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Aop: 305

AOP Title

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5α-reductase inhibition leading to short anogenital distance (AGD) in male (mammalian) offspring

Short name:

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5α-reductase inhibition leading to short AGD

Graphical Representation

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Authors

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Monica Kam Draskau; National Food Institute, Technical University of Denmark, Kongens Lyngby, 2800 Denmark

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 Do not cite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 September 08, 2020 14:48

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Revision dates for related pages

Page Revision Date/Time
5α-reductase, inhibition April 18, 2019 19:48
Decrease, dihydrotestosterone (DHT) level April 10, 2019 05:22
Decrease, androgen receptors (AR) activation April 10, 2019 05:24
decrease, transcription of genes by AR August 30, 2019 04:19
decrease, male anogenital distance June 09, 2020 12:07
5α-reductase, inhibition leads to Decrease, DHT level April 18, 2019 19:54
Decrease, DHT level leads to Decrease, AR activation June 03, 2019 08:41
Decrease, AR activation leads to decrease, transcription of genes by AR May 11, 2020 07:37
decrease, transcription of genes by AR leads to short male AGD May 11, 2020 07:37
Finasteride November 29, 2016 18:42

Abstract

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This AOP links 5α-reductase inhibition during fetal life 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).

5α-reductase is an enzyme responsible for the conversion of testosterone to DHT in target tissues. DHT is more potent agonist of the Androgen receptor (AR) than testosterone, so that DHT is necessary for proper masculinization of e.g. male external genitalia. Under normal physiological conditions, testosterone produced mainly 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 5α-reductase that converts testosterone into the more potent DHT in androgen sensitive target tissues. This includes developing perineal region, which, when DHT levels are low or absent, leads to inactivation of the AR and failure to properly masculinize the perineum/LABC complex.


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
MIE 1617 5α-reductase, inhibition 5α-reductase, inhibition
KE 1613 Decrease, dihydrotestosterone (DHT) level Decrease, DHT level
KE 1614 Decrease, androgen receptors (AR) activation Decrease, AR activation
KE 1687 decrease, transcription of genes by AR decrease, 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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Title Adjacency Evidence Quantitative Understanding
5α-reductase, inhibition leads to Decrease, DHT level adjacent High High
Decrease, DHT level leads to Decrease, AR activation adjacent High Moderate
Decrease, AR activation leads to decrease, transcription of genes by AR adjacent Moderate Low
decrease, transcription of genes by AR leads to short male AGD adjacent Moderate Low

Network View

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Stressors

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Name Evidence Term
Finasteride High

Life Stage Applicability

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Life stage Evidence
Pregnancy High

Taxonomic Applicability

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Term Scientific Term Evidence Link
human Homo sapiens Moderate NCBI
rat Rattus norvegicus High NCBI
mouse Mus musculus Moderate NCBI

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.