which is also associated with a series of male reproductive disorders, including genital malformations and infertility in humans (<a href="#_ENREF_21" title="Juul, 2014 #3">Juul et al, 2014</a>; <a href="#_ENREF_44" title="Skakkebaek, 2001 #9">Skakkebaek et al, 2001</a>).</p>
  • <h4>Key Event Description</h4>
  • <p><span style="font-size:11pt">This KE refers to decreased activation of the androgen receptor (AR) as occurring in complex biological systems such as tissues and organs in vivo. It is thus considered distinct from KEs describing either blocking of AR or decreased androgen synthesis.</span></p>
  • <p>There are numerous human epidemiological studies showing associations with intrauterine exposure to anti-androgenic chemicals and short AGD in newborn boys alongside other reproductive disorders (<a href="#_ENREF_42" title="Schwartz, 2019 #252">Schwartz et al, 2019</a>). This underscores the human relevance of this AO. However, in reproductive toxicity studies and chemical risk assessment, rodents (rats and mice) are what is tested on. The list of chemicals inducing short male AGD in male rat offspring is extensive, as evidenced by the &lsquo;stressor&rsquo; list and reviewed by (<a href="#_ENREF_42" title="Schwartz, 2019 #252">Schwartz et al, 2019</a>).</p>
  • <p style="text-align:justify"><span style="font-size:11pt">The AR is a nuclear transcription factor with canonical AR activation regulated by the binding of the androgens such as testosterone or dihydrotestosterone (DHT). Thus, AR activity can be decreased by reduced levels of steroidal ligands (testosterone, DHT) or the presence of compounds interfering with ligand binding to the receptor <span style="color:black">(Davey &amp; Grossmann, 2016; Gao et al., 2005)</span>.</span></p>
  • <p style="text-align:justify"><span style="font-size:11pt">In the inactive state, AR is sequestered in the cytoplasm of cells by molecular chaperones. In the classical (genomic) AR signaling pathway, AR activation causes dissociation of the chaperones, AR dimerization and translocation to the nucleus to modulate gene expression. AR binds to the androgen response element <span style="color:black">(Davey &amp; Grossmann, 2016; Gao et al., 2005)</span>. AR does not, however, act alone in regulating gene transcription, but together with other co-factors that may differ between cells and tissues and life stages. In this way, the functional consequence of AR activation is cell- and tissue-dependent. </span></p>
  • <p style="text-align:justify"><span style="font-size:11pt">Ligand-bound AR may also associate with cytoplasmic and membrane-bound proteins to initiate cytoplasmic signaling pathways with other functions than the nuclear pathway. Non-genomic AR signaling includes association with Src kinase to activate MAPK/ERK signaling and activation of the PI3K/Akt pathway. Decreased AR activity may therefore be a decrease in the genomic and/or non-genomic AR signaling pathways <span style="color:black">(Leung &amp; Sadar, 2017)</span>.</span></p>
  • <br>
  • </div>
  • <h4>How it is Measured or Detected</h4>
  • <p><span style="font-size:11pt">This KE specifically focuses on decreased <em>in vivo</em> activation, with most methods that can be used to measure AR activity carried out <em>in vitro</em>. They provide indirect information about the KE and are described in lower tier MIE/KEs (see MIE/KE-26 for AR antagonism, KE-1690 for decreased T levels and KE-1613 for decreased dihydrotestosterone levels). In this way, this KE is a placeholder for tissue-specific responses to AR activation or inactivation that will depend on the adverse outcome (AO) for which it is included. </span></p>
  • <p style="text-align:justify"><span style="font-size:11pt">It should be mentioned that the Rapid Androgen Disruption Activity Reporter (RADAR) assay included in OECD test guideline no. 251 detects AR antagonism in vivo in fish (OECD 2022).</span></p>
  • <h4>References</h4>
  • <p><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif">Davey, R. A., &amp; Grossmann, M. (2016). Androgen Receptor Structure, Function and Biology: From Bench to Bedside. <em>The Clinical Biochemist. Reviews</em>, <em>37</em>(1), 3&ndash;15.</span></span></p>
  • <p><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif">Gao, W., Bohl, C. E., &amp; Dalton, J. T. (2005). Chemistry and structural biology of androgen receptor. <em>Chemical Reviews</em>, <em>105</em>(9), 3352&ndash;3370. https://doi.org/10.1021/cr020456u</span></span></p>
  • <p><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif">Hutson, J. M. (1985). A biphasic model for the hormonal control of testicular descent. <em>The Lancet</em>, <em>24</em>, 419&ndash;421. https://doi.org/https://doi.org/10.1016/S0140-6736(85)92739-4</span></span></p>
  • <p><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif">Kaftanovskaya, E. M., Huang, Z., Barbara, A. M., de Gendt, K., Verhoeven, G., Gorlov, I. P., &amp; Agoulnik, A. I. (2012). Cryptorchidism in mice with an androgen receptor ablation in gubernaculum testis. <em>Molecular Endocrinology</em>, <em>26</em>(4), 598&ndash;607. https://doi.org/10.1210/me.2011-1283</span></span></p>
  • <p><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif">Lee, S. H., Hong, K. Y., Seo, H., Lee, H. S., &amp; Park, Y. (2021). Mechanistic insight into human androgen receptor-mediated endocrine-disrupting potentials by a stable bioluminescence resonance energy transfer-based dimerization assay. <em>Chemico-Biological Interactions</em>, <em>349</em>. https://doi.org/10.1016/j.cbi.2021.109655</span></span></p>
  • <p><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif">Leung, J. K., &amp; Sadar, M. D. (2017). Non-Genomic Actions of the Androgen Receptor in Prostate Cancer. <em>Frontiers in Endocrinology</em>, <em>8</em>. <a href="https://doi.org/10.3389/fendo.2017.00002" style="color:#0563c1; text-decoration:underline">https://doi.org/10.3389/fendo.2017.00002</a></span></span></p>
  • <p><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif">OECD (2022). Test No. 251: Rapid Androgen Disruption Activity Reporter (RADAR) assay. Paris: OECD Publishing doi:10.1787/da264d82-en.</span></span></p>
  • <p><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif">Pang, T. P. S., Clarke, M. v., Ghasem-Zadeh, A., Lee, N. K. L., Davey, R. A., &amp; MacLean, H. E. (2012). A physiological role for androgen actions in the absence of androgen receptor DNA binding activity. <em>Molecular and Cellular Endocrinology</em>, <em>348</em>(1), 189&ndash;197. https://doi.org/10.1016/j.mce.2011.08.017</span></span></p>
  • <table>
  • <tbody>
  • <tr>
  • <td colspan="1" rowspan="1">
  • <p>&nbsp;</p>
  • </td>
  • <td colspan="1" rowspan="1">
  • <p>&nbsp;</p>
  • </td>
  • </tr>
  • </tbody>
  • </table>
  • <!-- event text -->
  • <h4>Key Event Description</h4>
  • <p>The anogenital distance (AGD) refers to the distance between anus and the external genitalia. In rodents and humans, the male AGD is approximately twice the length as the female AGD (<a href="#_ENREF_39" title="Salazar-Martinez, 2004 #8">Salazar-Martinez et al, 2004</a>; <a href="#_ENREF_41" title="Schwartz, 2019 #252">Schwartz et al, 2019</a>). This sexual dimorphisms is a consequence of sex hormone-dependent development of secondary sexual characteristics (<a href="#_ENREF_41" title="Schwartz, 2019 #252">Schwartz et al, 2019</a>). In males, it is believed that androgens (primarily DHT) activate AR-positive cells in non-myotic cells in the fetal perineum region to initiate differentiation of the perineal <em>levator ani</em> and <em>bulbocavernosus </em>(LABC) muscle complex (<a href="#_ENREF_18" title="Ipulan, 2014 #185">Ipulan et al, 2014</a>). This AR-dependent process occurs within a critical window of development, around gestational days 15-18 in rats (<a href="#_ENREF_26" title="MacLeod, 2010 #27">MacLeod et al, 2010</a>). In females, the absence of DHT prevents this masculinization effect from occurring.</p>
  • <p>The involvement of androgens in masculinization of the male fetus, including the perineum, has been known for a very long time (<a href="#_ENREF_20" title="Jost, 1953 #151">Jost, 1953</a>), and AGD has historically been used to, for instance, sex newborn kittens. It is now well established that the AGD in newborns is a proxy readout for the intrauterine sex hormone milieu the fetus was developing. Too low androgen levels in XY fetuses makes the male AGD shorter, whereas excess (ectopic) androgen levels in XX fetuses makes the female AGD longer, in humans and rodents (<a href="#_ENREF_41" title="Schwartz, 2019 #252">Schwartz et al, 2019</a>).</p>
  • <h4><a href="/events/286">Event: 286: Altered, Transcription of genes by the androgen receptor</a></h4>
  • <h5>Short Name: Altered, Transcription of genes by the AR</h5>
  • <h4>Key Event Component</h4>
  • <div class="table-responsive">
  • <table class="table table-bordered table-fullwidth">
  • <thead class="thead-light">
  • <tr>
  • <th scope="col">Process</th>
  • <th scope="col">Object</th>
  • <th scope="col">Action</th>
  • </tr>
  • </thead>
  • <tbody class="tbody-striped">
  • <tr>
  • <td>regulation of gene expression</td>
  • <td>androgen receptor</td>
  • <td>decreased</td>
  • </tr>
  • </tbody>
  • </table>
  • </div>
  • <h4>AOPs Including This Key Event</h4>
  • <div class="table-responsive">
  • <table class="table table-bordered table-fullwidth">
  • <thead class="thead-light">
  • <tr>
  • <th scope="col">AOP ID and Name</th>
  • <th scope="col">Event Type</th>
  • </tr>
  • </thead>
  • <tbody class="tbody-striped">
  • <tr>
  • <td><a href="/aops/19">Aop:19 - Androgen receptor antagonism leading to adverse effects in the male foetus (mammals)</a></td>
  • <td>KeyEvent</td>
  • </tr>
  • <tr>
  • <td><a href="/aops/307">Aop:307 - Decreased testosterone synthesis leading to short anogenital distance (AGD) in male (mammalian) offspring</a></td>
  • <td>KeyEvent</td>
  • </tr>
  • <tr>
  • <td><a href="/aops/344">Aop:344 - Androgen receptor (AR) antagonism leading to nipple retention (NR) in male (mammalian) offspring</a></td>
  • <td>KeyEvent</td>
  • </tr>
  • <tr>
  • <td><a href="/aops/345">Aop:345 - Androgen receptor (AR) antagonism leading to decreased fertility in females</a></td>
  • <td>KeyEvent</td>
  • </tr>
  • <tr>
  • <td><a href="/aops/305">Aop:305 - 5α-reductase inhibition leading to short anogenital distance (AGD) in male (mammalian) offspring</a></td>
  • <td>KeyEvent</td>
  • </tr>
  • <tr>
  • <td><a href="/aops/495">Aop:495 - Androgen receptor activation leading to prostate cancer</a></td>
  • <td>KeyEvent</td>
  • </tr>
  • </tbody>
  • </table>
  • </div>
  • <br>
  • <h4>Stressors</h4>
  • <div class="table-responsive">
  • <table class="table table-bordered table-fullwidth">
  • <thead class="thead-light">
  • <tr><th scope="col">Name</th></tr>
  • </thead>
  • <tbody>
  • <tr><td>Bicalutamide</td></tr>
  • <tr><td>Cyproterone acetate</td></tr>
  • <tr><td>Epoxiconazole</td></tr>
  • <tr><td>Flutamide</td></tr>
  • <tr><td>Flusilazole</td></tr>
  • <tr><td>Prochloraz</td></tr>
  • <tr><td>Propiconazole</td></tr>
  • <tr><td>Stressor:286 Tebuconazole</td></tr>
  • <tr><td>Triticonazole</td></tr>
  • <tr><td>Vinclozalin</td></tr>
  • </tbody>
  • </table>
  • </div>
  • <h4>Biological Context</h4>
  • <div class="table-responsive">
  • <table class="table table-bordered table-fullwidth">
  • <thead class="thead-light">
  • <tr><th scope="col">Level of Biological Organization</th></tr>
  • </thead>
  • <tbody class="tbody-striped">
  • <tr><td>Tissue</td></tr>
  • </tbody>
  • </table>
  • </div>
  • <h4>Cell term</h4>
  • <div class="table-responsive">
  • <table class="table table-bordered table-fullwidth">
  • <thead class="thead-light">
  • <tr><th scope="col">Cell term</th></tr>
  • </thead>
  • <tbody class="tbody-striped">
  • <tr><td>eukaryotic cell</td></tr>
  • </tbody>
  • </table>
  • </div>
  • <h3>Evidence for Perturbation by Stressor</h3>
  • <h4>Bicalutamide</h4>
  • <p><p>Using analysis of androgen-regulated gene expression in the LNCaP prostate cancer cell line (Ngan et al. 2009).</p>
  • </p>
  • <h4>Cyproterone acetate</h4>
  • <p><p style="margin-left:18.0pt">Using analysis of androgen-regulated gene expression in the LNCaP prostate cancer cell line (Ngan et al. 2009) and using the AR-CALUX reporter assay in antagonism mode, cyproterone acetate showed an IC50 of 7.1 nM (Sonneveld et al. 2005).</p>
  • </p>
  • <h4>Epoxiconazole</h4>
  • <p><p>Using transiently AR-transfected CHO cells, epoxiconazole showed a LOEC of 1.6 mM and an IC50 of 10 mM (Kj&aelig;rstad et al. 2010).</p>
  • </p>
  • <h4>Flutamide</h4>
  • <p><p>Analysis of androgen-regulated gene expression in the LNCaP prostate cancer cell line (Ngan et al. 2009) and using the AR-CALUX reporter assay in antagonism mode, flutamide showed an IC50 of 1.3 uM (Sonneveld et al. 2005).</p>
  • </p>
  • <h4>Flusilazole</h4>
  • <p><p>Using hAR-EcoScreen Assay, triticonazole showed a LOEC for antagonisms of 0.8 mM and an IC50 of 2.8 (&plusmn;0.1) mM (Draskau et al. 2019)</p>
  • </p>
  • <h4>Prochloraz</h4>
  • <p><p>Using gene expression analysis of the androgen-regulated genes ornithine decarboxylase, prostatic binding protein C3 as well as insulin-like growth factor I. Gene expression levels were reduced in ventral prostates of male Wistar pups at postnatal day 16 following <em>in utero</em> and lactational exposure from maternal perinatal dosing with prochloraz (50 and 150 mg/kg/day) from gestational day 7 to postnatal day 16 (Laier et al. 2006). Also, using transiently AR-transfected CHO cells, prochloraz showed a LOEC of 6.3 mM and an IC50 of 13 mM (Kj&aelig;rstad et al. 2010).</p>
  • </p>
  • <h4>Propiconazole</h4>
  • <p><p>Using transiently AR-transfected CHO cells, propiconazole showed a LOEC of 12.5 mM and an IC50 of 18 mM (Kj&aelig;rstad et al. 2010).</p>
  • </p>
  • <h4>Stressor:286 Tebuconazole</h4>
  • <p><p>Using transiently AR-transfected CHO cells, tebuconazole showed a LOEC of 3.1 mM and an IC50 of 8.1 mM (Kj&aelig;rstad et al. 2010).</p>
  • </p>
  • <h4>Triticonazole</h4>
  • <p><p>Using hAR-EcoScreen Assay, triticonazole showed a LOEC for antagonisms of 0.2 mM and an IC50 of 0.3 (&plusmn;0.01) mM (Draskau et al. 2019).</p>
  • </p>
  • <h4>Vinclozalin</h4>
  • <p><p>Using the AR-CALUX reporter assay in antagonism mode, vinclozolin showed an IC50of 1.0 uM (Sonneveld et al. 2005).</p>
  • </p>
  • <h4>Domain of Applicability</h4>
  • <strong>Taxonomic Applicability</strong>
  • <div class="table-responsive">
  • <table class="table table-bordered table-fullwidth">
  • <thead class="thead-light">
  • <tr>
  • <th scope="col">Term</th>
  • <th scope="col">Scientific Term</th>
  • <th scope="col">Evidence</th>
  • <th scope="col">Links</th>
  • </tr>
  • </thead>
  • <tbody class="tbody-striped">
  • <tr>
  • <td>Vertebrates</td>
  • <td>Vertebrates</td>
  • <td>High</td>
  • <td><a href="http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&id=0" target="_blank">NCBI</a></td>
  • </tr>
  • </tbody>
  • </table>
  • </div>
  • <strong>Life Stage Applicability</strong>
  • <div class="table-responsive">
  • <table class="table table-bordered table-fullwidth">
  • <thead class="thead-light">
  • <tr>
  • <th scope="col">Life Stage</th>
  • <th scope="col">Evidence</th>
  • </tr>
  • </thead>
  • <tbody class="tbody-striped">
  • <tr>
  • <td>During development and at adulthood</td>
  • <td>High</td>
  • </tr>
  • </tbody>
  • </table>
  • </div>
  • <strong>Sex Applicability</strong>
  • <div class="table-responsive">
  • <table class="table table-bordered table-fullwidth">
  • <thead class="thead-light">
  • <tr>
  • <th scope="col">Sex</th>
  • <th scope="col">Evidence</th>
  • </tr>
  • </thead>
  • <tbody class="tbody-striped">
  • <tr>
  • <td>Mixed</td>
  • <td>High</td>
  • </tr>
  • </tbody>
  • </table>
  • </div>
  • <p>Both the DNA-binding and ligand-binding domains of the AR are highly evolutionary conserved, whereas the transactivation domain show more divergence, which may affect AR-mediated gene regulation across species (Davey and Grossmann 2016).&nbsp;Despite certain inter-species differences, AR function mediated through gene expression is highly conserved, with mutation studies from both humans and rodents showing strong correlation for AR-dependent development and function (Walters et al. 2010).&nbsp;<span style="font-size:12.0pt">Likewise in fish, androgens are important for development of sexual characteristics (Ogino et al., 2014, 2023). One difference that must be mentioned is that in teleost fish, 11-ketotestosterone is the main androgen in addition to testosterone and DHT and that most teleosts have two <em>ar</em> ohnologs, <em>ara</em> and <em>arb</em>, with arb functioning in a similar manner to the AR in other vertebrates (Ogino et al., 2023). </span></p>
  • <p><span style="font-size:11pt"><span style="font-size:12.0pt">This KE is considered broadly applicable across vertebrate taxa, sex and developmental stages, as all vertebrate animals express the AR in numerous cells and tissues where it regulates gene transcription required for developmental processes and function. </span></span></p>
  • <h4>How it is Measured or Detected</h4>
  • <p>The AGD is a morphometric measurement carried out by trained technicians (rodents) or medical staff (humans).</p>
  • <h4>Key Event Description</h4>
  • <p><span style="font-size:11pt"><span style="font-size:12.0pt">This KE refers to transcription of genes by the androgen receptor (AR) as occurring in complex biological systems such as tissues and organs <em>in vivo</em>.</span></span></p>
  • <p>In rodent studies AGD is assessed as the distance between the genital papilla and the anus, and measured using a stereomicroscope with a micrometer eyepiece. The AGD index (AGDi) is often calculated by dividing AGD by the cube root of the body weight.&nbsp; It is important in statistical analysis to use litter as the statistical unit. This is done when more than one pup from each litter is examined. Statistical analyses is adjusted using litter as an independent, random and nested factor. AGD are analysed using body weight as covariate as recommended in Guidance Document 151 (<a href="#_ENREF_37" title="OECD, 2013 #30">OECD, 2013</a>).</p>
  • <p><u>The Androgen Receptor and its function</u></p>
  • <p><span style="font-size:12.0pt">The AR belongs to the steroid hormone nuclear receptor family. It is a ligand-activated transcription factor with three domains: the N-terminal domain, the DNA-binding domain, and the ligand-binding domain with the latter being the most evolutionary conserved (Davey and Grossmann 2016). </span>Androgens <span style="font-size:12.0pt">(such as dihydrotestosterone and testosterone) are AR ligands and </span>act by binding to the AR&nbsp;in androgen-responsive tissues (Davey and Grossmann 2016). Human AR mutations and mouse knockout models have established a fundamental role for AR in masculinization and spermatogenesis (Maclean et al.; Walters et al. 2010; Rana et al. 2014). The AR is also expressed in many other tissues such as bone, muscles, ovaries and within the immune system (Rana et al. 2014).</p>
  • <p>&nbsp;</p>
  • <p><u>Altered transcription of genes by the AR as a Key Event</u></p>
  • <p>Upon activation by ligand-binding, the AR translocates from the cytoplasm to the cell nucleus, dimerizes, binds to androgen response elements in the DNA to modulate gene transcription (Davey and Grossmann 2016). The transcriptional targets vary between cells and tissues, as well as with developmental stages and is also dependent on available co-regulators (Bevan and Parker 1999; Heemers and Tindall 2007).&nbsp;<span style="font-size:12.0pt">It should also be mentioned that the AR can work in other &lsquo;non-canonial&rsquo; ways such as non-genomic signaling, and ligand-independent activation (Davey &amp; Grossmann, 2016; Estrada et al, 2003; Jin et al, 2013). </span></p>
  • <p>A large number of known, and proposed, target genes of AR canonical signaling have been identified by analysis of gene expression following treatments with AR agonists (Bolton et al. 2007; Ngan et al. 2009<span style="font-size:12.0pt">, Jin et al. 2013</span>).</p>
  • <h4>How it is Measured or Detected</h4>
  • <p>Altered transcription of genes by the AR can be measured by measuring the transcription level of known downstream target genes by RT-qPCR or other transcription analyses approaches, e.g. transcriptomics.</p>
  • <h4>References</h4>
  • <p>Bevan C, Parker M (1999) The role of coactivators in steroid hormone action. Exp. Cell Res. 253:349&ndash;356</p>
  • <p>Bolton EC, So AY, Chaivorapol C, et al (2007) Cell- and gene-specific regulation of primary target genes by the androgen receptor. Genes Dev 21:2005&ndash;2017. doi: 10.1101/gad.1564207</p>
  • <p>Davey RA, Grossmann M (2016) Androgen Receptor Structure, Function and Biology: From Bench to Bedside. Clin Biochem Rev 37:3&ndash;15</p>
  • <p>Estrada M, Espinosa A, M&uuml;ller M, Jaimovich E (2003) Testosterone Stimulates Intracellular Calcium Release and Mitogen-Activated Protein Kinases Via a G Protein-Coupled Receptor in Skeletal Muscle Cells. Endocrinology 144:3586&ndash;3597. doi: 10.1210/en.2002-0164</p>
  • <p>Heemers H V., Tindall DJ (2007) Androgen receptor (AR) coregulators: A diversity of functions converging on and regulating the AR transcriptional complex. Endocr. Rev. 28:778&ndash;808</p>
  • <p><span style="font-size:11pt"><span style="font-size:12.0pt">Jin, Hong Jian, Jung Kim, and Jindan Yu. 2013. &ldquo;Androgen Receptor Genomic Regulation.&rdquo; Translational Andrology and Urology 2(3):158&ndash;77. doi: 10.3978/j.issn.2223-4683.2013.09.01</span></span></p>
  • <p>Maclean HE, Chu S, Warne GL, Zajact JD Related Individuals with Different Androgen Receptor Gene Deletions</p>
  • <p>MacLeod DJ, Sharpe RM, Welsh M, et al (2010) Androgen action in the masculinization programming window and development of male reproductive organs. In: International Journal of Andrology. Blackwell Publishing Ltd, pp 279&ndash;287</p>
  • <p>Ngan S, Stronach EA, Photiou A, et al (2009) Microarray coupled to quantitative RT&amp;ndash;PCR analysis of androgen-regulated genes in human LNCaP prostate cancer cells. Oncogene 28:2051&ndash;2063. doi: 10.1038/onc.2009.68<span style="font-size:11pt"><span style="font-family:Calibri,sans-serif"><a name="_Hlk148352925"></a></span></span></p>
  • <p><span style="font-size:11pt"><a name="_Hlk148352925"><span style="font-size:12.0pt">Ogino, Y., Ansai, S., Watanabe, E., Yasugi, M., Katayama, Y., Sakamoto, H., et al. </span></a><span style="font-size:12.0pt">(2023). Evolutionary differentiation of androgen receptor is responsible for sexual characteristic development in a teleost fish. <em>Nat. Commun. 2023 141</em> 14, 1&ndash;16. doi:10.1038/s41467-023-37026-6.</span></span></p>
  • <p><span style="font-size:11pt"><span style="font-size:12.0pt">Ogino, Y., Hirakawa, I., Inohaya, K., Sumiya, E., Miyagawa, S., Denslow, N., et al. (2014). Bmp7 and Lef1 Are the Downstream Effectors of Androgen Signaling in Androgen-Induced Sex Characteristics Development in Medaka. </span><em><span style="font-size:12.0pt">Endocrinology</span></em><span style="font-size:12.0pt"> 155, 449&ndash;462. doi:10.1210/EN.2013-1507.</span></span></p>
  • <p>Rana K, Davey RA, Zajac JD (2014) Human androgen deficiency: Insights gained from androgen receptor knockout mouse models. Asian J. Androl. 16:169&ndash;177</p>
  • <p>Walters KA, Simanainen U, Handelsman DJ (2010) Molecular insights into androgen actions in male and female reproductive function from androgen receptor knockout models. Hum Reprod Update 16:543&ndash;558. doi: 10.1093/humupd/dmq003</p>
  • <h3>List of Adverse Outcomes in this AOP</h3>
  • <h4><a href="/events/1688">Event: 1688: anogenital distance (AGD), decreased</a></h4>
  • <h5>Short Name: AGD, decreased</h5>
  • <h4>Key Event Component</h4>
  • <div class="table-responsive">
  • <table class="table table-bordered table-fullwidth">
  • <thead class="thead-light">
  • <tr>
  • <th scope="col">Process</th>
  • <th scope="col">Object</th>
  • <th scope="col">Action</th>
  • </tr>
  • </thead>
  • <tbody class="tbody-striped">
  • <tr>
  • <td>androgen receptor signaling pathway</td>
  • <td>Musculature of male perineum</td>
  • <td>disrupted</td>
  • </tr>
  • </tbody>
  • </table>
  • </div>
  • <h4>AOPs Including This Key Event</h4>
  • <div class="table-responsive">
  • <table class="table table-bordered table-fullwidth">
  • <thead class="thead-light">
  • <tr>
  • <th scope="col">AOP ID and Name</th>
  • <th scope="col">Event Type</th>
  • </tr>
  • </thead>
  • <tbody class="tbody-striped">
  • <tr>
  • <td><a href="/aops/305">Aop:305 - 5α-reductase inhibition leading to short anogenital distance (AGD) in male (mammalian) offspring</a></td>
  • <td>AdverseOutcome</td>
  • </tr>
  • <tr>
  • <td><a href="/aops/306">Aop:306 - Androgen receptor (AR) antagonism leading to short anogenital distance (AGD) in male (mammalian) offspring</a></td>
  • <td>AdverseOutcome</td>
  • </tr>
  • <tr>
  • <td><a href="/aops/307">Aop:307 - Decreased testosterone synthesis leading to short anogenital distance (AGD) in male (mammalian) offspring</a></td>
  • <td>AdverseOutcome</td>
  • </tr>
  • <tr>
  • <td><a href="/aops/476">Aop:476 - Adverse Outcome Pathways diagram related to PBDEs associated male reproductive toxicity</a></td>
  • <td>AdverseOutcome</td>
  • </tr>
  • </tbody>
  • </table>
  • </div>
  • <h4>Stressors</h4>
  • <div class="table-responsive">
  • <table class="table table-bordered table-fullwidth">
  • <thead class="thead-light">
  • <tr><th scope="col">Name</th></tr>
  • </thead>
  • <tbody>
  • <tr><td>Butylparaben</td></tr>
  • <tr><td>p,p&#39;-DDE</td></tr>
  • <tr><td>Bis(2-ethylhexyl) phthalate</td></tr>
  • <tr><td>Dexamethasone</td></tr>
  • <tr><td>Fenitrothion</td></tr>
  • <tr><td>Finasteride</td></tr>
  • <tr><td>Flutamide</td></tr>
  • <tr><td>Ketoconazole</td></tr>
  • <tr><td>Linuron</td></tr>
  • <tr><td>Prochloraz</td></tr>
  • <tr><td>Procymidone</td></tr>
  • <tr><td>Triticonazole</td></tr>
  • <tr><td>Vinclozolin</td></tr>
  • <tr><td>di-n-hexyl phthalate</td></tr>
  • <tr><td>Dicyclohexyl phthalate</td></tr>
  • <tr><td>butyl benzyl phthalate</td></tr>
  • <tr><td>monobenzyl phthalate</td></tr>
  • <tr><td>di-n-heptyl phthalate</td></tr>
  • </tbody>
  • </table>
  • </div>
  • <h4>Biological Context</h4>
  • <div class="table-responsive">
  • <table class="table table-bordered table-fullwidth">
  • <thead class="thead-light">
  • <tr><th scope="col">Level of Biological Organization</th></tr>
  • </thead>
  • <tbody class="tbody-striped">
  • <tr><td>Tissue</td></tr>
  • </tbody>
  • </table>
  • </div>
  • <h4>Organ term</h4>
  • <div class="table-responsive">
  • <table class="table table-bordered table-fullwidth">
  • <thead class="thead-light">
  • <tr><th scope="col">Organ term</th></tr>
  • </thead>
  • <tbody class="tbody-striped">
  • <tr><td>perineum</td></tr>
  • </tbody>
  • </table>
  • </div>
  • <h3>Evidence for Perturbation by Stressor</h3>
  • <h4>Butylparaben</h4>
  • <p><p>Butylparaben has been shown to cause decreased male AGD in rats following intrauterine exposure to 500 and 1000 mg/kg bw/day (<a href="#_ENREF_1" title="Boberg, 2016 #12">Boberg et al, 2016</a>; <a href="#_ENREF_39" title="Zhang, 2014 #148">Zhang et al, 2014</a>). A separate study using 600 mg/kg bw/day did not see an effect on male AGD (<a href="#_ENREF_2" title="Boberg, 2008 #45">Boberg et al, 2008</a>).</p>
  • </p>
  • <h4>p,p'-DDE</h4>
  • <p><p>p,p,DDE has been shown to cause decreased male AGD in rats following intrauterine exposure to 100-200 mg/kg bw/day (<a href="#_ENREF_20" title="Loeffler, 1999 #60">Loeffler &amp; Peterson, 1999</a>; <a href="#_ENREF_38" title="Wolf, 1999 #146">Wolf et al, 1999</a>).</p>
  • </p>
  • <h4>Bis(2-ethylhexyl) phthalate</h4>
  • <p><p>DEHP has been shown to cause decreased male AGD in rats following intrauterine exposure to 300-1500 mg/kg bw/day (<a href="#_ENREF_4" title="Christiansen, 2010 #13">Christiansen et al, 2010</a>; <a href="#_ENREF_8" title="Gray, 2000 #110">Gray et al, 2000</a>; <a href="#_ENREF_13" title="Howdeshell, 2007 #111">Howdeshell et al, 2007</a>; <a href="#_ENREF_15" title="Jarfelt, 2005 #113">Jarfelt et al, 2005</a>; <a href="#_ENREF_16" title="Kita, 2016 #34">Kita et al, 2016</a>; <a href="#_ENREF_18" title="Li, 2013 #71">Li et al, 2013</a>; <a href="#_ENREF_19" title="Lin, 2009 #120">Lin et al, 2009</a>; <a href="#_ENREF_25" title="Moore, 2001 #124">Moore et al, 2001</a>; <a href="#_ENREF_27" title="Nardelli, 2017 #149">Nardelli et al, 2017</a>; <a href="#_ENREF_30" title="Saillenfait, 2009 #134">Saillenfait et al, 2009</a>; <a href="#_ENREF_38" title="Wolf, 1999 #146">Wolf et al, 1999</a>).</p>
  • </p>
  • <h4>Dexamethasone</h4>
  • <p><p>Dexamethasone has been shown to cause decreased male AGD in rats following intrauterine exposure to 0.1 mg/kg bw/day (<a href="#_ENREF_35" title="Van den Driesche, 2012 #144">Van den Driesche et al, 2012</a>).</p>
  • </p>
  • <h4>Fenitrothion</h4>
  • <p><p>Fenitrothion has been shown to cause decreased male AGD in rats following intrauterine exposure to 25 mg/kg bw/day (<a href="#_ENREF_34" title="Turner, 2002 #213">Turner et al, 2002</a>).</p>
  • </p>
  • <h4>Finasteride</h4>
  • <p><p>Finasteride has been shown to cause decreased male AGD in rats following intrauterine exposure to 100 mg/kg bw/day (<a href="#_ENREF_3" title="Bowman, 2003 #29">Bowman et al, 2003</a>).</p>
  • </p>
  • <h4>Flutamide</h4>
  • <p><p>Flutamide has been shown to cause decreased male AGD in rats following intrauterine exposure to doses between 16-100 mg/kg bw/day (<a href="#_ENREF_7" title="Foster, 2005 #53">Foster &amp; Harris, 2005</a>; <a href="#_ENREF_11" title="Hass, 2007 #76">Hass et al, 2007</a>; <a href="#_ENREF_16" title="Kita, 2016 #34">Kita et al, 2016</a>; <a href="#_ENREF_23" title="McIntyre, 2001 #36">McIntyre et al, 2001</a>; <a href="#_ENREF_26" title="Mylchreest, 1999 #126">Mylchreest et al, 1999</a>; <a href="#_ENREF_32" title="Scott, 2007 #139">Scott et al, 2007</a>; <a href="#_ENREF_36" title="Welsh, 2007 #56">Welsh et al, 2007</a>).</p>
  • </p>
  • <h4>Ketoconazole</h4>
  • <p><p>Ketoconazole has been shown to cause decreased male AGD in rats following intrauterine exposure to 50 mg/kg bw/day in one study (<a href="#_ENREF_33" title="Taxvig, 2008 #184">Taxvig et al, 2008</a>), but no effect in another study using same dose (<a href="#_ENREF_38" title="Wolf, 1999 #146">Wolf et al, 1999</a>).</p>
  • </p>
  • <h4>Linuron</h4>
  • <p><p>Linuron has been shown to cause decreased male AGD in rats following intrauterine exposure to 50-100 mg/kg bw/day (<a href="#_ENREF_12" title="Hotchkiss, 2004 #40">Hotchkiss et al, 2004</a>; <a href="#_ENREF_24" title="McIntyre, 2002 #38">McIntyre et al, 2002</a>; <a href="#_ENREF_38" title="Wolf, 1999 #146">Wolf et al, 1999</a>).</p>
  • </p>
  • <h4>Prochloraz</h4>
  • <p><p>Prochloraz has been shown to cause decreased male AGD in rats following intrauterine exposure to 150-250 mg/kg bw/day (<a href="#_ENREF_17" title="Laier, 2006 #15">Laier et al, 2006</a>; <a href="#_ENREF_28" title="Noriega, 2005 #54">Noriega et al, 2005</a>).</p>
  • </p>
  • <h4>Procymidone</h4>
  • <p><p style="margin-left:18.0pt">Procymidone has been shown to cause decreased male AGD in rats following intrauterine exposure to doses between 50-150 mg/kg bw/day (<a href="#_ENREF_10" title="Hass, 2012 #220">Hass et al, 2012</a>; <a href="#_ENREF_11" title="Hass, 2007 #76">Hass et al, 2007</a>; <a href="#_ENREF_38" title="Wolf, 1999 #146">Wolf et al, 1999</a>).</p>
  • </p>
  • <h4>Triticonazole</h4>
  • <p><p>Triticonazole has been shown to cause decreased male AGD in rats following intrauterine exposure to 150 and 450 mg/kg bw/day (<a href="#_ENREF_6" title="Draskau, 2019 #258">Draskau et al, 2019</a>).</p>
  • </p>
  • <h4>Vinclozolin</h4>
  • <p><p>Vinclozolin has been shown to cause decreased male AGD in rats following intrauterine exposure to doses between 50-200 mg/kg bw/day (<a href="#_ENREF_5" title="Christiansen, 2009 #14">Christiansen et al, 2009</a>; <a href="#_ENREF_9" title="Gray, 1994 #109">Gray et al, 1994</a>; <a href="#_ENREF_11" title="Hass, 2007 #76">Hass et al, 2007</a>; <a href="#_ENREF_22" title="Matsuura, 2005 #243">Matsuura et al, 2005</a>; <a href="#_ENREF_29" title="Ostby, 1999 #78">Ostby et al, 1999</a>; <a href="#_ENREF_31" title="Schneider, 2011 #245">Schneider et al, 2011</a>; <a href="#_ENREF_37" title="Wolf, 2004 #51">Wolf et al, 2004</a>).</p>
  • </p>
  • <h4>di-n-hexyl phthalate</h4>
  • <p><p>DnHP has been shown to cause decreased male AGD in rats following intrauterine exposure to 500-750 mg/kg bw/day (<a href="#_ENREF_35" title="Saillenfait, 2009 #133">Saillenfait et al, 2009a</a>; <a href="#_ENREF_36" title="Saillenfait, 2009 #134">Saillenfait et al, 2009b</a>).</p>
  • </p>
  • <h4>Dicyclohexyl phthalate</h4>
  • <p><p>DCHP has been shown to cause decreased male AGD in rats following intrauterine exposure to 350-750 mg/kg bw/day (<a href="#_ENREF_1" title="Aydoğan Ahbab, 2015 #95">Aydoğan Ahbab &amp; Barlas, 2015</a>; <a href="#_ENREF_13" title="Hoshino, 2005 #239">Hoshino et al, 2005</a>; <a href="#_ENREF_32" title="Saillenfait, 2009 #133">Saillenfait et al, 2009a</a>).</p>
  • </p>
  • <h4>butyl benzyl phthalate</h4>
  • <p><p>BBP has been shown to cause decreased male AGD in rats following intrauterine exposure to 500-1000 mg/kg bw/day (<a href="#_ENREF_8" title="Ema, 2002 #104">Ema &amp; Miyawaki, 2002</a>; <a href="#_ENREF_10" title="Gray, 2000 #110">Gray et al, 2000</a>; <a href="#_ENREF_15" title="Hotchkiss, 2004 #40">Hotchkiss et al, 2004</a>; <a href="#_ENREF_30" title="Nagao, 2000 #128">Nagao et al, 2000</a>; <a href="#_ENREF_41" title="Tyl, 2004 #240">Tyl et al, 2004</a>).</p>
  • </p>
  • <h4>monobenzyl phthalate</h4>
  • <p><p>MBeP has been shown to cause decreased male AGD in rats following intrauterine exposure to 375 mg/kg bw/day (<a href="#_ENREF_9" title="Ema, 2003 #107">Ema et al, 2003</a>).</p>
  • </p>
  • <h4>di-n-heptyl phthalate</h4>
  • <p><p>DHPP has been shown to cause decreased male AGD in rats following intrauterine exposure to 1000 mg/kg bw/day (<a href="#_ENREF_36" title="Saillenfait, 2011 #135">Saillenfait et al, 2011</a>).</p>
  • </p>
  • <h4>Domain of Applicability</h4>
  • <strong>Taxonomic Applicability</strong>
  • <div class="table-responsive">
  • <table class="table table-bordered table-fullwidth">
  • <thead class="thead-light">
  • <tr>
  • <th scope="col">Term</th>
  • <th scope="col">Scientific Term</th>
  • <th scope="col">Evidence</th>
  • <th scope="col">Links</th>
  • </tr>
  • </thead>
  • <tbody class="tbody-striped">
  • <tr>
  • <td>human</td>
  • <td>Homo sapiens</td>
  • <td>Moderate</td>
  • <td><a href="http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&id=9606" target="_blank">NCBI</a></td>
  • </tr>
  • <tr>
  • <td>rat</td>
  • <td>Rattus norvegicus</td>
  • <td>High</td>
  • <td><a href="http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&id=10116" target="_blank">NCBI</a></td>
  • </tr>
  • <tr>
  • <td>mouse</td>
  • <td>Mus musculus</td>
  • <td>High</td>
  • <td><a href="http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&id=10090" target="_blank">NCBI</a></td>
  • </tr>
  • </tbody>
  • </table>
  • </div>
  • <strong>Life Stage Applicability</strong>
  • <div class="table-responsive">
  • <table class="table table-bordered table-fullwidth">
  • <thead class="thead-light">
  • <tr>
  • <th scope="col">Life Stage</th>
  • <th scope="col">Evidence</th>
  • </tr>
  • </thead>
  • <tbody class="tbody-striped">
  • <tr>
  • <td>Foetal</td>
  • <td>High</td>
  • </tr>
  • </tbody>
  • </table>
  • </div>
  • <strong>Sex Applicability</strong>
  • <div class="table-responsive">
  • <table class="table table-bordered table-fullwidth">
  • <thead class="thead-light">
  • <tr>
  • <th scope="col">Sex</th>
  • <th scope="col">Evidence</th>
  • </tr>
  • </thead>
  • <tbody class="tbody-striped">
  • <tr>
  • <td>Male</td>
  • <td>High</td>
  • </tr>
  • </tbody>
  • </table>
  • </div>
  • <p>A short AGD in male offspring is a marker of insufficient androgen action during critical fetal developmental stages (<a href="#_ENREF_42" title="Schwartz, 2019 #252">Schwartz et al, 2019</a>; <a href="#_ENREF_49" title="Welsh, 2008 #23">Welsh et al, 2008</a>). A short AGD is thus a sign of undervirilization, which is also associated with a series of male reproductive disorders, including genital malformations and infertility in humans (<a href="#_ENREF_21" title="Juul, 2014 #3">Juul et al, 2014</a>; <a href="#_ENREF_44" title="Skakkebaek, 2001 #9">Skakkebaek et al, 2001</a>).</p>
  • <p>There are numerous human epidemiological studies showing associations with intrauterine exposure to anti-androgenic chemicals and short AGD in newborn boys alongside other reproductive disorders (<a href="#_ENREF_42" title="Schwartz, 2019 #252">Schwartz et al, 2019</a>). This underscores the human relevance of this AO. However, in reproductive toxicity studies and chemical risk assessment, rodents (rats and mice) are what is tested on. The list of chemicals inducing short male AGD in male rat offspring is extensive, as evidenced by the &lsquo;stressor&rsquo; list and reviewed by (<a href="#_ENREF_42" title="Schwartz, 2019 #252">Schwartz et al, 2019</a>).</p>
  • <br>
  • <h4>Key Event Description</h4>
  • <p>The anogenital distance (AGD) refers to the distance between anus and the external genitalia. In rodents and humans, the male AGD is approximately twice the length as the female AGD (<a href="#_ENREF_39" title="Salazar-Martinez, 2004 #8">Salazar-Martinez et al, 2004</a>; <a href="#_ENREF_41" title="Schwartz, 2019 #252">Schwartz et al, 2019</a>). This sexual dimorphisms is a consequence of sex hormone-dependent development of secondary sexual characteristics (<a href="#_ENREF_41" title="Schwartz, 2019 #252">Schwartz et al, 2019</a>). In males, it is believed that androgens (primarily DHT) activate AR-positive cells in non-myotic cells in the fetal perineum region to initiate differentiation of the perineal <em>levator ani</em> and <em>bulbocavernosus </em>(LABC) muscle complex (<a href="#_ENREF_18" title="Ipulan, 2014 #185">Ipulan et al, 2014</a>). This AR-dependent process occurs within a critical window of development, around gestational days 15-18 in rats (<a href="#_ENREF_26" title="MacLeod, 2010 #27">MacLeod et al, 2010</a>). In females, the absence of DHT prevents this masculinization effect from occurring.</p>
  • <p>The involvement of androgens in masculinization of the male fetus, including the perineum, has been known for a very long time (<a href="#_ENREF_20" title="Jost, 1953 #151">Jost, 1953</a>), and AGD has historically been used to, for instance, sex newborn kittens. It is now well established that the AGD in newborns is a proxy readout for the intrauterine sex hormone milieu the fetus was developing. Too low androgen levels in XY fetuses makes the male AGD shorter, whereas excess (ectopic) androgen levels in XX fetuses makes the female AGD longer, in humans and rodents (<a href="#_ENREF_41" title="Schwartz, 2019 #252">Schwartz et al, 2019</a>).</p>
  • <h4>Regulatory Significance of the AO</h4>
  • <p>In regulatory toxicology, the AGD is mandatory inclusions in OECD test guidelines used to test for developmental and reproductive toxicity of chemicals. Guidelines include &lsquo;TG 443 extended one-generation study&rsquo;, &lsquo;TG 421/422 reproductive toxicity screening studies&rsquo; and &lsquo;TG 414 developmental toxicity study&rsquo;.</p>
  • <h4>How it is Measured or Detected</h4>
  • <p>The AGD is a morphometric measurement carried out by trained technicians (rodents) or medical staff (humans).</p>
  • <p>In rodent studies AGD is assessed as the distance between the genital papilla and the anus, and measured using a stereomicroscope with a micrometer eyepiece. The AGD index (AGDi) is often calculated by dividing AGD by the cube root of the body weight.&nbsp; It is important in statistical analysis to use litter as the statistical unit. This is done when more than one pup from each litter is examined. Statistical analyses is adjusted using litter as an independent, random and nested factor. AGD are analysed using body weight as covariate as recommended in Guidance Document 151 (<a href="#_ENREF_37" title="OECD, 2013 #30">OECD, 2013</a>).</p>
  • <p>&nbsp;</p>
  • <br>
  • <h4>Regulatory Significance of the AO</h4>
  • <p>In regulatory toxicology, the AGD is mandatory inclusions in OECD test guidelines used to test for developmental and reproductive toxicity of chemicals. Guidelines include &lsquo;TG 443 extended one-generation study&rsquo;, &lsquo;TG 421/422 reproductive toxicity screening studies&rsquo; and &lsquo;TG 414 developmental toxicity study&rsquo;.</p>
  • <h4>References</h4>
  • <p><a name="_ENREF_1">Aydoğan Ahbab M, Barlas N (2015) Influence of in utero di-n-hexyl phthalate and dicyclohexyl phthalate on fetal testicular development in rats. <em>Toxicol Lett</em> <strong>233:</strong> 125-137</a></p>
  • <h4>References</h4>
  • <p><a name="_ENREF_1">Aydoğan Ahbab M, Barlas N (2015) Influence of in utero di-n-hexyl phthalate and dicyclohexyl phthalate on fetal testicular development in rats. <em>Toxicol Lett</em> <strong>233:</strong> 125-137</a></p>
  • <p><a name="_ENREF_2">Boberg J, Axelstad M, Svingen T, Mandrup K, Christiansen S, Vinggaard AM, Hass U (2016) Multiple endocrine disrupting effects in rats perinatally exposed to butylparaben. <em>Toxicol Sci</em> <strong>152:</strong> 244-256</a></p>
  • <p><a name="_ENREF_3">Boberg J, Metzdorff S, Wortziger R, Axelstad M, Brokken L, Vinggaard AM, Dalgaard M, Nellemann C (2008) Impact of diisobutyl phthalate and other PPAR agonists on steroidogenesis and plasma insulin and leptin levels in fetal rats. <em>Toxicology</em> <strong>250:</strong> 75-81</a></p>
  • <p><a name="_ENREF_4">Bowman CJ, Barlow NJ, Turner KJ, Wallace DG, Foster PM (2003) Effects of in utero exposure to finasteride on androgen-dependent reproductive development in the male rat. <em>Toxicol Sci</em> <strong>74:</strong> 393-406</a></p>
  • <p><a name="_ENREF_5">Christiansen S, Boberg J, Axelstad M, Dalgaard M, Vinggaard AM, Metzdorff SB, Hass U (2010) Low-dose perinatal exposure to di(2-ethylhexyl) phthalate induces anti-androgenic effects in male rats. <em>Reprod Toxicol</em> <strong>30:</strong> 313-321</a></p>
  • <p><a name="_ENREF_6">Christiansen S, Scholze M, Dalgaard M, Vinggaard AM, Axelstad M, Kortenkamp A, Hass U (2009) Synergistic disruption of external male sex organ development by a mixture of four antiandrogens. <em>Environ Health Perspect</em> <strong>117:</strong> 1839-1846</a></p>
  • <p><a name="_ENREF_7">Draskau MK, Boberg J, Taxvig C, Pedersen M, Frandsen HL, Christiansen S, Svingen T (2019) In vitro and in vivo endocrine disrupting effects of the azole fungicides triticonazole and flusilazole. <em>Environ Pollut</em> <strong>255:</strong> 113309</a></p>
  • <p><a name="_ENREF_8">Ema M, Miyawaki E (2002) Effects on development of the reproductive system in male offspring of rats given butyl benzyl phthalate during late pregnancy. <em>Reprod Toxicol</em> <strong>16:</strong> 71-76</a></p>
  • <p><a name="_ENREF_9">Ema M, Miyawaki E, Hirose A, Kamata E (2003) Decreased anogenital distance and increased incidence of undescended testes in fetuses of rats given monobenzyl phthalate, a major metabolite of butyl benzyl phthalate. <em>Reprod Toxicol</em> <strong>17:</strong> 407-412</a></p>
  • <p><a name="_ENREF_10">Foster PM, Harris MW (2005) Changes in androgen-mediated reproductive development in male rat offspring following exposure to a single oral dose of flutamide at different gestational ages. <em>Toxicol Sci</em> <strong>85:</strong> 1024-1032</a></p>
  • <p><a name="_ENREF_11">Gray LE, Jr., Ostby J, Furr J, Price M, Veeramachaneni DN, Parks L (2000) Perinatal exposure to the phthalates DEHP, BBP, and DINP, but not DEP, DMP, or DOTP, alters sexual differentiation of the male rat. <em>Toxicol Sci</em> <strong>58:</strong> 350-365</a></p>
  • <p><a name="_ENREF_12">Gray LEJ, Ostby JS, Kelce WR (1994) Developmental effects of an environmental antiandrogen: the fungicide vinclozolin alters sex differentiation of the male rat. <em>Toxicol Appl Pharmacol</em> <strong>129:</strong> 46-52</a></p>
  • <p><a name="_ENREF_13">Hass U, Boberg J, Christiansen S, Jacobsen PR, Vinggaard AM, Taxvig C, Poulsen ME, Herrmann SS, Jensen BH, Petersen A, Clemmensen LH, Axelstad M (2012) Adverse effects on sexual development in rat offspring after low dose exposure to a mixture of endocrine disrupting pesticides. <em>Reprod Toxicol</em> <strong>34:</strong> 261-274</a></p>
  • <p><a name="_ENREF_14">Hass U, Scholze M, Christiansen S, Dalgaard M, Vinggaard AM, Axelstad M, Metzdorff SB, Kortenkamp A (2007) Combined exposure to anti-androgens exacerbates disruption of sexual differentiation in the rat. <em>Environ Health Perspect</em> <strong>115 Suppl. 1:</strong> 122-128</a></p>
  • <p><a name="_ENREF_15">Hoshino N, Iwai M, Okazaki Y (2005) A two-generation reproductive toxicity study of dicyclohexyl phthalate in rats. <em>J Toxicol Sci</em> <strong>30 Spec No:</strong> 79-96</a></p>
  • <p><a name="_ENREF_16">Hotchkiss AK, Parks-Saldutti LG, Ostby JS, Lambright C, Furr J, Vandenbergh JG, Gray LEJ (2004) A mixture of the &quot;antiandrogens&quot; linuron and butyl benzyl phthalate alters sexual differentiation of the male rat in a cumulative fashion. <em>Biol Reprod</em> <strong>71:</strong> 1852-1861</a></p>
  • <p><a name="_ENREF_17">Howdeshell KL, Furr J, Lambright CR, Rider CV, Wilson VS, Gray LE, Jr. (2007) Cumulative effects of dibutyl phthalate and diethylhexyl phthalate on male rat reproductive tract development: altered fetal steroid hormones and genes. <em>Toxicol Sci</em> <strong>99:</strong> 190-202</a></p>
  • <p><a name="_ENREF_18">Ipulan LA, Suzuki K, Sakamoto Y, Murashima A, Imai Y, Omori A, Nakagata N, Nishinakamura R, Valasek P, Yamada G (2014) Nonmyocytic androgen receptor regulates the sexually dimorphic development of the embryonic bulbocavernosus muscle. <em>Endocrinology</em> <strong>155:</strong> 2467-2479</a></p>
  • <p><a name="_ENREF_19">Jarfelt K, Dalgaard M, Hass U, Borch J, Jacobsen H, Ladefoged O (2005) Antiandrogenic effects in male rats perinatally exposed to a mixture of di(2-ethylhexyl) phthalate and di(2-ethylhexyl) adipate. <em>Reprod Toxicol</em> <strong>19:</strong> 505-515</a></p>
  • <p><a name="_ENREF_20">Jost A (1953) Problems of fetal endocrinology: The gonadal and hypophyseal hormones. <em>Recent Prog Horm Res</em> <strong>8:</strong> 379-418</a></p>
  • <p><a name="_ENREF_21">Juul A, Almstrup K, Andersson AM, Jensen TK, Jorgensen N, Main KM, Rajpert-De Meyts E, Toppari J, Skakkebaek NE (2014) Possible fetal determinants of male infertility. <em>Nat Rev Endocrinol</em> <strong>10:</strong> 553-562</a></p>
  • <p><a name="_ENREF_22">Kita DH, Meyer KB, Venturelli AC, Adams R, Machado DL, Morais RN, Swan SH, Gennings C, Martino-Andrade AJ (2016) Manipulation of pre and postnatal androgen environments and anogenital distance in rats. <em>Toxicology</em> <strong>368-369:</strong> 152-161</a></p>
  • <p><a name="_ENREF_23">Laier P, Metzdorff SB, Borch J, Hagen ML, Hass U, Christiansen S, Axelstad M, Kledal T, Dalgaard M, McKinnell C, Brokken LJ, Vinggaard AM (2006) Mechanisms of action underlying the antiandrogenic effects of the fungicide prochloraz. <em>Toxicol Appl Pharmacol</em> <strong>213:</strong> 2</a></p>
  • <p><a name="_ENREF_24">Li M, Qiu L, Zhang Y, Hua Y, Tu S, He Y, Wen S, Wang Q, Wei G (2013) Dose-related effect by maternal exposure to di-(2-ethylhexyl) phthalate plasticizer on inducing hypospadiac male rats. <em>Environ Toxicol Pharmacol</em> <strong>35:</strong> 55-60</a></p>
  • <p><a name="_ENREF_25">Lin H, Lian QQ, Hu GX, Jin Y, Zhang Y, Hardy DO, Chen GR, Lu ZQ, Sottas CM, Hardy MP, Ge RS (2009) In utero and lactational exposures to diethylhexyl-phthalate affect two populations of Leydig cells in male Long-Evans rats. <em>Biol Reprod</em> <strong>80:</strong> 882-888</a></p>
  • <p><a name="_ENREF_26">Loeffler IK, Peterson RE (1999) Interactive effects of TCDD and p,p&#39;-DDE on male reproductive tract development in in utero and lactationally exposed rats. <em>Toxicol Appl Pharmacol</em> <strong>154:</strong> 28-39</a></p>
  • <p><a name="_ENREF_27">MacLeod DJ, Sharpe RM, Welsh M, Fisken M, Scott HM, Hutchison GR, Drake AJ, van den Driesche S (2010) Androgen action in the masculinization programming window and development of male reproductive organs. <em>Int J Androl</em> <strong>33:</strong> 279-287</a></p>
  • <p><a name="_ENREF_28">Matsuura I, Saitoh T, Ashina M, Wako Y, Iwata H, Toyota N, Ishizuka Y, Namiki M, Hoshino N, Tsuchitani M (2005) Evaluation of a two-generation reproduction toxicity study adding endpoints to detect endocrine disrupting activity using vinclozolin. <em>J Toxicol Sci</em> <strong>30 Spec No:</strong> 163-168</a></p>
  • <p><a name="_ENREF_29">McIntyre BS, Barlow NJ, Foster PM (2001) Androgen-mediated development in male rat offspring exposed to flutamide in utero: permanence and correlation of early postnatal changes in anogenital distance and nipple retention with malformations in androgen-dependent tissues. <em>Toxicol Sci</em> <strong>62:</strong> 236-249</a></p>
  • <p><a name="_ENREF_30">McIntyre BS, Barlow NJ, Sar M, Wallace DG, Foster PM (2002) Effects of in utero linuron exposure on rat Wolffian duct development. <em>Reprod Toxicol</em> <strong>16:</strong> 131-139</a></p>
  • <p><a name="_ENREF_31">Melching-Kollmuss S, Fussell KC, Schneider S, Buesen R, Groeters S, Strauss V, van Ravenzwaay B (2017) Comparing effect levels of regulatory studies with endpoints derived in targeted anti-androgenic studies: example prochloraz. <em>Arch Toxicol</em> <strong>91:</strong> 143-162</a></p>
  • <p><a name="_ENREF_32">Moore RW, Rudy TA, Lin TM, Ko K, Peterson RE (2001) Abnormalities of sexual development in male rats with in utero and lactational exposure to the antiandrogenic plasticizer Di(2-ethylhexyl) phthalate. <em>Environ Health Perspect</em> <strong>109:</strong> 229-237</a></p>
  • <p><a name="_ENREF_33">Mylchreest E, Sar M, Cattley RC, Foster PM (1999) Disruption of androgen-regulated male reproductive development by di(n-butyl) phthalate during late gestation in rats is different from flutamide. <em>Toxicol Appl Pharmacol</em> <strong>156:</strong> 81-95</a></p>
  • <p><a name="_ENREF_34">Nagao T, Ohta R, Marumo H, Shindo T, Yoshimura S, Ono H (2000) Effect of butyl benzyl phthalate in Sprague-Dawley rats after gavage administration: a two-generation reproductive study. <em>Reprod Toxicol</em> <strong>14:</strong> 513-532</a></p>
  • <p><a name="_ENREF_35">Nardelli TC, Albert O, Lalancette C, Culty M, Hales BF, Robaire B (2017) In utero and lactational exposure study in rats to identify replacements for di(2-ethylhexyl) phthalate. <em>Sci Rep</em> <strong>7:</strong> 3862</a></p>
  • <p><a name="_ENREF_36">Noriega NC, Ostby J, Lambright C, Wilson VS, Gray LE, Jr. (2005) Late gestational exposure to the fungicide prochloraz delays the onset of parturition and causes reproductive malformations in male but not female rat offspring. <em>Biol Reprod</em> <strong>72:</strong> 1324-1335</a></p>
  • <p><a name="_ENREF_37">OECD. (2013) Guidance document in support of the test guideline on the extended one generation reproductive toxicity study No. 151.</a></p>
  • <p><a name="_ENREF_38">Ostby J, Kelce WR, Lambright C, Wolf CJ, Mann P, Gray CLJ (1999) The fungicide procymidone alters sexual differentiation in the male rat by acting as an androgen-receptor antagonist in vivo and in vitro. <em>Toxicol Ind Health</em> <strong>15:</strong> 80-93</a></p>
  • <p><a name="_ENREF_39">Saillenfait AM, Gallissot F, Sabat&eacute; JP (2009a) Differential developmental toxicities of di-n-hexyl phthalate and dicyclohexyl phthalate administered orally to rats. <em>J Appl Toxicol</em> <strong>29:</strong> 510-521</a></p>
  • <p><a name="_ENREF_40">Saillenfait AM, Roudot AC, Gallissot F, Sabat&eacute; JP (2011) Prenatal developmental toxicity studies on di-n-heptyl and di-n-octyl phthalates in Sprague-Dawley rats. <em>Reprod Toxicol</em> <strong>32:</strong> 268-276</a></p>
  • <p><a name="_ENREF_41">Saillenfait AM, Sabat&eacute; JP, Gallissot F (2009b) Effects of in utero exposure to di-n-hexyl phthalate on the reproductive development of the male rat. <em>Reprod Toxicol</em> <strong>28:</strong> 468-476</a></p>
  • <p><a name="_ENREF_42">Salazar-Martinez E, Romano-Riquer P, Yanez-Marquez E, Longnecker MP, Hernandez-Avila M (2004) Anogenital distance in human male and female newborns: a descriptive, cross-sectional study. <em>Environ Health</em> <strong>3:</strong> 8</a></p>
  • <p><a name="_ENREF_43">Schneider S, Kaufmann W, Strauss V, van Ravenzwaay B (2011) Vinclozolin: a feasibility and sensitivity study of the ILSI-HESI F1-extended one-generation rat reproduction protocol. <em>Regulatory Toxicology and Pharmacology</em> <strong>59:</strong> 91-100</a></p>
  • <p><a name="_ENREF_44">Schwartz CL, Christiansen S, Vinggaard AM, Axelstad M, Hass U, Svingen T (2019) Anogenital distance as a toxicological or clinical marker for fetal androgen action and risk for reproductive disorders. <em>Arch Toxicol</em> <strong>93:</strong> 253-272</a></p>
  • <p><a name="_ENREF_45">Scott HM, Hutchison GR, Mahood IK, Hallmark N, Welsh M, De Gendt K, Verhoeven H, O&#39;Shaughnessy P, Sharpe RM (2007) Role of androgens in fetal testis development and dysgenesis. <em>Endocrinology</em> <strong>148:</strong> 2027-2036</a></p>
  • <p><a name="_ENREF_46">Skakkebaek NE, Rajpert-De Meyts E, Main KM (2001) Testicular dysgenesis syndrome: an increasingly common developmental disorder with environmental aspects. <em>Hum Reprod</em> <strong>16:</strong> 972-978</a></p>
  • <p><a name="_ENREF_47">Taxvig C, Vinggaard AM, Hass U, Axelstad M, Metzdorff S, Nellemann C (2008) Endocrine-disrupting properties in vivo of widely used azole fungicides. <em>Int J Androl</em> <strong>31:</strong> 170-177</a></p>
  • <p><a name="_ENREF_48">Turner KJ, Barlow NJ, Struve MF, Wallace DG, Gaido KW, Dorman DC, Foster PM (2002) Effects of in utero exposure to the organophosphate insecticide fenitrothion on androgen-dependent reproductive development in the Crl:CD(SD)BR rat. <em>Toxicol Sci</em> <strong>68:</strong> 174-183</a></p>
  • <p><a name="_ENREF_49">Tyl RW, Myers CB, Marr MC, Fail PA, Seely JC, Brine DR, Barter RA, Butala JH (2004) Reproductive toxicity evaluation of dietary butyl benzyl phthalate (BBP) in rats. <em>Reprod Toxicol</em> <strong>18:</strong> 241-264</a></p>
  • <p><a name="_ENREF_50">Van den Driesche S, Kolovos P, Platts S, Drake AJ, Sharpe RM (2012) Inter-relationship between testicular dysgenesis and Leydig cell function in the masculinization programming window in the rat. <em>PloS one</em> <strong>7:</strong> e30111</a></p>
  • <p><a name="_ENREF_51">Welsh M, Saunders PT, Fisken M, Scott HM, Hutchison GR, Smith LB, Sharpe RM (2008) Identification in rats of a programming window for reproductive tract masculinization, disruption of which leads to hypospadias and cryptorchidism. <em>J Clin Invest</em> <strong>118:</strong> 1479-1490</a></p>
  • <p><a name="_ENREF_52">Welsh M, Saunders PT, Sharpe RM (2007) The critical time window for androgen-dependent development of the Wolffian duct in the rat. <em>Endocrinology</em> <strong>148:</strong> 3185-3195</a></p>
  • <p><a name="_ENREF_53">Wolf CJ, LeBlanc GA, Gray LE, Jr. (2004) Interactive effects of vinclozolin and testosterone propionate on pregnancy and sexual differentiation of the male and female SD rat. <em>Toxicol Sci</em> <strong>78:</strong> 135-143</a></p>
  • <p><a name="_ENREF_54">Wolf CJJ, Lambright C, Mann P, Price M, Cooper RL, Ostby J, Gray CLJ (1999) Administration of potentially antiandrogenic pesticides (procymidone, linuron, iprodione, chlozolinate, p,p&#39;-DDE, and ketoconazole) and toxic substances (dibutyl- and diethylhexyl phthalate, PCB 169, and ethane dimethane sulphonate) during sexual differentiation produces diverse profiles of reproductive malformations in the male rat. <em>Toxicol Ind Health</em> <strong>15:</strong> 94-118</a></p>
  • <p><a name="_ENREF_55">Zhang L, Dong L, Ding S, Qiao P, Wang C, Zhang M, Zhang L, Du Q, Li Y, Tang N, Chang B (2014) Effects of n-butylparaben on steroidogenesis and spermatogenesis through changed E₂ levels in male rat offspring. <em>Environ Toxicol Pharmacol</em> <strong>37:</strong> 705-717</a></p>
  • <br>
  • <!-- end event text -->
  • </div>
  • <h2>Appendix 2</h2>
  • <h2>List of Key Event Relationships in the AOP</h2>
  • <!-- Evidence for relationship links section, this lists the relationships and then supports them -->
  • <div id="evidence_supporting_links">
  • <hr>
  • <h3>List of Adjacent Key Event Relationships</h3>
  • <div>
  • <h4><a href="/relationships/2125">Relationship: 2125: Reduction, Testosterone synthesis in Leydig cells leads to reduction, testosterone levels </a></h4>
  • <div id="evidence_supporting_links">
  • <h3>List of Adjacent Key Event Relationships</h3>
  • <div>
  • <h4><a href="/relationships/2125">Relationship: 2125: Reduction, Testosterone synthesis in Leydig cells leads to Decrease, testosterone levels</a></h4>
  • <h4>AOPs Referencing Relationship</h4>
  • <div class="panel panel-default">
  • <table class="table table-bordered table-striped">
  • <thead>
  • <div class="table-responsive">
  • <table class="table table-bordered table-fullwidth">
  • <thead class="thead-light">
  • <tr>
  • <th scope="col">AOP Name</th>
  • <th scope="col">Adjacency</th>
  • <th scope="col">Weight of Evidence</th>
  • <th scope="col">Quantitative Understanding</th>
  • </tr>
  • </thead>
  • <tbody class="tbody-striped">
  • <tr>
  • <th>AOP Name</th>
  • <th>Adjacency</th>
  • <th>Weight of Evidence</th>
  • <th>Quantitative Understanding</th>
  • <td><a href="/aops/307">Decreased testosterone synthesis leading to short anogenital distance (AGD) in male (mammalian) offspring</a></td>
  • <td>adjacent</td>
  • <td>High</td>
  • <td>Moderate</td>
  • </tr>
  • </thead>
  • <tbody>
  • <tr>
  • <th><a href="/aops/307">Decreased testosterone synthesis leading to short anogenital distance (AGD) in male (mammalian) offspring</a></th>
  • <th>adjacent</th>
  • <th>High </th>
  • <th>Moderate</th>
  • </tr>
  • </tbody>
  • </table>
  • </div>
  • <!-- if nothing shows up in any of these fields, then evidence supporting this KER will not be displayed -->
  • <!--<!% unless aop_rel.relationship.relationship_taxons.blank? %>-->
  • <!--<!%= render 'snapshot_taxons', taxons: aop_rel.relationship.relationship_taxons %>-->
  • <!--<!% unless aop_rel.relationship.taxon_evidence.blank? %>-->
  • <!--<h3>Domain of Applicability</h3>-->
  • <!--<!%== aop_rel.relationship.taxon_evidence %>-->
  • <!--<!% end %>-->
  • <!--<!% end %>-->
  • </tbody>
  • </table>
  • </div>
  • </div>
  • <br>
  • <div>
  • <h4><a href="/relationships/2126">Relationship: 2126: reduction, testosterone levels leads to Decrease, DHT level</a></h4>
  • <div>
  • <h4><a href="/relationships/2126">Relationship: 2126: Decrease, testosterone levels leads to Decrease, DHT level</a></h4>
  • <h4>AOPs Referencing Relationship</h4>
  • <div class="panel panel-default">
  • <table class="table table-bordered table-striped">
  • <thead>
  • <div class="table-responsive">
  • <table class="table table-bordered table-fullwidth">
  • <thead class="thead-light">
  • <tr>
  • <th scope="col">AOP Name</th>
  • <th scope="col">Adjacency</th>
  • <th scope="col">Weight of Evidence</th>
  • <th scope="col">Quantitative Understanding</th>
  • </tr>
  • </thead>
  • <tbody class="tbody-striped">
  • <tr>
  • <th>AOP Name</th>
  • <th>Adjacency</th>
  • <th>Weight of Evidence</th>
  • <th>Quantitative Understanding</th>
  • <td><a href="/aops/307">Decreased testosterone synthesis leading to short anogenital distance (AGD) in male (mammalian) offspring</a></td>
  • <td>adjacent</td>
  • <td>Moderate</td>
  • <td>Low</td>
  • </tr>
  • </thead>
  • <tbody>
  • <tr>
  • <th><a href="/aops/307">Decreased testosterone synthesis leading to short anogenital distance (AGD) in male (mammalian) offspring</a></th>
  • <th>adjacent</th>
  • <th>Moderate </th>
  • <th>Low</th>
  • </tr>
  • </tbody>
  • </table>
  • </div>
  • <!-- if nothing shows up in any of these fields, then evidence supporting this KER will not be displayed -->
  • </tbody>
  • </table>
  • </div>
  • <h4>Evidence Supporting Applicability of this Relationship</h4>
  • <div>
  • <strong>Taxonomic Applicability</strong>
  • <div class="table-responsive">
  • <table class="table table-bordered table-fullwidth">
  • <thead class="thead-light">
  • <tr>
  • <th scope="col">Term</th>
  • <th scope="col">Scientific Term</th>
  • <th scope="col">Evidence</th>
  • <th scope="col">Links</th>
  • </tr>
  • </thead>
  • <tbody class="tbody-striped">
  • <tr>
  • <td>Vertebrates</td>
  • <td>Vertebrates</td>
  • <td>High</td>
  • <td><a href="http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&id=0" target="_blank">NCBI</a></td>
  • </tr>
  • </tbody>
  • </table>
  • </div>
  • </div>
  • <div>
  • <strong>Life Stage Applicability</strong>
  • <div class="table-responsive">
  • <table class="table table-bordered table-fullwidth">
  • <thead class="thead-light">
  • <tr>
  • <th scope="col">Life Stage</th>
  • <th scope="col">Evidence</th>
  • </tr>
  • </thead>
  • <tbody class="tbody-striped">
  • <tr>
  • <td>During development and at adulthood</td>
  • <td>High</td>
  • </tr>
  • </tbody>
  • </table>
  • </div>
  • </div>
  • <div>
  • <strong>Sex Applicability</strong>
  • <div class="table-responsive">
  • <table class="table table-bordered table-fullwidth">
  • <thead class="thead-light">
  • <tr>
  • <th scope="col">Sex</th>
  • <th scope="col">Evidence</th>
  • </tr>
  • </thead>
  • <tbody class="tbody-striped">
  • <tr>
  • <td>Mixed</td>
  • <td>High</td>
  • </tr>
  • </tbody>
  • </table>
  • </div>
  • </div>
  • <p style="text-align:justify"><span style="font-size:11pt"><span style="font-size:12.0pt">T and DHT are androgens present in all vertebrates. They play a role in development and fertility in both males and females <span style="color:black">(Ogino et al., 2011; Prizant et al., 2014; Rey, 2021; Swerdloff et al., 2017)</span>. All tissues expressing 5&alpha;-reductase are applicable to this KER <span style="color:black">(Azzouni et al., 2012)</span>.</span></span></p>
  • <!--<!% unless aop_rel.relationship.relationship_taxons.blank? %>-->
  • <!--<!%= render 'snapshot_taxons', taxons: aop_rel.relationship.relationship_taxons %>-->
  • <!--<!% unless aop_rel.relationship.taxon_evidence.blank? %>-->
  • <!--<h3>Domain of Applicability</h3>-->
  • <!--<!%== aop_rel.relationship.taxon_evidence %>-->
  • <!--<!% end %>-->
  • <!--<!% end %>-->
  • <h4>Key Event Relationship Description</h4>
  • <p style="text-align:justify"><span style="font-size:11pt"><span style="font-size:12.0pt">Testosterone (T) and dihydrotestosterone (DHT) are androgens that are involved in numerous developmental and functional processes across animal taxa. In vertebrates, testosterone can be aromatized into estrogens catalyzed by the enzyme aromatase (CYP19) or be metabolized to DHT by the enzyme 5&alpha;-reductase <span style="color:black">(Azzouni et al., 2012; Naamneh Elzenaty et al., 2022; Swerdloff et al., 2017)</span>. Both T and DHT binds to the androgen receptor (AR), but with different affinities. DHT has a higher affinity for the AR than T. DHT also has a longer half-life and slower dissociation rate than T and cannot be aromatized into estrogens <span style="color:black"><span style="font-size:11.0pt">(Gerald &amp; Raj, 2022; Naamneh Elzenaty et al., 2022; Swerdloff et al., 2017)</span></span>. </span></span></p>
  • <p style="text-align:justify"><span style="font-size:11pt"><span style="font-size:12.0pt">During mammalian development, T is primarily produced by the fetal testes and is needed for differentiation of the Wolffian ducts, the epididymis, and the ejaculatory duct. In pubertal and adult mammals, T is produced by the testes, the ovaries (although at a much lower level), and the adrenal glands <span style="color:black">(Ogino et al., 2011; Rey, 2021)</span>. In peripheral tissues (i.e. relative to the testes), DHT is converted from T by 5&alpha;-reductase to induce the differentiation of the urogenital sinus and genital tubercle to form the prostate, penis, scrotum and urethra <span style="color:black">(Swerdloff et al., 2017)</span>. Both androgens are essential for masculinization, sexual development, and fertility. </span></span></p>
  • <h4>Evidence Supporting this KER</h4>
  • <strong>Biological Plausibility</strong>
  • <p style="text-align:justify"><span style="font-size:11pt"><span style="font-size:12.0pt">The biological plausibility for this KER is considered high</span></span></p>
  • <p style="text-align:justify"><span style="font-size:11pt"><span style="font-size:12.0pt">It is well established that DHT is synthesized from circulating T. 5&alpha;-reductase is the enzyme responsible for the conversion of T into DHT. Multiple isoforms of this enzyme are expressed in different tissues. Expression of 5&alpha;-reductase in peripheral tissues dictates where DHT will be formed from circulating T <span style="color:black">(Azzouni et al., 2012; Swerdloff et al., 2017)</span>.</span></span></p>
  • <p style="text-align:justify"><span style="font-size:11pt"><span style="font-size:12.0pt">Since T can be converted to DHT, it stands to reason that a lack of T can lead to a lack of DHT. Therefore, if there is a marked reduction in the availability of T, it can be surmised that DHT levels are consequently affected. However, to what extent T needs to be diminished in tissues before there is a functionally relevant decrease in DHT is largely unknown. In addition, the quantitative relationship between substrate (T) availability and levels of synthesized DHT is not well characterized in tissues <em>in vivo</em>. Notably, DHT can be produced via other steroid intermediates through the &lsquo;backdoor pathway&rsquo; in mammals such as marsupials and humans (Renfree &amp; Shaw 2023). </span></span></p>
  • </div>
  • <strong>Empirical Evidence</strong>
  • <p style="text-align:justify"><span style="font-size:11pt"><span style="font-size:12.0pt">The empirical evidence for this KER is considered moderate</span></span></p>
  • <p style="text-align:justify"><span style="font-size:11pt"><span style="font-size:12.0pt">As per Table 1, empirical data exists for effects on both T and DHT following chemical exposures, but it is not always possible to deduce if the reduction in DHT is a direct consequence of reduced T or because of other mechanisms such as e.g. interference with 5&alpha;-reductase. However, some studies do include 5&alpha;-reductase mRNA expression or measure the ratio of T/DHT which if unchanged, indicates that the decrease would most likely be due to decrease in T availability.</span></span></p>
  • <p style="text-align:justify"><span style="font-size:11pt"><strong><span style="font-size:12.0pt">Table 1</span></strong></span></p>
  • <table align="left" cellspacing="0" class="MsoTableGrid" style="border-collapse:collapse; border:none; margin-left:9px; margin-right:9px; width:709px">
  • <tbody>
  • <tr>
  • <td style="border-bottom:3px solid black; border-left:3px solid black; border-right:3px solid black; border-top:3px solid black; height:43px; width:101px">
  • <p><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif"><strong><span style="font-size:12.0pt"><span style="color:#212529">Compound</span></span></strong></span></span></p>
  • </td>
  • <td style="border-bottom:3px solid black; border-left:none; border-right:3px solid black; border-top:3px solid black; height:43px; width:64px">
  • <p><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif"><strong><span style="font-size:12.0pt"><span style="color:#212529">Species</span></span></strong></span></span></p>
  • </td>
  • <td style="border-bottom:3px solid black; border-left:none; border-right:3px solid black; border-top:3px solid black; height:43px; width:98px">
  • <p><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif"><strong><span style="font-size:12.0pt"><span style="color:#212529">Effect level</span></span></strong></span></span></p>
  • </td>
  • <td style="border-bottom:3px solid black; border-left:none; border-right:3px solid black; border-top:3px solid black; height:43px; width:155px">
  • <p><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif"><strong><span style="font-size:12.0pt"><span style="color:#212529">KE: testosterone, decrease</span></span></strong></span></span></p>
  • </td>
  • <td style="border-bottom:3px solid black; border-left:none; border-right:3px solid black; border-top:3px solid black; height:43px; width:74px">
  • <p><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif"><strong><span style="font-size:12.0pt"><span style="color:#212529">KE: DHT, decrease</span></span></strong></span></span></p>
  • </td>
  • <td style="border-bottom:3px solid black; border-left:none; border-right:3px solid black; border-top:3px solid black; height:43px; width:129px">
  • <p><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif"><strong><span style="font-size:12.0pt"><span style="color:#212529">Details</span></span></strong></span></span></p>
  • </td>
  • <td style="border-bottom:3px solid black; border-left:none; border-right:3px solid black; border-top:3px solid black; height:43px; width:88px">
  • <p><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif"><strong><span style="font-size:12.0pt"><span style="color:#212529">References</span></span></strong></span></span></p>
  • </td>
  • </tr>
  • <tr>
  • <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; height:20px; vertical-align:top; width:101px">
  • <p><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif">DEHP</span></span></p>
  • </td>
  • <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; height:20px; vertical-align:top; width:64px">
  • <p><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif"><span style="font-size:10.0pt">rat</span></span></span></p>
  • </td>
  • <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; height:20px; vertical-align:top; width:98px">
  • <p><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif"><span style="font-size:10.0pt">LOEL = 117 mg/kg/day</span></span></span></p>
  • </td>
  • <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; height:20px; vertical-align:top; width:155px">
  • <p><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif"><span style="font-size:10.0pt">Significant decrease day 1, 2, 3:</span></span></span></p>
  • <p><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif"><span style="font-size:10.0pt">from 4 to 2</span> <span style="font-size:10.0pt">ng/testis</span></span></span></p>
  • </td>
  • <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; height:20px; vertical-align:top; width:74px">
  • <p><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif"><span style="font-size:10.0pt">Significant decrease day 1</span></span></span></p>
  • <p><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif"><span style="font-size:10.0pt">from 2.5 to 1 ng/testis</span></span></span></p>
  • </td>
  • <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; height:20px; vertical-align:top; width:129px">
  • <p><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif"><span style="font-size:10.0pt">In utero exposure, fetal testes ex vivo from GD20 rats. </span></span></span></p>
  • </td>
  • <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; height:20px; vertical-align:top; width:88px">
  • <p><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif"><span style="font-size:10.0pt"><span style="color:black">(Culty et al., 2008)</span></span></span></span></p>
  • </td>
  • </tr>
  • <tr>
  • <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; height:20px; vertical-align:top; width:101px">
  • <p><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif"><span style="font-size:12.0pt">Ibuprofen</span></span></span></p>
  • </td>
  • <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; height:20px; vertical-align:top; width:64px">
  • <p><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif"><span style="font-size:10.0pt">human</span></span></span></p>
  • </td>
  • <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; height:20px; vertical-align:top; width:98px">
  • <p><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif"><span style="font-size:10.0pt">One concentration tested: 10<sup>-5</sup>M</span></span></span></p>
  • </td>
  • <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; height:20px; vertical-align:top; width:155px">
  • <p><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif"><span style="font-size:10.0pt">48h: significant decrease</span></span></span></p>
  • <p><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif"><span style="font-size:10.0pt">-36.8%</span></span></span></p>
  • </td>
  • <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; height:20px; vertical-align:top; width:74px">
  • <p><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif"><span style="font-size:10.0pt">48h: significant decrease</span></span></span></p>
  • <p><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif"><span style="font-size:10.0pt">-70.2%</span></span></span></p>
  • </td>
  • <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; height:20px; vertical-align:top; width:129px">
  • <p><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif"><span style="font-size:10.0pt">Human fetal testes explants, measurements were done using the exposure media.</span></span></span></p>
  • <p><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif"><span style="font-size:10.0pt">No effect on SRD5A3 mRNA levels (5&alpha;-R3)</span></span></span></p>
  • </td>
  • <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; height:20px; vertical-align:top; width:88px">
  • <p><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif"><span style="font-size:10.0pt"><span style="color:black">(Ben Maamar et al., 2017)</span></span></span></span></p>
  • </td>
  • </tr>
  • <tr>
  • <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; height:20px; vertical-align:top; width:101px">
  • <p><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif"><span style="font-size:12.0pt">Rosiglitazone</span></span></span></p>
  • </td>
  • <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; height:20px; vertical-align:top; width:64px">
  • <p><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif"><span style="font-size:10.0pt">human</span></span></span></p>
  • </td>
  • <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; height:20px; vertical-align:top; width:98px">
  • <p><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif"><span style="font-size:10.0pt">One concentration tested: 8mg/day </span></span></span></p>
  • </td>
  • <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; height:20px; vertical-align:top; width:155px">
  • <p><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif"><span style="font-size:10.0pt">significant decrease of production rates</span></span></span></p>
  • <p><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif"><span style="font-size:10.0pt">318</span><em><span style="font-size:10.0pt"><span style="font-family:&quot;Cambria Math&quot;,serif">&plusmn;</span></span></em><span style="font-size:11.0pt"><span style="font-family:&quot;Calibri&quot;,sans-serif"><img src="data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAAoAAAARCAIAAABrQaqyAAAAAXNSR0IArs4c6QAAAAlwSFlzAAAOxAAADsQBlSsOGwAAAEpJREFUKFNj/P//PwNuwIRHDihFRent6Yzp21Fso6LhWHzx//+2NKyes5pwGxgkwGCBA6DCtG3IAv9p6jRG/FECdBo+lxPQTcDlAFUsM+fb7MHLAAAAAElFTkSuQmCC" style="height:17px; width:10px" /></span></span><span style="font-size:10.0pt">62 </span><span style="font-size:10.0pt">&micro;</span><span style="font-size:10.0pt">g/h to 272</span><em><span style="font-size:10.0pt"><span style="font-family:&quot;Cambria Math&quot;,serif">&plusmn;7</span></span></em><span style="font-size:11.0pt"><span style="font-family:&quot;Calibri&quot;,sans-serif"><img src="data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAABEAAAARCAIAAAC0D9CtAAAAAXNSR0IArs4c6QAAAAlwSFlzAAAOxAAADsQBlSsOGwAAAJ5JREFUOE9j/P//PwOJgIlE9SDlA6Jnezpj+nY0xwLFUABQARFuS9sGDCcwuD3BKi3Ak4EBxgfR29IYEAqQJSDsbWlWE24DaSLsgTr2zsSWK2HeKiAe2HRsAGImHCC5gUi3AX2CcDZxbtveXcAwoRToezAgRg/QJ7OsoF4hUs+drauOpdXkg30PBozkpVH0mIZGu/XEOzjSL5n2kJwbACTonjvoSWgWAAAAAElFTkSuQmCC" style="height:17px; width:17px" /></span></span><span style="font-size:10.0pt">2 </span><span style="font-size:10.0pt">&micro;</span><span style="font-size:10.0pt">g/h &nbsp;</span></span></span></p>
  • </td>
  • <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; height:20px; vertical-align:top; width:74px">
  • <p><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif"><span style="font-size:10.0pt">significant decrease of production rates</span></span></span></p>
  • <p><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif"><span style="font-size:10.0pt">21</span><em><span style="font-size:10.0pt"><span style="font-family:&quot;Cambria Math&quot;,serif">&plusmn;</span></span></em><span style="font-size:11.0pt"><span style="font-family:&quot;Calibri&quot;,sans-serif"><img src="data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAAoAAAARCAIAAABrQaqyAAAAAXNSR0IArs4c6QAAAAlwSFlzAAAOxAAADsQBlSsOGwAAAEpJREFUKFNj/P//PwNuwIRHDihFRent6Yzp21Fso6LhWHzx//+2NKyes5pwGxgkwGCBA6DCtG3IAv9p6jRG/FECdBo+lxPQTcDlAFUsM+fb7MHLAAAAAElFTkSuQmCC" style="height:17px; width:10px" /></span></span><span style="font-size:10.0pt">6 </span><span style="font-size:10.0pt">&micro;</span><span style="font-size:10.0pt">g/h to 17</span><em><span style="font-size:10.0pt"><span style="font-family:&quot;Cambria Math&quot;,serif">&plusmn;</span></span></em><span style="font-size:11.0pt"><span style="font-family:&quot;Calibri&quot;,sans-serif"><img src="data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAAoAAAARCAIAAABrQaqyAAAAAXNSR0IArs4c6QAAAAlwSFlzAAAOxAAADsQBlSsOGwAAAEpJREFUKFNj/P//PwNuwIRHDihFRent6Yzp21Fso6LhWHzx//+2NKyes5pwGxgkwGCBA6DCtG3IAv9p6jRG/FECdBo+lxPQTcDlAFUsM+fb7MHLAAAAAElFTkSuQmCC" style="height:17px; width:10px" /></span></span><span style="font-size:10.0pt">5 </span><span style="font-size:10.0pt">&micro;</span><span style="font-size:10.0pt">g/h</span></span></span></p>
  • </td>
  • <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; height:20px; vertical-align:top; width:129px">
  • <p><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif"><span style="font-size:10.0pt">Serum levels after 7 days of treatment in healthy men: &ldquo;Calculated </span>&nbsp;<span style="font-size:10.0pt">from the product of the known infusion rate</span></span></span></p>
  • <p><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif"><span style="font-size:10.0pt">(Rt) and the ratio of tracer infusate enrichment (Et) to tracer dilution in</span></span></span></p>
  • <p><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif"><span style="font-size:10.0pt">the plasma&rdquo;</span></span></span></p>
  • <p><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif"><span style="font-size:10.0pt">Ratio T/DHT remained unchanged.</span></span></span></p>
  • </td>
  • <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; height:20px; vertical-align:top; width:88px">
  • <p><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif"><span style="font-size:10.0pt"><span style="color:black">(Vierhapper et al., 2003)</span></span></span></span></p>
  • </td>
  • </tr>
  • <tr>
  • <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; height:20px; vertical-align:top; width:101px">
  • <p><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif"><span style="font-size:12.0pt">PTU</span></span></span></p>
  • </td>
  • <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; height:20px; vertical-align:top; width:64px">
  • <p><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif"><span style="font-size:10.0pt">rats</span></span></span></p>
  • </td>
  • <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; height:20px; vertical-align:top; width:98px">
  • <p><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif"><span style="font-size:10.0pt">One concentration tested: 240 mg/kg/day</span></span></span></p>
  • </td>
  • <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; height:20px; vertical-align:top; width:155px">
  • <p><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif"><span style="font-size:10.0pt">significant decrease</span></span></span></p>
  • <p><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif"><span style="font-size:10.0pt">&tilde;</span><span style="font-size:10.0pt">2ng/ml to 0.15ng/ml</span></span></span></p>
  • </td>
  • <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; height:20px; vertical-align:top; width:74px">
  • <p><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif"><span style="font-size:10.0pt">significant decrease</span></span></span></p>
  • <p><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif"><span style="font-size:10.0pt">&tilde;</span><span style="font-size:10.0pt">0.5ng/ml to 0.17ng/ml </span></span></span></p>
  • </td>
  • <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; height:20px; vertical-align:top; width:129px">
  • <p><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif"><span style="font-size:10.0pt">Oral exposure of 14day old rats treated until day 51. Serum testosterone and DHT measured</span></span></span></p>
  • </td>
  • <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; height:20px; vertical-align:top; width:88px">
  • <p><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif"><span style="font-size:10.0pt"><span style="color:black">(Marty et al., 2001)(</span></span></span></span></p>
  • </td>
  • </tr>
  • <tr>
  • <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; height:20px; vertical-align:top; width:101px">
  • <p><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif"><span style="font-size:12.0pt">Dibutyltin</span></span></span></p>
  • </td>
  • <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; height:20px; vertical-align:top; width:64px">
  • <p><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif"><span style="font-size:10.0pt">Carp fish</span></span></span></p>
  • </td>
  • <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; height:20px; vertical-align:top; width:98px">
  • <p><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif"><span style="font-size:10.0pt">One concentration tested: 100</span><span style="font-size:10.0pt">&micro;</span><span style="font-size:10.0pt">M</span></span></span></p>
  • </td>
  • <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; height:20px; vertical-align:top; width:155px">
  • <p><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif"><span style="font-size:10.0pt">significant decrease</span></span></span></p>
  • <p><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif"><span style="font-size:10.0pt">-16%</span></span></span></p>
  • <p>&nbsp;</p>
  • </td>
  • <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; height:20px; vertical-align:top; width:74px">
  • <p><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif"><span style="font-size:10.0pt">significant decrease</span></span></span></p>
  • <p><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif"><span style="font-size:10.0pt">-24%</span></span></span></p>
  • </td>
  • <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; height:20px; vertical-align:top; width:129px">
  • <p><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif"><span style="font-size:10.0pt">Gonad microsomes. Dibultyltin <strong>inhibited 5</strong></span><strong><span style="font-size:10.0pt">&alpha;</span></strong><strong><span style="font-size:10.0pt">-reductase</span></strong><span style="font-size:10.0pt">, whichdecreases possibility that this is solely due to decrease of testosterone</span></span></span></p>
  • </td>
  • <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; height:20px; vertical-align:top; width:88px">
  • <p><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif">(Thibaut &amp; Porte, 2004)</span></span></p>
  • </td>
  • </tr>
  • <tr>
  • <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; height:20px; vertical-align:top; width:101px">
  • <p><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif"><span style="font-size:12.0pt">TCDD</span></span></span></p>
  • </td>
  • <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; height:20px; vertical-align:top; width:64px">
  • <p><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif"><span style="font-size:10.0pt">rats</span></span></span></p>
  • </td>
  • <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; height:20px; vertical-align:top; width:98px">
  • <p><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif"><span style="font-size:10.0pt">Effects observed at 15</span><span style="font-size:10.0pt">&micro;</span><span style="font-size:10.0pt">g/kg</span></span></span></p>
  • </td>
  • <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; height:20px; vertical-align:top; width:155px">
  • <p><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif"><span style="font-size:10.0pt">significant decrease</span></span></span></p>
  • <p><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif"><span style="font-size:10.0pt">-90%</span></span></span></p>
  • </td>
  • <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; height:20px; vertical-align:top; width:74px">
  • <p><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif"><span style="font-size:10.0pt">significant decrease</span></span></span></p>
  • <p><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif"><span style="font-size:10.0pt">-75%</span></span></span></p>
  • </td>
  • <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; height:20px; vertical-align:top; width:129px">
  • <p><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif"><span style="font-size:10.0pt">Oral exposure of 66-68 day old rats. Serum or plasma measurements. &nbsp;Dose dependent decrease of both was observed. Ratio T/DHT indicates effect is due to reduced testosterone.</span></span></span></p>
  • </td>
  • <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; height:20px; vertical-align:top; width:88px">
  • <p><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif"><span style="font-size:10.0pt"><span style="color:black">(Moore et al., 1985)</span></span></span></span></p>
  • </td>
  • </tr>
  • </tbody>
  • </table>
  • <p>&nbsp;</p>
  • <p>&nbsp;</p>
  • <p><span style="font-size:11pt"><strong><em><span style="font-size:12.0pt">Dose concordance:</span></em></strong></span></p>
  • <p><span style="font-size:11pt"><span style="font-size:12.0pt">All the exposure data shown above indicates dose-concordance, since the same concentration tested affects both the upstream and downstream key event.</span></span></p>
  • <p><span style="font-size:11pt"><strong><em><span style="font-size:12.0pt">Other evidence</span></em></strong></span></p>
  • <p style="text-align:justify"><span style="font-size:11pt"><span style="background-color:white"><span style="font-size:12.0pt"><span style="color:black">One study focused on the condition Leydig cell hypoplasia (LCH) in one patient. This patient had mutations in the LHCGR, and when measuring the levels of testosterone and DHT before and after hCG stimulation a decrease in both levels under the normal range were observed, even with hCG stimulation<strong> </strong>(Xu et al., 2018)<strong>. </strong></span></span></span></span></p>
  • <p>&nbsp;</p>
  • <p>&nbsp;</p>
  • <p>&nbsp;</p>
  • <p>&nbsp;</p>
  • <p>&nbsp;</p>
  • <p>&nbsp;</p>
  • <p>&nbsp;</p>
  • <br>
  • <strong>Uncertainties and Inconsistencies</strong>
  • <p style="text-align:justify"><span style="font-size:11pt"><span style="font-size:12.0pt">The levels of T do not always reflect the levels of DHT. T is also converted to estradiol <span style="color:black">(Naamneh Elzenaty et al., 2022)</span>. Therefore, the decrease in T may lead to a decrease in estradiol while DHT levels remain unchanged. <strong>&nbsp;</strong></span></span></p>
  • <p style="text-align:justify"><span style="font-size:11pt"><span style="font-size:12.0pt">Several studies have shown the existence of an alternative (&lsquo;backdoor&rsquo;) pathway for DHT synthesis that is independent of T in marsupials and humans, but not in rodents <span style="color:black">(Marilyn B. Renfree et al., 1995)</span>. Instead of proceeding through the canonical pathway, progesterone or 17-OH progesterone, can be converted into</span> <span style="font-size:12.0pt">allopregnanolone and 17OH-allopregnanolone.</span> 17-OH <span style="font-size:12.0pt">allopregnanolone is then converted into androsterone leading to androstanediol that can finally be oxidized to produce DHT. Therefore, through this pathway, DHT can be synthesized without the presence of T <span style="color:black"><span style="font-size:11.0pt">(Auchus, 2004; Miller &amp; Auchus, 2019)</span>. </span></span></span></p>
  • <div>
  • <h4>Quantitative Understanding of the Linkage</h4>
  • <strong>Response-response relationship</strong>
  • <p style="text-align:justify"><span style="font-size:11pt"><span style="font-size:12.0pt">The response-response relationship is not clearly established.</span></span></p>
  • <h4><a href="/relationships/1935">Relationship: 1935: Decrease, DHT level leads to Decrease, AR activation</a></h4>
  • <strong>Time-scale</strong>
  • <p style="text-align:justify"><span style="font-size:11pt"><span style="font-size:12.0pt">Different time scales have been observed in the studies above, the shortest one found being 48h. With Ibuprofen treatment, a decrease in both testosterone and DHT was observed after 48h in human fetal explant&rsquo;s exposure media <span style="color:black">(Ben Maamar et al., 2017)</span>. However, it is not evident that this effect is direct and only due to a decrease in T.</span></span></p>
  • <h4>AOPs Referencing Relationship</h4>
  • <strong>Known Feedforward/Feedback loops influencing this KER</strong>
  • <p style="text-align:justify"><span style="font-size:11pt"><span style="font-size:12.0pt">Activity of 5&alpha;-reductase type 1 and 2: The activity of this enzyme determines how much T is converted into DHT. There are two isomers, with type 2 being the primary isomer expressed in DHT target organs. In deficiencies of this enzyme, there are studies that observe maintained DHT levels. This indicates that the type 1 enzyme can take over if needed <span style="color:black">(Azzouni et al., 2012)</span>. </span></span></p>
  • <p style="text-align:justify"><span style="font-size:11pt"><span style="font-size:12.0pt">Conversion of T to estradiol (E2): Aromatase can convert T into estrogens. The activity of this enzyme may push towards a decrease of T levels and an increase in estrogen levels without necessarily affecting DHT levels <span style="color:black">(Naamneh Elzenaty et al., 2022)</span>.</span></span></p>
  • <p style="text-align:justify"><span style="font-size:11pt"><span style="font-size:12.0pt">Hypothalamus-pituitary-gonadal (HPG) axis: Like most sex steroids, T production is controlled by the HPG axis during puberty and adulthood, but also during certain periods of development. For humans, the HPG axis is active following birth between 1-3 months in both males and females. Increase of LH and FSH are observed in infants up to 4-6months old. This stage is also known as the minipuberty <span style="color:black">(Lanciotti et al., 2018; Renault et al., 2020)</span>. Once GnRH is released from the hypothalamus, the pituitary gland secretes LH in pulses, which then stimulates the cells in the testes to produce T. A negative feedback loop can then occur, where testosterone then inhibits the release of GnRH and LH, in turn slowing down T production (Gerald &amp; Raj, 2022; Naamneh Elzenaty et al., 2022; Nef &amp; Parada, 2000).</span></span></p>
  • <h4>References</h4>
  • <p><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif">Auchus, R. J. (2004). The backdoor pathway to dihydrotestosterone. <em>Trends in Endocrinology &amp; Metabolism</em>, <em>15</em>(9), 432&ndash;438. https://doi.org/10.1016/j.tem.2004.09.004</span></span></p>
  • <p><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif">Azzouni, F., Godoy, A., Li, Y., &amp; Mohler, J. (2012). The 5 Alpha-Reductase Isozyme Family: A Review of Basic Biology and Their Role in Human Diseases. <em>Advances in Urology</em>, <em>2012</em>, 1&ndash;18. https://doi.org/10.1155/2012/530121</span></span></p>
  • <p><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif">Ben Maamar, M., Lesn&eacute;, L., Hennig, K., Desdoits-Lethimonier, C., Kilcoyne, K. R., Coiffec, I., Rolland, A. D., Chevrier, C., Kristensen, D. M., Lavou&eacute;, V., Antignac, J.-P., Le Bizec, B., Dejucq-Rainsford, N., Mitchell, R. T., Mazaud-Guittot, S., &amp; J&eacute;gou, B. (2017). Ibuprofen results in alterations of human fetal testis development. <em>Scientific Reports</em>, <em>7</em>(1), 44184. https://doi.org/10.1038/srep44184</span></span></p>
  • <p><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif">Culty, M., Thuillier, R., Li, W., Wang, Y., Martinez-Arguelles, D. B., Benjamin, C. G., Triantafilou, K. M., Zirkin, B. R., &amp; Papadopoulos, V. (2008). In Utero Exposure to Di-(2-ethylhexyl) Phthalate Exerts Both Short-Term and Long-Lasting Suppressive Effects on Testosterone Production in the Rat1. <em>Biology of Reproduction</em>, <em>78</em>(6), 1018&ndash;1028. https://doi.org/10.1095/biolreprod.107.065649</span></span></p>
  • <p><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif">Gerald, T., &amp; Raj, G. (2022). Testosterone and the Androgen Receptor. <em>Urologic Clinics of North America</em>, <em>49</em>(4), 603&ndash;614. https://doi.org/10.1016/j.ucl.2022.07.004</span></span></p>
  • <p><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif">Lanciotti, L., Cofini, M., Leonardi, A., Penta, L., &amp; Esposito, S. (2018). Up-To-Date Review About Minipuberty and Overview on Hypothalamic-Pituitary-Gonadal Axis Activation in Fetal and Neonatal Life. <em>Frontiers in Endocrinology</em>, <em>9</em>. https://doi.org/10.3389/fendo.2018.00410</span></span></p>
  • <p><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif">Marilyn B. Renfree, Jenny L. Harry, &amp; Geoffrey Shaw. (1995). The marsupial male: a role model for sexual development. <em>Philosophical Transactions of the Royal Society of London. Series B: Biological Sciences</em>, <em>350</em>(1333), 243&ndash;251. https://doi.org/10.1098/rstb.1995.0158</span></span></p>
  • <p><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif">Marty, M. S., Crissman, J. W., &amp; Carney, E. W. (2001). Evaluation of the Male Pubertal Assay&rsquo;s Ability to Detect Thyroid Inhibitors and Dopaminergic Agents. <em>Toxicological Sciences</em>, <em>60</em>(1), 63&ndash;76. https://doi.org/10.1093/toxsci/60.1.63</span></span></p>
  • <p><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif">Miller, W. L., &amp; Auchus, R. J. (2019). The &ldquo;backdoor pathway&rdquo; of androgen synthesis in human male sexual development. <em>PLOS Biology</em>, <em>17</em>(4), e3000198. https://doi.org/10.1371/journal.pbio.3000198</span></span></p>
  • <p><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif">Moore, R. W., Potter, C. L., Theobald, H. M., Robinson, J. A., &amp; Peterson, R. E. (1985). Androgenic deficiency in male rats treated with 2,3,7,8-tetrachlorodibenzo-p-dioxin. <em>Toxicology and Applied Pharmacology</em>, <em>79</em>(1), 99&ndash;111. https://doi.org/10.1016/0041-008X(85)90372-2</span></span></p>
  • <p><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif">Naamneh Elzenaty, R., du Toit, T., &amp; Fl&uuml;ck, C. E. (2022). Basics of androgen synthesis and action. <em>Best Practice &amp; Research Clinical Endocrinology &amp; Metabolism</em>, <em>36</em>(4), 101665. https://doi.org/10.1016/j.beem.2022.101665</span></span></p>
  • <p><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif">Nef, S., &amp; Parada, L. F. (2000). Hormones in male sexual development. <em>Genes &amp; Development</em>, <em>14</em>(24), 3075&ndash;3086. https://doi.org/10.1101/gad.843800</span></span></p>
  • <p><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif">Ogino, Y., Miyagawa, S., Katoh, H., Prins, G. S., Iguchi, T., &amp; Yamada, G. (2011). Essential functions of androgen signaling emerged through the developmental analysis of vertebrate sex characteristics. <em>Evolution &amp; Development</em>, <em>13</em>(3), 315&ndash;325. https://doi.org/10.1111/j.1525-142X.2011.00482.x</span></span></p>
  • <p><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif">Prizant, H., Gleicher, N., &amp; Sen, A. (2014). Androgen actions in the ovary: balance is key. <em>Journal of Endocrinology</em>, <em>222</em>(3), R141&ndash;R151. https://doi.org/10.1530/JOE-14-0296</span></span></p>
  • <p><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif">Renault, C. H., Aksglaede, L., W&oslash;jdemann, D., Hansen, A. B., Jensen, R. B., &amp; Juul, A. (2020). Minipuberty of human infancy &ndash; A window of opportunity to evaluate hypogonadism and differences of sex development? <em>Annals of Pediatric Endocrinology &amp; Metabolism</em>, <em>25</em>(2), 84&ndash;91. <a href="https://doi.org/10.6065/apem.2040094.047" style="color:blue; text-decoration:underline">https://doi.org/10.6065/apem.2040094.047</a></span></span></p>
  • <p><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif">Renfree, M., &amp; Shaw G. (2023). The alternate pathway of androgen metabolism and window of sensitivity. <em>Journal of Endocrinology, JOE-22-0296, </em>https://doi.org/<em>10.1530/JOE-22-0296</em></span></span></p>
  • <p><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif">Rey, R. A. (2021). The Role of Androgen Signaling in Male Sexual Development at Puberty. <em>Endocrinology</em>, <em>162</em>(2). https://doi.org/10.1210/endocr/bqaa215</span></span></p>
  • <p><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif">Swerdloff, R. S., Dudley, R. E., Page, S. T., Wang, C., &amp; Salameh, W. A. (2017). Dihydrotestosterone: Biochemistry, Physiology, and Clinical Implications of Elevated Blood Levels. <em>Endocrine Reviews</em>, <em>38</em>(3), 220&ndash;254. https://doi.org/10.1210/er.2016-1067</span></span></p>
  • <p><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif">Thibaut, R., &amp; Porte, C. (2004). Effects of endocrine disrupters on sex steroid synthesis and metabolism pathways in fish. <em>The Journal of Steroid Biochemistry and Molecular Biology</em>, <em>92</em>(5), 485&ndash;494. https://doi.org/10.1016/j.jsbmb.2004.10.008</span></span></p>
  • <p><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif">Vierhapper, H., Nowotny, P., &amp; Waldh&auml;usl, W. (2003). Reduced production rates of testosterone and dihydrotestosterone in healthy men treated with rosiglitazone. <em>Metabolism</em>, <em>52</em>(2), 230&ndash;232. https://doi.org/10.1053/meta.2003.50028</span></span></p>
  • <p><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif">Xu, Y., Chen, Y., Li, N., Hu, X., Li, G., Ding, Y., Li, J., Shen, Y., Wang, X., &amp; Wang, J. (2018). Novel compound heterozygous variants in the <em>LHCGR</em> gene identified in a subject with Leydig cell hypoplasia type 1. <em>Journal of Pediatric Endocrinology and Metabolism</em>, <em>31</em>(2), 239&ndash;245. https://doi.org/10.1515/jpem-2016-0445</span></span></p>
  • <div class="panel panel-default">
  • <table class="table table-bordered table-striped">
  • <thead>
  • </div>
  • <div>
  • <h4><a href="/relationships/1935">Relationship: 1935: Decrease, DHT level leads to Decrease, AR activation</a></h4>
  • <h4>AOPs Referencing Relationship</h4>
  • <div class="table-responsive">
  • <table class="table table-bordered table-fullwidth">
  • <thead class="thead-light">
  • <tr>
  • <th scope="col">AOP Name</th>
  • <th scope="col">Adjacency</th>
  • <th scope="col">Weight of Evidence</th>
  • <th scope="col">Quantitative Understanding</th>
  • </tr>
  • </thead>
  • <tbody class="tbody-striped">
  • <tr>
  • <th>AOP Name</th>
  • <th>Adjacency</th>
  • <th>Weight of Evidence</th>
  • <th>Quantitative Understanding</th>
  • <td><a href="/aops/288">Inhibition of 17α-hydrolase/C 10,20-lyase (Cyp17A1) activity leads to birth reproductive defects (cryptorchidism) in male (mammals)</a></td>
  • <td>adjacent</td>
  • <td>High</td>
  • <td>High</td>
  • </tr>
  • </thead>
  • <tbody>
  • <tr>
  • <th><a href="/aops/288">Inhibition of 17α-hydrolase/C 10,20-lyase (Cyp17A1) activity leads to birth reproductive defects (cryptorchidism) in male (mammals)</a></th>
  • <th>adjacent</th>
  • <th>High </th>
  • <th>High</th>
  • </tr>
  • <tr>
  • <th><a href="/aops/307">Decreased testosterone synthesis leading to short anogenital distance (AGD) in male (mammalian) offspring</a></th>
  • <th>adjacent</th>
  • <th>High </th>
  • <th>Moderate</th>
  • </tr>
  • <tr>
  • <th><a href="/aops/305">5α-reductase inhibition leading to short anogenital distance (AGD) in male (mammalian) offspring</a></th>
  • <th>adjacent</th>
  • <th>High </th>
  • <th>Moderate</th>
  • </tr>
  • </tbody>
  • </table>
  • </div>
  • <!-- if nothing shows up in any of these fields, then evidence supporting this KER will not be displayed -->
  • <tr>
  • <td><a href="/aops/307">Decreased testosterone synthesis leading to short anogenital distance (AGD) in male (mammalian) offspring</a></td>
  • <td>adjacent</td>
  • <td>High</td>
  • <td>Moderate</td>
  • </tr>
  • <tr>
  • <td><a href="/aops/305">5α-reductase inhibition leading to short anogenital distance (AGD) in male (mammalian) offspring</a></td>
  • <td>adjacent</td>
  • <td></td>
  • <td></td>
  • </tr>
  • </tbody>
  • </table>
  • </div>
  • <h4>Evidence Supporting Applicability of this Relationship</h4>
  • <div>
  • <strong>Taxonomic Applicability</strong>
  • <div class="table-responsive">
  • <table class="table table-bordered table-fullwidth">
  • <thead class="thead-light">
  • <tr>
  • <th scope="col">Term</th>
  • <th scope="col">Scientific Term</th>
  • <th scope="col">Evidence</th>
  • <th scope="col">Links</th>
  • </tr>
  • </thead>
  • <tbody class="tbody-striped">
  • <tr>
  • <td>Vertebrates</td>
  • <td>Vertebrates</td>
  • <td>High</td>
  • <td><a href="http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&id=0" target="_blank">NCBI</a></td>
  • </tr>
  • </tbody>
  • </table>
  • </div>
  • </div>
  • <div>
  • <strong>Life Stage Applicability</strong>
  • <div class="table-responsive">
  • <table class="table table-bordered table-fullwidth">
  • <thead class="thead-light">
  • <tr>
  • <th scope="col">Life Stage</th>
  • <th scope="col">Evidence</th>
  • </tr>
  • </thead>
  • <tbody class="tbody-striped">
  • <tr>
  • <td>During development and at adulthood</td>
  • <td>High</td>
  • </tr>
  • </tbody>
  • </table>
  • </div>
  • </div>
  • <div>
  • <strong>Sex Applicability</strong>
  • <div class="table-responsive">
  • <table class="table table-bordered table-fullwidth">
  • <thead class="thead-light">
  • <tr>
  • <th scope="col">Sex</th>
  • <th scope="col">Evidence</th>
  • </tr>
  • </thead>
  • <tbody class="tbody-striped">
  • <tr>
  • <td>Mixed</td>
  • <td>High</td>
  • </tr>
  • </tbody>
  • </table>
  • </div>
  • </div>
  • <p><span style="font-size:11pt"><strong>Taxonomic applicability</strong></span></p>
  • <p><span style="font-size:11pt">KER1935 is assessed applicable to vertebrates, as DHT and AR activation are known to be related in these species.</span></p>
  • <p><span style="font-size:11pt"><strong>Sex applicability</strong></span></p>
  • <p><span style="font-size:11pt">KER1935 is assessed applicable to both sexes, as DHT activates AR in both males and females.</span></p>
  • <p><span style="font-size:11pt"><strong>Life-stage applicability</strong></span></p>
  • <p><span style="font-size:11pt">KER1935 is considered applicable to developmental and adult life stages, as DHT-mediated AR activation is relevant from the AR is expressed.</span></p>
  • <h4>Key Event Relationship Description</h4>
  • <p><span style="font-size:11.0pt">Dihydrotestosterone (DHT) is&nbsp;a primary ligand for the Androgen receptor (AR), a nuclear receptor and transcription factor. DHT is an endogenous sex hormone that is synthesized&nbsp;from e.g. testosterone by the enzyme 5&alpha;-reductase in different tissues&nbsp;and organs </span><span style="font-size:11.0pt">(<a href="#_ENREF_1" title="Davey, 2016 #250">Davey &amp; Grossmann, 2016</a>; <a href="#_ENREF_3" title="Marks, 2004 #283">Marks, 2004</a>)</span><span style="font-size:11.0pt">. In the absence of ligand (e.g. DHT) the AR is localized in the cytoplasm in complex with molecular chaperones. Upon ligand binding, AR is activated,&nbsp;translocated into the nucleus, and dimerizes to&nbsp;carry out its &lsquo;genomic function&rsquo;&nbsp;</span><span style="font-size:11.0pt">(<a href="#_ENREF_1" title="Davey, 2016 #250">Davey &amp; Grossmann, 2016</a>)</span><span style="font-size:11.0pt">. Hence, AR transcriptional function is directly dependent on the presence of ligands, with DHT being a more potent AR activator than testosterone (<a href="#_ENREF_2" title="Grino, 1990 #284">Grino et al, 1990</a>). Reduced levels of DHT may thus&nbsp;lead to reduced AR activation. Besides its genomic actions, the AR can also mediate rapid, non-genomic second messenger signaling (Davey and Grossmann, 2016). Decreased DHT levels that lead to reduced AR activation can thus entail downstream effects on both genomic and non-genomic signaling. </span></p>
  • <h4>Evidence Supporting this KER</h4>
  • <strong>Biological Plausibility</strong>
  • <p><span style="font-size:11pt">The biological plausibility of KER1935 is considered high.</span></p>
  • <p><span style="font-size:11pt">The activation of AR is dependent on binding of ligands (though a few cases of ligand-independent AR activation has been shown, see <em>uncertainties and inconsistencies</em>), primarily testosterone and DHT in most vertebrates and 11-ketotestosterone in teleost fishes (Schuppe et al., 2020). Without ligand activation, the AR will remain in the cytoplasm associated with heat-shock and other chaperones and not be able to carry out its canonical (&lsquo;genomic&rsquo;) function. Upon androgen binding, the AR undergoes a conformational change, chaperones dissociate, and a nuclear localization signal is exposed. The androgen/AR complex can now translocate to the nucleus, dimerize and bind AR response elements to regulate target gene expression (Davey and Grossmann, 2016; Eder et al., 2001).</span></p>
  • <p><span style="font-size:11pt">The requirement for androgens binding to the AR for transcriptional activity has been extensively studied and proven and is generally considered textbook knowledge. The OECD test guideline no. 458 uses DHT as the reference chemical for testing androgen receptor activation <em>in vitro</em> (OECD, 2020). In the absence of DHT during development caused by 5&alpha;-reductase deficiency (i.e. still in the presence of testosterone) male fetuses fail to masculinize properly. This is evidenced by, for instance, individuals with congenital 5&alpha;-reductase deficiency conditions (Costa et al., 2012); conditions not limited to humans (Robitaille and Langlois, 2020), testifying to the importance of specifically DHT for AR activation and subsequent masculinization of certain reproductive tissues. </span></p>
  • <p><span style="font-size:11pt">Binding of testosterone or DHT has differential effects in different tissues. E.g. in the developing mammalian male; testosterone is required for development of the internal sex organs (epididymis, vas deferens and the seminal vesicles), whereas DHT is crucial for development of the external sex organs (Keller et al., 1996; Robitaille and Langlois, 2020). </span></p>
  • <strong>Empirical Evidence</strong>
  • <p><span style="font-size:11pt">The empirical support for KER1935 is considered high.</span></p>
  • <p><span style="font-size:11pt">Dose concordance:</span></p>
  • <ul>
  • <li><span style="font-size:11pt">Increasing concentrations of DHT lead to increasing AR activation <em>in vitro</em> in AR reporter gene assays (OECD, 2020; Williams et al., 2017).</span></li>
  • <li><span style="font-size:11pt">In cell lines where proliferation can be induced by androgens (such as prostate cancer cells) proliferation can be used as a readout for AR-activation. Finasteride, a 5&alpha;-reductase inhibitor, dose-dependently decreases AR-mediated prostate cancer cell line proliferation (Bologna et al., 1995). 0.001 &micro;M finasteride decreased the growth rate with 44%, 0.1 &micro;M decreased the growth rate with 80%. </span></li>
  • <li><span style="font-size:11pt">Specific events of masculinization during development are dependent on AR activation by DHT, including the development and length of the perineum which can be measured as the anogenital distance (AGD, (Schwartz et al., 2019)). E.g. a dose-dependent effect of rat <em>in utero</em> exposure to the 5&alpha;-reductase inhibitor finasteride was observed on the length of the AGD, where 0.01 mg/kg bw/day finasteride reduced the AGD measured at pup day 1 by 8%, whereas 1 mg/kg bw/day reduced the AGD by 23% (Bowman et al., 2003).</span></li>
  • </ul>
  • <p><span style="font-size:11pt">Other evidence:</span></p>
  • <ul>
  • <li><span style="font-size:11pt">Male individuals with congenital 5&alpha;-reductase deficiency (absence of DHT) fail to masculinize properly (Costa et al., 2012). </span></li>
  • <li><span style="font-size:11pt">A major driver of prostate cancer growth is AR activation (Davey and Grossmann, 2016; Huggins and Hodges, 1941). Androgen deprivation is used as treatment including 5&alpha;-reductase inhibitors to reduce DHT levels (Aggarwal et al., 2010).</span></li>
  • </ul>
  • <strong>Uncertainties and Inconsistencies</strong>
  • <p><span style="font-size:11pt">Ligand-independent actions of the AR have been identified. To what extent and of which biological consequences is not well defined (Bennesch and Picard, 2015). </span></p>
  • <p><span style="font-size:11pt">It should be noted, that in tissues, that are not DHT-dependent but rather respond to T, a decrease in DHT level may not influence AR activation significantly in that specific tissue. </span></p>
  • <h4>Quantitative Understanding of the Linkage</h4>
  • <strong>Response-response relationship</strong>
  • <p style="text-align:justify"><span style="font-size:11pt">There is a positive dose-response relationship between increasing concentrations of DHT and AR activation (Dalton et al., 1998; OECD, 2020). However, there is not enough data, or overview of the data, to define a quantitative linkage <em>in vivo</em>, and such a relationship will differ between biological systems (species, tissue, cell type).</span></p>
  • <strong>Time-scale</strong>
  • <p><span style="font-size:11pt">Upon DHT binding to the AR, a conformational change that brings the amino (N) and carboxy (C) termini into close proximity occurs with a t<sub>1/2</sub> of approximately 3.5 minutes, around 6 minutes later the AR dimerizes as shown in transfected HeLa cells (Schaufele et al., 2005). Addition of 5 nM DHT to the culture medium of &lsquo;AR-resistant&rsquo; transfected prostatic cancer cells resulted in a rapid (from 15 minutes, maximal at 30 minutes) nuclear translocation of the AR with minimal residual cytosolic expression (Nightingale et al., 2003). AR and promoter interactions occur within 15 minutes of ligand binding, and RNA polymerase II and coactivator recruitment are then proposed to occur transiently with cycles of approximately 90 minutes (Kang et al., 2002).</span></p>
  • <strong>Known modulating factors</strong>
  • <div>
  • <table class="table table-bordered table-fullwidth">
  • <thead>
  • <tr>
  • <th>Modulating Factor (MF)</th>
  • <th>MF Specification</th>
  • <th>Effect(s) on the KER</th>
  • <th>Reference(s)</th>
  • </tr>
  • </thead>
  • <tbody>
  • <tr>
  • <td>Age</td>
  • <td><span style="font-size:11.0pt">AR expression changes with aging</span></td>
  • <td><span style="font-size:11.0pt"><span style="font-family:&quot;Calibri&quot;,sans-serif">Tissue-specific alterations in AR activity with aging</span></span></td>
  • <td><span style="font-size:11.0pt"><span style="font-family:&quot;Calibri&quot;,sans-serif"><span style="color:black">(Supakar et al., 1993; Wu et al., 2009)</span></span></span></td>
  • </tr>
  • <tr>
  • <td>Genotype</td>
  • <td><span style="font-size:11.0pt"><span style="font-family:&quot;Calibri&quot;,sans-serif">Number of CAG repeats in the first exon of AR</span></span></td>
  • <td><span style="font-size:11.0pt"><span style="font-family:&quot;Calibri&quot;,sans-serif">Decreased AR activation with increased number of CAGs</span></span></td>
  • <td><span style="font-size:11.0pt"><span style="font-family:&quot;Calibri&quot;,sans-serif">(Chamberlain et al., 1994; Tut et al., 1997)</span></span></td>
  • </tr>
  • <tr>
  • <td>Androgen deficiency syndrome</td>
  • <td><span style="font-size:11.0pt"><span style="font-family:&quot;Calibri&quot;,sans-serif">Low circulating testosterone levels due to primary (testicular) or secondary (pituitary-hypothalamic) hypogonadism</span></span></td>
  • <td><span style="font-size:11.0pt"><span style="font-family:&quot;Calibri&quot;,sans-serif">Reduced levels of circulating testosterone, precurser of DHT</span></span></td>
  • <td><span style="font-size:11.0pt"><span style="font-family:&quot;Calibri&quot;,sans-serif"><span style="color:black">(Bhasin et al., 2010)</span></span></span></td>
  • </tr>
  • <tr>
  • <td>Castration</td>
  • <td><span style="font-size:11.0pt"><span style="font-family:&quot;Calibri&quot;,sans-serif">Removal of testicles</span></span></td>
  • <td><span style="font-size:11.0pt"><span style="font-family:&quot;Calibri&quot;,sans-serif">Reduced levels of circulating testosterone, precurser of DHT</span></span></td>
  • <td><span style="font-size:11.0pt"><span style="font-family:&quot;Calibri&quot;,sans-serif"><span style="color:black">(Krotkiewski et al., 1980)</span></span></span></td>
  • </tr>
  • </tbody>
  • </table>
  • </div>
  • <!--<!% unless aop_rel.relationship.relationship_taxons.blank? %>-->
  • <!--<!%= render 'snapshot_taxons', taxons: aop_rel.relationship.relationship_taxons %>-->
  • <!--<!% unless aop_rel.relationship.taxon_evidence.blank? %>-->
  • <!--<h3>Domain of Applicability</h3>-->
  • <!--<!%== aop_rel.relationship.taxon_evidence %>-->
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  • <!--<!% end %>-->
  • <strong>Known Feedforward/Feedback loops influencing this KER</strong>
  • <p><span style="font-size:11pt">Androgens can upregulate and downregulate AR expression as well as 5&alpha;-reductase expression, but for 5&alpha;-reductase, each isoform in each tissue is differently regulated by androgens and can display sexual dimorphism (Lee and Chang, 2003; Robitaille and Langlois, 2020). </span></p>
  • <h4>References</h4>
  • <p style="margin-left:32px"><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif">Aggarwal, S., Thareja, S., Verma, A., Bhardwaj, T.R., Kumar, M., 2010. An overview on 5&alpha;-reductase inhibitors. Steroids 75, 109&ndash;153. https://doi.org/10.1016/j.steroids.2009.10.005</span></span></p>
  • <p style="margin-left:32px"><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif">Bennesch, M.A., Picard, D., 2015. Minireview: Tipping the Balance: Ligand-Independent Activation of Steroid Receptors. Mol. Endocrinol. 29, 349&ndash;363. https://doi.org/10.1210/ME.2014-1315</span></span></p>
  • <p style="margin-left:32px"><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif">Bhasin, S., Cunningham, G.R., Hayes, F.J., Matsumoto, A.M., Snyder, P.J., Swerdloff, R.S., Montori, V.M., 2010. Testosterone Therapy in Men with Androgen Deficiency Syndromes: An Endocrine Society Clinical Practice Guideline. J. Clin. Endocrinol. Metab. 95, 2536&ndash;2559. https://doi.org/10.1210/JC.2009-2354</span></span></p>
  • <p style="margin-left:32px"><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif">Bologna, M., Muzi, P., Biordi, L., Festuccia, C., Vicentini, C., 1995. Finasteride dose-dependently reduces the proliferation rate of the LnCap human prostatic cancer cell line in vitro. Urology 45, 282&ndash;290. https://doi.org/10.1016/0090-4295(95)80019-0</span></span></p>
  • <p style="margin-left:32px"><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif">Bowman, C.J., Barlow, N.J., Turner, K.J., Wallace, D.G., Foster, P.M.D., 2003. Effects of in Utero Exposure to Finasteride on Androgen-Dependent Reproductive Development in the Male Rat. Toxicol. Sci. 74, 393&ndash;406. https://doi.org/10.1093/TOXSCI/KFG128</span></span></p>
  • <p style="margin-left:32px"><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif">Chamberlain, N.L., Driver, E.D., Miesfeld, R.L., 1994. The length and location of CAG trinucleotide repeats in the androgen receptor N-terminal domain affect transactivation function. Nucleic Acids Res. 22, 3181. https://doi.org/10.1093/NAR/22.15.3181</span></span></p>
  • <p style="margin-left:32px"><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif">Costa, E.F., Domenice, S., Sircili, M., Inacio, M., Mendonca, B., 2012. DSD due to 5&alpha;-reductase 2 deficiency - From diagnosis to long term outcome. Semin. Reprod. Med. 30, 427&ndash;431. https://doi.org/10.1055/S-0032-1324727/ID/JR00766-20/BIB</span></span></p>
  • <p style="margin-left:32px"><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif">Dalton, J.T., Mukherjee, A., Zhu, Z., Kirkovsky, L., Miller, D.D., 1998. Discovery of nonsteroidal androgens. Biochem. Biophys. Res. Commun. 244, 1&ndash;4. https://doi.org/10.1006/bbrc.1998.8209</span></span></p>
  • <p style="margin-left:32px"><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif">Davey, R.A., Grossmann, M., 2016. Androgen Receptor Structure, Function and Biology: From Bench to Bedside. Clin. Biochem. Rev. 37, 3&ndash;15.</span></span></p>
  • <p style="margin-left:32px"><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif">Eder, I.E., Culig, Z., Putz, T., Nessler-Menardi, C., Bartsch, G., Klocker, H., 2001. Molecular Biology of the Androgen Receptor: From Molecular Understanding to the Clinic. Eur. Urol. 40, 241&ndash;251. https://doi.org/10.1159/000049782</span></span></p>
  • <p style="margin-left:32px"><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif">Grino, P.B., Griffin, J.E., Wilson, J.D., 1990. Testosterone at High Concentrations Interacts with the Human Androgen Receptor Similarly to Dihydrotestosterone. Endocrinology 126, 1165&ndash;1172. https://doi.org/10.1210/endo-126-2-1165</span></span></p>
  • <p style="margin-left:32px"><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif">Huggins, C., Hodges, C. V., 1941. Studies on prostatic cancer: I. The effect of castration, of estrogen and of androgen injection on serum phosphatases in metastatic carcinoma of the prostate. Cancer Res. 1, 293&ndash;297.</span></span></p>
  • <p style="margin-left:32px"><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif">Kang, Z., Pirskanen, A., J&auml;nne, O.A., Palvimo, J.J., 2002. Involvement of proteasome in the dynamic assembly of the androgen receptor transcription complex. J. Biol. Chem. 277, 48366&ndash;48371. https://doi.org/10.1074/jbc.M209074200</span></span></p>
  • <p style="margin-left:32px"><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif">Keller, E.T., Ershler, W.B., Chang, C., 1996. The androgen receptor: a mediator of diverse responses. Front. Biosci. (Landmark Ed) 1, 59&ndash;71. https://doi.org/10.2741/A116</span></span></p>
  • <p style="margin-left:32px"><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif">Krotkiewski, M., Kral, J.G., Karlsson, J., 1980. Effects of castration and testosterone substitution on body composition and muscle metabolism in rats. Acta Physiol. Scand. 109, 233&ndash;237. https://doi.org/10.1111/J.1748-1716.1980.TB06592.X</span></span></p>
  • <p style="margin-left:32px"><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif">Lee, D.K., Chang, C., 2003. Expression and Degradation of Androgen Receptor: Mechanism and Clinical Implication. J. Clin. Endocrinol. Metab. 88, 4043&ndash;4054. https://doi.org/10.1210/JC.2003-030261</span></span></p>
  • <p style="margin-left:32px"><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif">Marks, L.S., 2004. 5Alpha-Reductase: History and Clinical Importance. Rev. Urol. 6 Suppl 9, S11-21.</span></span></p>
  • <p style="margin-left:32px"><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif">Nightingale, J., Chaudhary, K.S., Abel, P.D., Stubbs, A.P., Romanska, H.M., Mitchell, S.E., Stamp, G.W.H., Lalani, E.N., 2003. Ligand Activation of the Androgen Receptor Downregulates E-Cadherin-Mediated Cell Adhesion and Promotes Apoptosis of Prostatic Cancer Cells. Neoplasia 5, 347. https://doi.org/10.1016/S1476-5586(03)80028-3</span></span></p>
  • <p style="margin-left:32px"><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif">OECD, 2020. Test No. 458: Stably Transfected Human Androgen Receptor Transcriptional Activation Assay for Detection of Androgenic Agonist and Antagonist Activity of Chemicals, OECD Guidelines for the Testing of Chemicals, Section 4. OECD Publishing, Paris. https://doi.org/10.1787/9789264264366-en</span></span></p>
  • <p style="margin-left:32px"><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif">Robitaille, J., Langlois, V.S., 2020. Consequences of steroid-5&alpha;-reductase deficiency and inhibition in vertebrates. Gen. Comp. Endocrinol. 290. https://doi.org/10.1016/j.ygcen.2020.113400</span></span></p>
  • <p style="margin-left:32px"><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif">Schaufele, F., Carbonell, X., Guerbadot, M., Borngraeber, S., Chapman, M.S., Ma, A.A.K., Miner, J.N., Diamond, M.I., 2005. The structural basis of androgen receptor activation: Intramolecular and intermolecular amino-carboxy interactions. Proc. Natl. Acad. Sci. U. S. A. 102, 9802&ndash;9807. https://doi.org/10.1073/pnas.0408819102</span></span></p>
  • <p style="margin-left:32px"><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif">Schuppe, E.R., Miles, M.C., Fuxjager, M.J., 2020. Evolution of the androgen receptor: Perspectives from human health to dancing birds. Mol. Cell. Endocrinol. 499, 110577. https://doi.org/10.1016/J.MCE.2019.110577</span></span></p>
  • <p style="margin-left:32px"><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif">Schwartz, C.L., Christiansen, S., Vinggaard, A.M., Axelstad, M., Hass, U., Svingen, T., 2019. Anogenital distance as a toxicological or clinical marker for fetal androgen action and risk for reproductive disorders. Arch. Toxicol. 93, 253&ndash;272. https://doi.org/10.1007/s00204-018-2350-5</span></span></p>
  • <p style="margin-left:32px"><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif">Supakar, P.C., Song, C.S., Jung, M.H., Slomczynska, M.A., Kim, J.M., Vellanoweth, R.L., Chatterjee, B., Roy, A.K., 1993. A novel regulatory element associated with age-dependent expression of the rat androgen receptor gene. J. Biol. Chem. 268, 26400&ndash;26408. https://doi.org/10.1016/S0021-9258(19)74328-2</span></span></p>
  • <p style="margin-left:32px"><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif">Tut, T.G., Ghadessy, F.J., Trifiro, M.A., Pinsky, L., Yong, E.L., 1997. Long Polyglutamine Tracts in the Androgen Receptor Are Associated with Reduced Trans-Activation, Impaired Sperm Production, and Male Infertility. J. Clin. Endocrinol. Metab. 82, 3777&ndash;3782. https://doi.org/10.1210/JCEM.82.11.4385</span></span></p>
  • <p style="margin-left:32px"><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif">Williams, A.J., Grulke, C.M., Edwards, J., McEachran, A.D., Mansouri, K., Baker, N.C., Patlewicz, G., Shah, I., Wambaugh, J.F., Judson, R.S., Richard, A.M., 2017. The CompTox Chemistry Dashboard: a community data resource for environmental chemistry. J. Cheminform. 9, 61. https://doi.org/10.1186/s13321-017-0247-6</span></span></p>
  • <p style="margin-left:32px"><span style="font-size:11.0pt"><span style="font-family:&quot;Calibri&quot;,sans-serif">Wu, D., Lin, G., Gore, A.C., 2009. Age-related Changes in Hypothalamic Androgen Receptor and Estrogen Receptor </span></span><span style="font-size:11.0pt"><span style="font-family:&quot;Calibri&quot;,sans-serif">&alpha;</span></span><span style="font-size:11.0pt"><span style="font-family:&quot;Calibri&quot;,sans-serif"> in Male Rats. J. Comp. </span></span><span style="font-size:11.0pt"><span style="font-family:&quot;Calibri&quot;,sans-serif">Neurol. 512, 688. https://doi.org/10.1002/CNE.21925</span></span></p>
  • </div>
  • <br>
  • <div>
  • <h4><a href="/relationships/2124">Relationship: 2124: Decrease, AR activation leads to Decreased, Transcription of genes by AR</a></h4>
  • <div>
  • <h4><a href="/relationships/2124">Relationship: 2124: Decrease, AR activation leads to Altered, Transcription of genes by the AR</a></h4>
  • <h4>AOPs Referencing Relationship</h4>
  • <div class="panel panel-default">
  • <table class="table table-bordered table-striped">
  • <thead>
  • <div class="table-responsive">
  • <table class="table table-bordered table-fullwidth">
  • <thead class="thead-light">
  • <tr>
  • <th scope="col">AOP Name</th>
  • <th scope="col">Adjacency</th>
  • <th scope="col">Weight of Evidence</th>
  • <th scope="col">Quantitative Understanding</th>
  • </tr>
  • </thead>
  • <tbody class="tbody-striped">
  • <tr>
  • <th>AOP Name</th>
  • <th>Adjacency</th>
  • <th>Weight of Evidence</th>
  • <th>Quantitative Understanding</th>
  • <td><a href="/aops/307">Decreased testosterone synthesis leading to short anogenital distance (AGD) in male (mammalian) offspring</a></td>
  • <td>adjacent</td>
  • <td>High</td>
  • <td>Moderate</td>
  • </tr>
  • </thead>
  • <tbody>
  • <tr>
  • <th><a href="/aops/307">Decreased testosterone synthesis leading to short anogenital distance (AGD) in male (mammalian) offspring</a></th>
  • <th>adjacent</th>
  • <th>High </th>
  • <th>Moderate</th>
  • </tr>
  • <tr>
  • <th><a href="/aops/344">Androgen receptor (AR) antagonism leading to nipple retention (NR) in male (mammalian) offspring</a></th>
  • <th>adjacent</th>
  • <th>Moderate </th>
  • <th>Moderate</th>
  • </tr>
  • </tbody>
  • </table>
  • </div>
  • <!-- if nothing shows up in any of these fields, then evidence supporting this KER will not be displayed -->
  • <tr>
  • <td><a href="/aops/344">Androgen receptor (AR) antagonism leading to nipple retention (NR) in male (mammalian) offspring</a></td>
  • <td>adjacent</td>
  • <td>Moderate</td>
  • <td>Moderate</td>
  • </tr>
  • </tbody>
  • </table>
  • </div>
  • <h4>Evidence Supporting Applicability of this Relationship</h4>
  • <div>
  • <strong>Taxonomic Applicability</strong>
  • <div class="table-responsive">
  • <table class="table table-bordered table-fullwidth">
  • <thead class="thead-light">
  • <tr>
  • <th scope="col">Term</th>
  • <th scope="col">Scientific Term</th>
  • <th scope="col">Evidence</th>
  • <th scope="col">Links</th>
  • </tr>
  • </thead>
  • <tbody class="tbody-striped">
  • <tr>
  • <td>Vertebrates</td>
  • <td>Vertebrates</td>
  • <td>High</td>
  • <td><a href="http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&id=0" target="_blank">NCBI</a></td>
  • </tr>
  • </tbody>
  • </table>
  • </div>
  • </div>
  • <div>
  • <strong>Life Stage Applicability</strong>
  • <div class="table-responsive">
  • <table class="table table-bordered table-fullwidth">
  • <thead class="thead-light">
  • <tr>
  • <th scope="col">Life Stage</th>
  • <th scope="col">Evidence</th>
  • </tr>
  • </thead>
  • <tbody class="tbody-striped">
  • <tr>
  • <td>During development and at adulthood</td>
  • <td>High</td>
  • </tr>
  • </tbody>
  • </table>
  • </div>
  • </div>
  • <div>
  • <strong>Sex Applicability</strong>
  • <div class="table-responsive">
  • <table class="table table-bordered table-fullwidth">
  • <thead class="thead-light">
  • <tr>
  • <th scope="col">Sex</th>
  • <th scope="col">Evidence</th>
  • </tr>
  • </thead>
  • <tbody class="tbody-striped">
  • <tr>
  • <td>Mixed</td>
  • <td>High</td>
  • </tr>
  • </tbody>
  • </table>
  • </div>
  • </div>
  • <h4>Key Event Relationship Description</h4>
  • <p style="text-align:justify"><span style="font-size:12pt">The androgen receptor (AR) is a ligand-dependent nuclear transcription factor that upon activation translocates to the nucleus, dimerizes, and binds androgen response elements (AREs) to modulate transcription of target genes <span style="color:black">(Lamont and Tindall, 2010, Roy et al. 2001)</span>. Decreased activation of the AR affects its transcription factor activity, therefore leading to altered AR-target gene expression. This KER refers to decreased AR activation and altered gene expression occurring in complex systems, such as <em>in vivo</em> and the specific effect on transcription of AR target genes will depend on species, life stage, tissue, cell type etc. </span></p>
  • <h4>Evidence Supporting this KER</h4>
  • <strong>Biological Plausibility</strong>
  • <p style="text-align:justify"><span style="font-size:12pt">The biological plausibility for this KER is considered high</span></p>
  • <p style="text-align:justify"><span style="font-size:12pt">The AR is a ligand-activated transcription factor part of the steroid hormone nuclear receptor family. Non-activated AR is found in the cytoplasm as a multiprotein complex with heat-shock proteins, immunophilins and, other chaperones <span style="color:black">(Roy et al. 2001)</span>. Upon activation through ligand binding, the AR dissociates from the protein complex, translocates to the nucleus and homodimerizes. Facilitated by co-regulators, AR can bind to DNA regions containing AREs and initiate transcription of target genes, that thus will be different in e.g. different tissues, life-stages, species etc. </span></p>
  • <p style="text-align:justify"><span style="font-size:12pt">Through mapping of AREs and ChIP sequencing studies, several AR target genes have been identified, mainly studied in prostate cells <span style="color:black">(Jin, Kim, and Yu 2013)</span>. Different co-regulators and ligands lead to altered expression of different sets of genes <span style="color:black">(Jin et al. 2013; Kanno et al. 2022)</span>. Alternative splicing of the AR can lead to different AR variants that also affects which genes are transcribed <span style="color:black">(Jin et al. 2013)</span>.</span></p>
  • <p style="text-align:justify"><span style="font-size:12pt">Apart from this canonical signaling pathway, the AR can suppress gene expression, indirectly regulate miRNA transcription, and have non-genomic effects by rapid activation of second messenger pathways in either presence or absence of a ligand <span style="color:black">(Jin et al. 2013)</span>.</span></p>
  • <strong>Empirical Evidence</strong>
  • <p style="text-align:justify"><span style="font-size:12pt">The empirical evidence for this KER is considered high</span></p>
  • <p style="text-align:justify"><span style="font-size:12pt">In humans, altered gene expression profiling in individuals with androgen insensitivity syndrome (AIS) can provide supporting empirical evidence <span style="color:black">(Holterhus et al. 2003; Peng et al. 2021)</span>. In rodent AR knockout (KO) models, gene expression profiling studies and gene-targeted approaches have provided information on differentially expressed genes in several organ systems including male and female reproductive, endocrine, muscular, cardiovascular and nervous systems <span style="color:black">(Denolet et al. 2006; Fan et al. 2005; Holterhus et al. 2003; Ikeda et al. 2005; Karlsson et al. 2016; MacLean et al. 2008; Rana et al. 2011; Russell et al. 2012; Shiina et al. 2006; Wang et al. 2006; Welsh et al. 2012; Willems et al. 2010; Yu et al. 2008, 2012; Zhang et al. 2006; Zhou et al. 2011)</span>.</span></p>
  • <p style="text-align:justify"><span style="font-size:12pt">Exposure to known antiandrogens has been shown to alter transcriptional profiles, for example of neonatal pig ovaries <span style="color:black">(Knapczyk-Stwora et al. 2019)</span>. </span></p>
  • <p style="text-align:justify"><span style="font-size:12pt">Dose concordance has also been observed for instance in zebrafish embryos; a dose of 50 &micro;g/L of the AR antagonist flutamide resulted in 674 differentially expressed genes at 96 h post fertilization whereas 500&thinsp;&micro;g/L flutamide resulted in 2871 differentially expressed genes (Ayobahan et al., 2023). </span></p>
  • <strong>Uncertainties and Inconsistencies</strong>
  • <p style="text-align:justify"><span style="font-size:12pt">AR action has been reported to occur also without ligand binding. However, not much is known about the extent and biological implications of such non-canonical, ligand-independent AR activation <span style="color:black">(Bennesch and Picard 2015)</span>.</span></p>
  • <h4>Quantitative Understanding of the Linkage</h4>
  • <strong>Response-response relationship</strong>
  • <p style="text-align:justify"><span style="font-size:12pt">There is not enough data to define a quantitative relationship between AR activation and alteration of AR target gene transcription, and such a relationship will differ between biological systems (species, tissue, cell type, life stage etc).</span></p>
  • <strong>Time-scale</strong>
  • <p style="text-align:justify"><span style="font-size:12pt">AR and promoter interactions occur within 15 minutes of ligand binding, RNA polymerase II and coactivator recruitment are proposed to occur transiently with cycles of approximately 90 minutes in LNCaP cells <span style="color:black">(Kang et al. 2002)</span>. RNA polymerase II elongation rates in mammalian cells have been shown to range between 1.3 and 4.3 kb/min <span style="color:black">(Maiuri et al. 2011)</span>. Therefore, depending on the cell type and the half-life of the AR target gene transcripts, changes are to be expected within hours. </span></p>
  • <strong>Known modulating factors</strong>
  • <div>
  • <table class="table table-bordered table-fullwidth">
  • <thead>
  • <tr>
  • <th>Modulating Factor (MF)</th>
  • <th>MF Specification</th>
  • <th>Effect(s) on the KER</th>
  • <th>Reference(s)</th>
  • </tr>
  • </thead>
  • <tbody>
  • <tr>
  • <td>Age</td>
  • <td><span style="font-size:12.0pt"><span style="font-family:&quot;Calibri&quot;,sans-serif">AR expression in aging male rats</span></span></td>
  • <td><span style="font-size:12.0pt"><span style="font-family:&quot;Calibri&quot;,sans-serif">Tissue-specific alterations in AR activity with aging</span></span></td>
  • <td><span style="font-size:12.0pt"><span style="font-family:&quot;Calibri&quot;,sans-serif"><span style="color:black">(Supakar et al. 1993; Wu, Lin, and Gore 2009)</span></span></span></td>
  • </tr>
  • <tr>
  • <td>Genotype</td>
  • <td><span style="font-size:12.0pt"><span style="font-family:&quot;Calibri&quot;,sans-serif">Number of CAG repeats in the first exon of AR</span></span></td>
  • <td><span style="font-size:12.0pt"><span style="font-family:&quot;Calibri&quot;,sans-serif">Decreased AR activation with increased number of CAGs</span></span></td>
  • <td>
  • <p style="text-align:center"><span style="font-size:12pt"><span style="font-family:Calibri,sans-serif"><span style="color:black">(Tut et al. 1997; Chamberlain et al. 1994)</span></span></span></p>
  • </td>
  • </tr>
  • </tbody>
  • </table>
  • </div>
  • <!--<!% unless aop_rel.relationship.relationship_taxons.blank? %>-->
  • <!--<!%= render 'snapshot_taxons', taxons: aop_rel.relationship.relationship_taxons %>-->
  • <!--<!% unless aop_rel.relationship.taxon_evidence.blank? %>-->
  • <!--<h3>Domain of Applicability</h3>-->
  • <!--<!%== aop_rel.relationship.taxon_evidence %>-->
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  • <!--<!% end %>-->
  • <strong>Known Feedforward/Feedback loops influencing this KER</strong>
  • <p style="text-align:justify"><span style="font-size:12pt">AR has been hypothesized to auto-regulate its mRNA and protein levels <span style="color:black">(Mora and Mahesh 1999)</span>.</span></p>
  • <h4>References</h4>
  • <p><span style="font-size:12pt"><span style="font-family:Calibri,sans-serif">Ayobahan, S. U., Alvincz, J., Reinwald, H., Strompen, J., Salinas, G., Sch&auml;fers, C., et al. (2023). Comprehensive identification of gene expression fingerprints and biomarkers of sexual endocrine disruption in zebrafish embryo. Ecotoxicol. Environ. Saf. 250, 114514. doi:10.1016/J.ECOENV.2023.114514.</span></span></p>
  • <p><span style="font-size:12pt"><span style="font-family:Calibri,sans-serif">Bennesch, Marcela A., and Didier Picard. 2015. &ldquo;Minireview: Tipping the Balance: Ligand-Independent Activation of Steroid Receptors.&rdquo; <em>Molecular Endocrinology</em> 29(3):349&ndash;63.</span></span></p>
  • <p><span style="font-size:12pt"><span style="font-family:Calibri,sans-serif">Chamberlain, Nancy L., Erika D. Driverand, and Roger L. Miesfeldi. 1994. <em>The Length and Location of CAG Trinucleotide Repeats in the Androgen Receptor N-Terminal Domain Affect Transactivation Function</em>. Vol. 22.</span></span></p>
  • <p><span style="font-size:12pt"><span style="font-family:Calibri,sans-serif">Denolet, Evi, Karel De Gendt, Joke Allemeersch, Kristof Engelen, Kathleen Marchal, Paul Van Hummelen, Karen A. L. Tan, Richard M. Sharpe, Philippa T. K. Saunders, Johannes V. Swinnen, and Guido Verhoeven. 2006. &ldquo;The Effect of a Sertoli Cell-Selective Knockout of the Androgen Receptor on Testicular Gene Expression in Prepubertal Mice.&rdquo; <em>Molecular Endocrinology</em> 20(2):321&ndash;34. doi: 10.1210/me.2005-0113.</span></span></p>
  • <p><span style="font-size:12pt"><span style="font-family:Calibri,sans-serif">Fan, Wuqiang, Toshihiko Yanase, Masatoshi Nomura, Taijiro Okabe, Kiminobu Goto, Takashi Sato, Hirotaka Kawano, Shigeaki Kato, and Hajime Nawata. 2005. <em>Androgen Receptor Null Male Mice Develop Late-Onset Obesity Caused by Decreased Energy Expenditure and Lipolytic Activity but Show Normal Insulin Sensitivity With High Adiponectin Secretion</em>. Vol. 54.</span></span></p>
  • <p><span style="font-size:12pt"><span style="font-family:Calibri,sans-serif">Holterhus, Paul-Martin, Olaf Hiort, Janos Demeter, Patrick O. Brown, and James D. Brooks. 2003. <em>Differential Gene-Expression Patterns in Genital Fibroblasts of Normal Males and 46,XY Females with Androgen Insensitivity Syndrome: Evidence for Early Programming Involving the Androgen Receptor</em>. Vol. 4.</span></span></p>
  • <p><span style="font-size:12pt"><span style="font-family:Calibri,sans-serif">Ikeda, Yasumasa, Ken Ichi Aihara, Takashi Sato, Masashi Akaike, Masanori Yoshizumi, Yuki Suzaki, Yuki Izawa, Mitsunori Fujimura, Shunji Hashizume, Midori Kato, Shusuke Yagi, Toshiaki Tamaki, Hirotaka Kawano, Takahiro Matsumoto, Hiroyuki Azuma, Shigeaki Kato, and Toshio Matsumoto. 2005. &ldquo;Androgen Receptor Gene Knockout Male Mice Exhibit Impaired Cardiac Growth and Exacerbation of Angiotensin II-Induced Cardiac Fibrosis.&rdquo; <em>Journal of Biological Chemistry</em> 280(33):29661&ndash;66. doi: 10.1074/jbc.M411694200.</span></span></p>
  • <p><span style="font-size:12pt"><span style="font-family:Calibri,sans-serif">Jin, Hong Jian, Jung Kim, and Jindan Yu. 2013. &ldquo;Androgen Receptor Genomic Regulation.&rdquo; <em>Translational Andrology and Urology</em> 2(3):158&ndash;77.</span></span></p>
  • <p><span style="font-size:12pt"><span style="font-family:Calibri,sans-serif">Kang, Zhigang, Asta Pirskanen, Olli A. J&auml;nne, and Jorma J. Palvimo. 2002. &ldquo;Involvement of Proteasome in the Dynamic Assembly of the Androgen Receptor Transcription Complex.&rdquo; <em>Journal of Biological Chemistry</em> 277(50):48366&ndash;71. doi: 10.1074/jbc.M209074200.</span></span></p>
  • <p><span style="font-size:12pt"><span style="font-family:Calibri,sans-serif">Kanno, Yuichiro, Nao Saito, Ryota Saito, Tomohiro Kosuge, Ryota Shizu, Tomofumi Yatsu, Takuomi Hosaka, Kiyomitsu Nemoto, Keisuke Kato, and Kouichi Yoshinari. 2022. &ldquo;Differential DNA-Binding and Cofactor Recruitment Are Possible Determinants of the Synthetic Steroid YK11-Dependent Gene Expression by Androgen Receptor in Breast Cancer MDA-MB 453 Cells.&rdquo; <em>Experimental Cell Research</em> 419(2). doi: 10.1016/j.yexcr.2022.113333.</span></span></p>
  • <p><span style="font-size:12pt"><span style="font-family:Calibri,sans-serif">Karlsson, Sara A., Erik Studer, Petronella Kettunen, and Lars Westberg. 2016. &ldquo;Neural Androgen Receptors Modulate Gene Expression and Social Recognition but Not Social Investigation.&rdquo; <em>Frontiers in Behavioral Neuroscience</em> 10(MAR). doi: 10.3389/fnbeh.2016.00041.</span></span></p>
  • <p><span style="font-size:12pt"><span style="font-family:Calibri,sans-serif">Knapczyk-Stwora, Katarzyna, Anna Nynca, Renata E. Ciereszko, Lukasz Paukszto, Jan P. Jastrzebski, Elzbieta Czaja, Patrycja Witek, Marek Koziorowski, and Maria Slomczynska. 2019. &ldquo;Flutamide-Induced Alterations in Transcriptional Profiling of Neonatal Porcine Ovaries.&rdquo; <em>Journal of Animal Science and Biotechnology</em> 10(1):1&ndash;15. doi: 10.1186/s40104-019-0340-y.</span></span></p>
  • <p><span style="font-size:12pt"><span style="font-family:Calibri,sans-serif">Lamont, K. R., and Tindall, D. J. (2010). Androgen Regulation of Gene Expression. Adv. Cancer Res. 107, 137&ndash;162. doi:10.1016/S0065-230X(10)07005-3.</span></span></p>
  • <p><span style="font-size:12pt"><span style="font-family:Calibri,sans-serif">MacLean, Helen E., W. S. Maria Chiu, Amanda J. Notini, Anna-Maree Axell, Rachel A. Davey, Julie F. McManus, Cathy Ma, David R. Plant, Gordon S. Lynch, and Jeffrey D. Zajac. 2008. &ldquo; Impaired Skeletal Muscle Development and Function in Male, but Not Female, Genomic Androgen Receptor Knockout Mice .&rdquo; <em>The FASEB Journal</em> 22(8):2676&ndash;89. doi: 10.1096/fj.08-105726.</span></span></p>
  • <p><span style="font-size:12pt"><span style="font-family:Calibri,sans-serif">Maiuri, Paolo, Anna Knezevich, Alex De Marco, Davide Mazza, Anna Kula, Jim G. McNally, and Alessandro Marcello. 2011. &ldquo;Fast Transcription Rates of RNA Polymerase II in Human Cells.&rdquo; <em>EMBO Reports</em> 12(12):1280&ndash;85. doi: 10.1038/embor.2011.196.</span></span></p>
  • <p><span style="font-size:12pt"><span style="font-family:Calibri,sans-serif">Mora, Gloria R., and Virendra B. Mahesh. 1999. <em>Autoregulation of the Androgen Receptor at the Translational Level: Testosterone Induces Accumulation of Androgen Receptor MRNA in the Rat Ventral Prostate Polyribosomes</em>.</span></span></p>
  • <p><span style="font-size:12pt"><span style="font-family:Calibri,sans-serif">Peng, Yajie, Hui Zhu, Bing Han, Yue Xu, Xuemeng Liu, Huaidong Song, and Jie Qiao. 2021. &ldquo;Identification of Potential Genes in Pathogenesis and Diagnostic Value Analysis of Partial Androgen Insensitivity Syndrome Using Bioinformatics Analysis.&rdquo; <em>Frontiers in Endocrinology</em> 12. doi: 10.3389/fendo.2021.731107.</span></span></p>
  • <p><span style="font-size:12pt"><span style="font-family:Calibri,sans-serif">Rana, Kesha, Barbara C. Fam, Michele V Clarke, Tammy P. S. Pang, Jeffrey D. Zajac, and Helen E. Maclean. 2011. &ldquo;Increased Adiposity in DNA Binding-Dependent Androgen Receptor Knockout Male Mice Associated with Decreased Voluntary Activity and Not Insulin Resistance.&rdquo; <em>Am J Physiol Endocrinol Me-Tab</em> 301:767&ndash;78. doi: 10.1152/ajpendo.00584.2010.-In.</span></span></p>
  • <p><span style="font-size:12pt"><span style="font-family:Calibri,sans-serif">Roy, Arun K., Rakesh K. Tyagi, Chung S. Song, Yan Lavrovsky, Soon C. Ahn, Tae Sung Oh, and Bandana Chatterjee. 2001. &ldquo;Androgen Receptor: Structural Domains and Functional Dynamics after Ligand-Receptor Interaction.&rdquo; Pp. 44&ndash;57 in <em>Annals of the New York Academy of Sciences</em>. Vol. 949. New York Academy of Sciences.</span></span></p>
  • <p><span style="font-size:12pt"><span style="font-family:Calibri,sans-serif">Russell, Patricia K., Michele V. Clarke, Jarrod P. Skinner, Tammy P. S. Pang, Jeffrey D. Zajac, and Rachel A. Davey. 2012. &ldquo;Identification of Gene Pathways Altered by Deletion of the Androgen Receptor Specifically in Mineralizing Osteoblasts and Osteocytes in Mice.&rdquo; <em>Journal of Molecular Endocrinology</em> 49(1):1&ndash;10. doi: 10.1530/JME-12-0014.</span></span></p>
  • <p><span style="font-size:12pt"><span style="font-family:Calibri,sans-serif">Shiina, Hiroko, Takahiro Matsumoto, Takashi Sato, Katsuhide Igarashi, Junko Miyamoto, Sayuri Takemasa, Matomo Sakari, Ichiro Takada, Takashi Nakamura, Daniel Metzger, Pierre Chambon, Jun Kanno, Hiroyuki Yoshikawa, and Shigeaki Kato. 2006. <em>Premature Ovarian Failure in Androgen Receptor-Deficient Mice</em>. Vol. 103.</span></span></p>
  • <p><span style="font-size:12pt"><span style="font-family:Calibri,sans-serif">Supakar, P. C., C. S. Song, M. H. Jung, M. A. Slomczynska, J. M. Kim, R. L. Vellanoweth, B. Chatterjee, and A. K. Roy. 1993. &ldquo;A Novel Regulatory Element Associated with Age-Dependent Expression of the Rat Androgen Receptor Gene.&rdquo; <em>Journal of Biological Chemistry</em> 268(35):26400&ndash;408. doi: 10.1016/s0021-9258(19)74328-2.</span></span></p>
  • <p><span style="font-size:12pt"><span style="font-family:Calibri,sans-serif">Tut, Thein G., Farid J. Ghadessy, M. A. Trifiro, L. Pinsky, and E. L. Yong. 1997. <em>Long Polyglutamine Tracts in the Androgen Receptor Are Associated with Reduced Trans-Activation, Impaired Sperm Production, and Male Infertility*</em>. Vol. 82.</span></span></p>
  • <p><span style="font-size:12pt"><span style="font-family:Calibri,sans-serif">Wang, Ruey Sheng, Shuyuan Yeh, Lu Min Chen, Hung Yun Lin, Caixia Zhang, Jing Ni, Cheng Chia Wu, P. Anthony Di Sant&rsquo;Agnese, Karen L. DeMesy-Bentley, Chii Ruey Tzeng, and Chawnshang Chang. 2006. &ldquo;Androgen Receptor in Sertoli Cell Is Essential for Germ Cell Nursery and Junctional Complex Formation in Mouse Testes.&rdquo; <em>Endocrinology</em> 147(12):5624&ndash;33. doi: 10.1210/en.2006-0138.</span></span></p>
  • <p><span style="font-size:12pt"><span style="font-family:Calibri,sans-serif">Welsh, M., L. Moffat, K. Belling, L. R. de Fran&ccedil;a, T. M. Segatelli, P. T. K. Saunders, R. M. Sharpe, and L. B. Smith. 2012. &ldquo;Androgen Receptor Signalling in Peritubular Myoid Cells Is Essential for Normal Differentiation and Function of Adult Leydig Cells.&rdquo; <em>International Journal of Andrology</em> 35(1):25&ndash;40. doi: 10.1111/j.1365-2605.2011.01150.x.</span></span></p>
  • <p><span style="font-size:12pt"><span style="font-family:Calibri,sans-serif">Willems, Ariane, Sergio R. Batlouni, Arantza Esnal, Johannes V. Swinnen, Philippa T. K. Saunders, Richard M. Sharpe, Luiz R. Fran&ccedil;a, Karel de Gendt, and Guido Verhoeven. 2010. &ldquo;Selective Ablation of the Androgen Receptor in Mouse Sertoli Cells Affects Sertoli Cell Maturation, Barrier Formation and Cytoskeletal Development.&rdquo; <em>PLoS ONE</em> 5(11). doi: 10.1371/journal.pone.0014168.</span></span></p>
  • <p><span style="font-size:12pt"><span style="font-family:Calibri,sans-serif">Wu, D. I., Grace Lin, and Andrea C. Gore. 2009. &ldquo;Age-Related Changes in Hypothalamic Androgen Receptor and Estrogen Receptor in Male Rats.&rdquo; <em>The Journal of Comparative Neurology</em> 512:688&ndash;701. doi: 10.1002/cne.21925.</span></span></p>
  • <p><span style="font-size:12pt"><span style="font-family:Calibri,sans-serif">Yu, I. Chen, Hung Yun Lin, Ning Chun Liu, Ruey Shen Wang, Janet D. Sparks, Shuyuan Yeh, and Chawnshang Chang. 2008. &ldquo;Hyperleptinemia without Obesity in Male Mice Lacking Androgen Receptor in Adipose Tissue.&rdquo; <em>Endocrinology</em> 149(5):2361&ndash;68. doi: 10.1210/en.2007-0516.</span></span></p>
  • <p><span style="font-size:12pt"><span style="font-family:Calibri,sans-serif">Yu, Shengqiang, Chiuan Ren Yeh, Yuanjie Niu, Hong Chiang Chang, Yu Chieh Tsai, Harold L. Moses, Chih Rong Shyr, Chawnshang Chang, and Shuyuan Yeh. 2012. &ldquo;Altered Prostate Epithelial Development in Mice Lacking the Androgen Receptor in Stromal Fibroblasts.&rdquo; <em>Prostate</em> 72(4):437&ndash;49. doi: 10.1002/pros.21445.</span></span></p>
  • <p><span style="font-size:12pt"><span style="font-family:Calibri,sans-serif">Zhang, Caixia, Shuyuan Yeh, Yen-Ta Chen, Cheng-Chia Wu, Kuang-Hsiang Chuang, Hung-Yun Lin, Ruey-Sheng Wang, Yu-Jia Chang, Chamindrani Mendis-Handagama, Liquan Hu, Henry Lardy, Chawnshang Chang, and &dagger; &dagger; George. 2006. <em>Oligozoospermia with Normal Fertility in Male Mice Lacking the Androgen Receptor in Testis Peritubular Myoid Cells</em>.</span></span></p>
  • <p><span style="font-size:12pt"><span style="font-family:Calibri,sans-serif">Zhou, Wei, Gensheng Wang, Christopher L. Small, Zhilin Liu, Connie C. Weng, Lizhong Yang, Michael D. Griswold, and Marvin L. Meistrich. 2011. &ldquo;Erratum: Gene Expression Alterations by Conditional Knockout of Androgen Receptor in Adult Sertoli Cells of Utp14bjsd/Jsd (Jsd) Mice (Biology of Reproduction (2010) 83, (759-766) DOI: 10.1095/Biolreprod.110.085472).&rdquo; <em>Biology of Reproduction</em> 84(2):400&ndash;408.</span></span></p>
  • </div>
  • <br>
  • <div>
  • <h4><a href="/relationships/2127">Relationship: 2127: Decreased, Transcription of genes by AR leads to short male AGD</a></h4>
  • <div>
  • <h4><a href="/relationships/2127">Relationship: 2127: Altered, Transcription of genes by the AR leads to AGD, decreased</a></h4>
  • <h4>AOPs Referencing Relationship</h4>
  • <div class="panel panel-default">
  • <table class="table table-bordered table-striped">
  • <thead>
  • <div class="table-responsive">
  • <table class="table table-bordered table-fullwidth">
  • <thead class="thead-light">
  • <tr>
  • <th scope="col">AOP Name</th>
  • <th scope="col">Adjacency</th>
  • <th scope="col">Weight of Evidence</th>
  • <th scope="col">Quantitative Understanding</th>
  • </tr>
  • </thead>
  • <tbody class="tbody-striped">
  • <tr>
  • <th>AOP Name</th>
  • <th>Adjacency</th>
  • <th>Weight of Evidence</th>
  • <th>Quantitative Understanding</th>
  • <td><a href="/aops/307">Decreased testosterone synthesis leading to short anogenital distance (AGD) in male (mammalian) offspring</a></td>
  • <td>adjacent</td>
  • <td>Moderate</td>
  • <td>Moderate</td>
  • </tr>
  • </thead>
  • <tbody>
  • <tr>
  • <th><a href="/aops/307">Decreased testosterone synthesis leading to short anogenital distance (AGD) in male (mammalian) offspring</a></th>
  • <th>adjacent</th>
  • <th>Moderate </th>
  • <th>Moderate</th>
  • </tr>
  • </tbody>
  • </table>
  • </div>
  • <!-- if nothing shows up in any of these fields, then evidence supporting this KER will not be displayed -->
  • <!--<!% unless aop_rel.relationship.relationship_taxons.blank? %>-->
  • <!--<!%= render 'snapshot_taxons', taxons: aop_rel.relationship.relationship_taxons %>-->
  • <!--<!% unless aop_rel.relationship.taxon_evidence.blank? %>-->
  • <!--<h3>Domain of Applicability</h3>-->
  • <!--<!%== aop_rel.relationship.taxon_evidence %>-->
  • <!--<!% end %>-->
  • <!--<!% end %>-->
  • </tbody>
  • </table>
  • </div>
  • </div>
  • <br>
  • <h3>List of Non Adjacent Key Event Relationships</h3>
  • <div>
  • <h4><a href="/relationships/2131">Relationship: 2131: reduction, testosterone levels leads to Decrease, AR activation</a></h4>
  • <h3>List of Non Adjacent Key Event Relationships</h3>
  • <div>
  • <h4><a href="/relationships/2131">Relationship: 2131: Decrease, testosterone levels leads to Decrease, AR activation</a></h4>
  • <h4>AOPs Referencing Relationship</h4>
  • <div class="panel panel-default">
  • <table class="table table-bordered table-striped">
  • <thead>
  • <div class="table-responsive">
  • <table class="table table-bordered table-fullwidth">
  • <thead class="thead-light">
  • <tr>
  • <th scope="col">AOP Name</th>
  • <th scope="col">Adjacency</th>
  • <th scope="col">Weight of Evidence</th>
  • <th scope="col">Quantitative Understanding</th>
  • </tr>
  • </thead>
  • <tbody class="tbody-striped">
  • <tr>
  • <th>AOP Name</th>
  • <th>Adjacency</th>
  • <th>Weight of Evidence</th>
  • <th>Quantitative Understanding</th>
  • <td><a href="/aops/307">Decreased testosterone synthesis leading to short anogenital distance (AGD) in male (mammalian) offspring</a></td>
  • <td>non-adjacent</td>
  • <td>Moderate</td>
  • <td>Moderate</td>
  • </tr>
  • </thead>
  • <tbody>
  • <tr>
  • <th><a href="/aops/307">Decreased testosterone synthesis leading to short anogenital distance (AGD) in male (mammalian) offspring</a></th>
  • <th>non-adjacent</th>
  • <th>Moderate </th>
  • <th>Moderate</th>
  • </tr>
  • </tbody>
  • </table>
  • </div>
  • <!-- if nothing shows up in any of these fields, then evidence supporting this KER will not be displayed -->
  • </tbody>
  • </table>
  • </div>
  • <h4>Evidence Supporting Applicability of this Relationship</h4>
  • <div>
  • <strong>Taxonomic Applicability</strong>
  • <div class="table-responsive">
  • <table class="table table-bordered table-fullwidth">
  • <thead class="thead-light">
  • <tr>
  • <th scope="col">Term</th>
  • <th scope="col">Scientific Term</th>
  • <th scope="col">Evidence</th>
  • <th scope="col">Links</th>
  • </tr>
  • </thead>
  • <tbody class="tbody-striped">
  • <tr>
  • <td>Vertebrates</td>
  • <td>Vertebrates</td>
  • <td>High</td>
  • <td><a href="http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&id=0" target="_blank">NCBI</a></td>
  • </tr>
  • </tbody>
  • </table>
  • </div>
  • </div>
  • <div>
  • <strong>Life Stage Applicability</strong>
  • <div class="table-responsive">
  • <table class="table table-bordered table-fullwidth">
  • <thead class="thead-light">
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  • <th scope="col">Life Stage</th>
  • <th scope="col">Evidence</th>
  • </tr>
  • </thead>
  • <tbody class="tbody-striped">
  • <tr>
  • <td>During development and at adulthood</td>
  • <td>High</td>
  • </tr>
  • </tbody>
  • </table>
  • </div>
  • </div>
  • <div>
  • <strong>Sex Applicability</strong>
  • <div class="table-responsive">
  • <table class="table table-bordered table-fullwidth">
  • <thead class="thead-light">
  • <tr>
  • <th scope="col">Sex</th>
  • <th scope="col">Evidence</th>
  • </tr>
  • </thead>
  • <tbody class="tbody-striped">
  • <tr>
  • <td>Mixed</td>
  • <td>High</td>
  • </tr>
  • </tbody>
  • </table>
  • </div>
  • </div>
  • <h4>Key Event Relationship Description</h4>
  • <p><span style="font-size:11pt">This key event relationship links decreased testosterone (T) levels to decreased androgen receptor (AR) activation. T is an endogenous steroid hormone important for, amongst other things, reproductive organ development and growth as well as muscle mass and spermatogenesis <span style="color:black">(Marks, 2004)</span>.T is, together with dihydrotestosterone (DHT), a primary ligand for the AR in mammals, whereas in teleost fishes 11-ketotestosterone is another main androgen (Schuppe et al., 2020). Besides its genomic actions, the AR can also mediate rapid, non-genomic second messenger signaling (Davey &amp; Grossmann, 2016). When T levels are reduced, less substrate is available for the AR, and hence, AR activation is decreased <span style="color:black">(Gao et al., 2005)</span>. </span></p>
  • <h4>Evidence Supporting this KER</h4>
  • <strong>Biological Plausibility</strong>
  • <p><span style="font-size:11pt">The biological plausibility for this KER is considered high</span></p>
  • <p><span style="font-size:11pt"><strong>&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; </strong></span></p>
  • <p style="text-align:justify"><span style="font-size:11pt">AR activation is dependent on ligand binding (though a few cases of ligand-independent AR activation has been shown, see <em>uncertainties and inconsistencies</em>). T is a primary ligand for the AR, and when T levels are decreased there is less substrate for the AR, and hence, AR activation is decreased. In the male, T is primarily synthesized by the testes, and in some target tissues T is irreversibly metabolized to the more potent metabolite DHT. T and DHT both bind to the AR, but DHT has a higher binding affinity <span style="color:black">(Gao et al., 2005)</span>. The lower binding affinity of T compared to DHT is due to the faster dissociation rate of T from the full-length AR, as T has less effective FXXLF motif binding to AF2 <span style="color:black">(Askew et al., 2007)</span>. Binding of T or DHT has different effects in different tissues. E.g. in the developing male, T is required for development of the internal sex organs (epididymis, vas deferens and the seminal vesicles), whereas DHT is crucial for development of the external sex organs <span style="color:black">(Keller et al., 1996)</span>. In the adult male, androgen action in the reproductive tissues is DHT dependent, whereas action in muscle and bone is DHT independent <span style="color:black">(Gao et al., 2005)</span>. In patients with male androgen deficiency syndrome (AIS), clinically low levels of T leads to reduced AR activation (either due to low T or DHT in target tissue), which manifests as both androgenic related symptoms (such as incomplete or delayed sexual development, loss of body hair, small or shrinking testes, low or zero sperm count) as well as anabolic related symptoms (such as height loss, low trauma fracture, low bone mineral density, reduced muscle bulk and strength, increased body fat). All symptoms can be counteracted by treatment with T, which acts directly on the AR receptor in anabolic tissue <span style="color:black">(Bhasin et al., 2010)</span>. Similarly, removal of the testicles in weanling rats results in a feminized body composition and muscle metabolism, which is reversed by administration of testosterone <span style="color:black">(Krotkiewski et al., 1980)</span>. As this demonstrates, the consequences of low T regarding AR activation will depend on tissue, life stage, species etc. </span></p>
  • <strong>Empirical Evidence</strong>
  • <p style="text-align:justify"><span style="font-size:11pt">The empirical evidence for this KER is considered high</span></p>
  • <p style="text-align:justify"><span style="font-size:11pt"><strong><em>Dose concordance</em></strong></span></p>
  • <p style="text-align:justify"><span style="font-size:11pt">There is a positive dose-response relationship between increasing concentrations of T and AR activation <span style="color:black">(U.S. EPA., 2023)</span>. </span></p>
  • <p style="text-align:justify"><span style="font-size:11pt"><strong><em>Other evidence </em></strong></span></p>
  • <ul>
  • <li style="text-align:justify"><span style="color:black">In male patients with androgen deficiency, treatment with T counteracts anabolic (DHT independent) related symptoms such as height loss, low trauma fracture, low bone mineral density, reduced muscle bulk and strength, increased </span>body fat <span style="color:black">(Bhasin et al., 2010; Katznelson et al., 1996)</span>.</li>
  • <li style="text-align:justify"><span style="font-size:11pt">Removal of the testicles in weanling rats result in a feminized body composition and muscle metabolism, which is reversed by administration of T <span style="color:black">(Krotkiewski et al., 1980)</span>.</span></li>
  • </ul>
  • <strong>Uncertainties and Inconsistencies</strong>
  • <p><span style="font-size:11pt">Ligand-independent actions of the AR have been identified. To what extent and of which biological significance is not well defined (Bennesch &amp; Picard, 2015). </span></p>
  • <h4>Quantitative Understanding of the Linkage</h4>
  • <strong>Response-response relationship</strong>
  • <p><span style="font-size:11pt">There is a positive dose-response relationship between increasing concentrations of T and AR activation <span style="color:black">(U.S. EPA., 2023)</span>. However, there is not enough data, or overview of the data, to define a quantitative linkage <em>in vivo</em>, and such a relationship will differ between biological systems (species, tissue, cell type).</span></p>
  • <strong>Time-scale</strong>
  • <p style="text-align:justify"><span style="font-size:11pt">AR and promoter interactions occur within 15 minutes of ligand binding, and RNA polymerase II and coactivator recruitment are then proposed to occur transiently with cycles of approximately 90 minutes <span style="color:black">(Kang et al., 2002)</span>. </span></p>
  • <strong>Known modulating factors</strong>
  • <table class="table table-bordered table-fullwidth">
  • <thead>
  • <tr>
  • <th>Modulating Factor (MF)</th>
  • <th>MF Specification</th>
  • <th>Effect(s) on the KER</th>
  • <th>Reference(s)</th>
  • </tr>
  • </thead>
  • <tbody>
  • <tr>
  • <td><span style="font-size:11.0pt"><span style="font-family:&quot;Calibri&quot;,sans-serif">Age</span></span></td>
  • <td><span style="font-size:11.0pt"><span style="font-family:&quot;Calibri&quot;,sans-serif">AR expression changes with aging </span></span></td>
  • <td><span style="font-size:11.0pt"><span style="font-family:&quot;Calibri&quot;,sans-serif">Tissue-specific alterations in AR activity with aging</span></span></td>
  • <td><span style="font-size:11.0pt"><span style="font-family:&quot;Calibri&quot;,sans-serif"><span style="color:black">(Supakar et al., 1993; Wu et al., 2009)</span></span></span></td>
  • </tr>
  • <tr>
  • <td><span style="font-size:11.0pt"><span style="font-family:&quot;Calibri&quot;,sans-serif">Genotype</span></span></td>
  • <td><span style="font-size:11.0pt"><span style="font-family:&quot;Calibri&quot;,sans-serif">Number of CAG repeats in the first exon of AR</span></span></td>
  • <td><span style="font-size:11.0pt"><span style="font-family:&quot;Calibri&quot;,sans-serif">Decreased AR activation with increased number of CAGs</span></span></td>
  • <td><span style="font-size:11.0pt"><span style="font-family:&quot;Calibri&quot;,sans-serif">(Chamberlain et al., 1994; Tut et al., 1997)</span></span></td>
  • </tr>
  • <tr>
  • <td><span style="font-size:11.0pt"><span style="font-family:&quot;Calibri&quot;,sans-serif">Male androgen deficiency syndrome</span></span></td>
  • <td><span style="font-size:11.0pt"><span style="font-family:&quot;Calibri&quot;,sans-serif">Low circulating testosterone levels due to primary (testicular) or secondary (pituitary-hypothalamic) hypogonadism</span></span></td>
  • <td><span style="font-size:11.0pt"><span style="font-family:&quot;Calibri&quot;,sans-serif">Reduced levels of circulating testosterone</span></span></td>
  • <td><span style="font-size:11.0pt"><span style="font-family:&quot;Calibri&quot;,sans-serif"><span style="color:black">(Bhasin et al., 2010)</span></span></span></td>
  • </tr>
  • <tr>
  • <td><span style="font-size:11.0pt"><span style="font-family:&quot;Calibri&quot;,sans-serif">Castration</span></span></td>
  • <td><span style="font-size:11.0pt"><span style="font-family:&quot;Calibri&quot;,sans-serif">Removal of testicles</span></span></td>
  • <td><span style="font-size:11.0pt"><span style="font-family:&quot;Calibri&quot;,sans-serif">Reduced levels of circulating testosterone</span></span></td>
  • <td><span style="font-size:11.0pt"><span style="font-family:&quot;Calibri&quot;,sans-serif"><span style="color:black">(Krotkiewski et al., 1980)</span></span></span></td>
  • </tr>
  • </tbody>
  • </table>
  • <!--<!% unless aop_rel.relationship.relationship_taxons.blank? %>-->
  • <!--<!%= render 'snapshot_taxons', taxons: aop_rel.relationship.relationship_taxons %>-->
  • <!--<!% unless aop_rel.relationship.taxon_evidence.blank? %>-->
  • <!--<h3>Domain of Applicability</h3>-->
  • <!--<!%== aop_rel.relationship.taxon_evidence %>-->
  • <!--<!% end %>-->
  • <!--<!% end %>-->
  • <strong>Known Feedforward/Feedback loops influencing this KER</strong>
  • <p><span style="font-size:11pt">Androgens can upregulate and downregulate AR expression (Lee &amp; Chang, 2003).</span></p>
  • <h4>References</h4>
  • <p><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif">Askew, E. B., Gampe, R. T., Stanley, T. B., Faggart, J. L., &amp; Wilson, E. M. (2007). Modulation of Androgen Receptor Activation Function 2 by Testosterone and Dihydrotestosterone. <em>Journal of Biological Chemistry</em>, <em>282</em>(35), 25801&ndash;25816. https://doi.org/10.1074/jbc.M703268200</span></span></p>
  • <p><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif">Bennesch, M. A., &amp; Picard, D. (2015). Minireview: Tipping the Balance: Ligand-Independent Activation of Steroid Receptors. <em>Molecular Endocrinology</em>, <em>29</em>(3), 349&ndash;363. https://doi.org/10.1210/me.2014-1315</span></span></p>
  • <p><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif">Bhasin, S., Cunningham, G. R., Hayes, F. J., Matsumoto, A. M., Snyder, P. J., Swerdloff, R. S., &amp; Montori, V. M. (2010). Testosterone Therapy in Men with Androgen Deficiency Syndromes: An Endocrine Society Clinical Practice Guideline. <em>The Journal of Clinical Endocrinology &amp; Metabolism</em>, <em>95</em>(6), 2536&ndash;2559. https://doi.org/10.1210/jc.2009-2354</span></span></p>
  • <p><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif">Davey, R. A., &amp; Grossmann, M. (2016). Androgen Receptor Structure, Function and Biology: From Bench to Bedside. <em>The Clinical Biochemist. Reviews</em>, <em>37</em>(1), 3&ndash;15. http://www.ncbi.nlm.nih.gov/pubmed/27057074</span></span></p>
  • <p><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif">Gao, W., Bohl, C. E., &amp; Dalton, J. T. (2005). Chemistry and Structural Biology of Androgen Receptor. <em>Chemical Reviews</em>, <em>105</em>(9), 3352&ndash;3370. https://doi.org/10.1021/cr020456u</span></span></p>
  • <p><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif">Kang, Z., Pirskanen, A., J&auml;nne, O. A., &amp; Palvimo, J. J. (2002). Involvement of Proteasome in the Dynamic Assembly of the Androgen Receptor Transcription Complex. <em>Journal of Biological Chemistry</em>, <em>277</em>(50), 48366&ndash;48371. https://doi.org/10.1074/jbc.M209074200</span></span></p>
  • <p><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif">Katznelson, L., Finkelstein, J. S., Schoenfeld, D. A., Rosenthal, D. I., Anderson, E. J., &amp; Klibanski, A. (1996). Increase in bone density and lean body mass during testosterone administration in men with acquired hypogonadism. <em>The Journal of Clinical Endocrinology &amp; Metabolism</em>, <em>81</em>(12), 4358&ndash;4365. https://doi.org/10.1210/jcem.81.12.8954042</span></span></p>
  • <p><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif">Keller, E. T., Ershler, W. B., &amp; Chang, Chawnshang. (1996). The androgen receptor: A mediator of diverse responses. <em>Frontiers in Bioscience</em>, <em>1</em>(4), 59&ndash;71. https://doi.org/10.2741/A116</span></span></p>
  • <p><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif">Krotkiewski, M., Kral, J. G., &amp; Karlsson, J. (1980). Effects of castration and testosterone substitution on body composition and muscle metabolism in rats. <em>Acta Physiologica Scandinavica</em>, <em>109</em>(3), 233&ndash;237. https://doi.org/10.1111/j.1748-1716.1980.tb06592.x</span></span></p>
  • <p><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif">Lee, D. K., &amp; Chang, C. (2003). Expression and Degradation of Androgen Receptor: Mechanism and Clinical Implication. <em>The Journal of Clinical Endocrinology &amp; Metabolism</em>, <em>88</em>(9), 4043&ndash;4054. https://doi.org/10.1210/jc.2003-030261</span></span></p>
  • <p><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif">Marks, L. S. (2004). 5alpha-reductase: history and clinical importance. <em>Reviews in Urology</em>, <em>6 Suppl 9</em>(Suppl 9), S11-21. <a href="http://www.ncbi.nlm.nih.gov/pubmed/16985920" style="color:#0563c1; text-decoration:underline">http://www.ncbi.nlm.nih.gov/pubmed/16985920</a></span></span></p>
  • <p><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif">Schuppe, E. R., Miles, M. C., and Fuxjager, M. J. (2020). Evolution of the androgen receptor: Perspectives from human health to dancing birds. Mol. Cell. Endocrinol. 499, 110577. doi:10.1016/J.MCE.2019.110577.</span></span></p>
  • <p><span style="font-size:11.0pt"><span style="font-family:&quot;Calibri&quot;,sans-serif">U.S. EPA. (2023). <em>ToxCast &amp; Tox21 AR agonism of testosterone.</em> Retrieved from Https://Www.Epa.Gov/Chemical-Research/Toxicity-Forecaster-Toxcasttm-Data June 23, 2023. </span></span><span style="font-size:11.0pt"><span style="font-family:&quot;Calibri&quot;,sans-serif">Data Released October 2018.</span></span></p>
  • </div>
  • <br>
  • <div>
  • <h4><a href="/relationships/2820">Relationship: 2820: Decrease, AR activation leads to AGD, decreased</a></h4>
  • <h4>AOPs Referencing Relationship</h4>
  • <div class="table-responsive">
  • <table class="table table-bordered table-fullwidth">
  • <thead class="thead-light">
  • <tr>
  • <th scope="col">AOP Name</th>
  • <th scope="col">Adjacency</th>
  • <th scope="col">Weight of Evidence</th>
  • <th scope="col">Quantitative Understanding</th>
  • </tr>
  • </thead>
  • <tbody class="tbody-striped">
  • <tr>
  • <td><a href="/aops/305">5α-reductase inhibition leading to short anogenital distance (AGD) in male (mammalian) offspring</a></td>
  • <td>non-adjacent</td>
  • <td></td>
  • <td></td>
  • </tr>
  • <tr>
  • <td><a href="/aops/306">Androgen receptor (AR) antagonism leading to short anogenital distance (AGD) in male (mammalian) offspring</a></td>
  • <td>non-adjacent</td>
  • <td></td>
  • <td></td>
  • </tr>
  • <tr>
  • <td><a href="/aops/307">Decreased testosterone synthesis leading to short anogenital distance (AGD) in male (mammalian) offspring</a></td>
  • <td>non-adjacent</td>
  • <td></td>
  • <td></td>
  • </tr>
  • </tbody>
  • </table>
  • </div>
  • <!-- end relationship loop -->
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