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Aop: 307

AOP Title

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Decreased testosterone synthesis leading to short anogenital distance (AGD) in male (mammalian) offspring

Short name:

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Decreased testosterone synthesis leading to short AGD

Graphical Representation

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Authors

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Terje Svingen; National Food Institute, Technical University of Denmark, Kongens Lyngby, 2800 Denmark

Point of Contact

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Terje Svingen   (email point of contact)

Contributors

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  • Terje Svingen

Status

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Author status OECD status OECD project SAAOP status
Under development: Not open for comment. Do not cite


This AOP was last modified on August 30, 2019 04:47

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Revision dates for related pages

Page Revision Date/Time
Reduction, Testosterone synthesis in Leydig cells September 16, 2017 10:14
reduction, testosterone levels August 30, 2019 04:40
Decrease, dihydrotestosterone (DHT) level April 10, 2019 05:22
Decrease, androgen receptors (AR) activation April 10, 2019 05:24
Decreased, Transcription of genes by AR September 16, 2017 10:14
decrease, male anogenital distance August 31, 2019 12:07
Dibutyl phthalate November 29, 2016 18:42
Bis(2-ethylhexyl) phthalate November 29, 2016 18:42

Abstract

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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 ‘adverse’ from a human health perspective, it is considered an ‘adverse outcome’ 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).

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 5α-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.

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 5α-reductase). Low DHT fails to properly activate AR in target tissues, including  the developing perineal region, which leads to failure to properly masculinize the perineum/LABC complex and ultimately a short AGD.


Background (optional)

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Summary of the AOP

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Events: Molecular Initiating Events (MIE)

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Key Events (KE)

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Adverse Outcomes (AO)

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Sequence Type Event ID Title Short name
KE 413 Reduction, Testosterone synthesis in Leydig cells Reduction, Testosterone synthesis in Leydig cells
KE 1690 reduction, testosterone levels reduction, testosterone levels
KE 1613 Decrease, dihydrotestosterone (DHT) level Decrease, DHT level
KE 1614 Decrease, androgen receptors (AR) activation Decrease, AR activation
KE 286 Decreased, Transcription of genes by AR Decreased, Transcription of genes by AR
AO 1688 decrease, male anogenital distance short male AGD

Relationships Between Two Key Events
(Including MIEs and AOs)

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Network View

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Stressors

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Name Evidence Term
Dibutyl phthalate High
Bis(2-ethylhexyl) phthalate High

Life Stage Applicability

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Life stage Evidence
Foetal High

Taxonomic Applicability

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Sex Applicability

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Sex Evidence
Male High

Overall Assessment of the AOP

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Domain of Applicability

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Essentiality of the Key Events

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Evidence Assessment

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Quantitative Understanding

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Considerations for Potential Applications of the AOP (optional)

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References

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1. Schwartz CL, Christiansen S, Vinggaard AM, Axelstad M, Hass U and Svingen T (2019), Anogenital distance as a toxicological or clinical marker for fetal androgen action and risk for reproductive disorders. Arch Toxicol 93: 253-272.