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AOP: 307

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

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Handbook Version v2.0

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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Cataia Ives (email point of contact)

Contributors

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Terje Svingen
Cataia Ives

Coaches

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Judy Choi
Shihori Tanabe

OECD Information Table

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OECD Project #	OECD Status	Reviewer's Reports	Journal-format Article	OECD iLibrary Published Version
1.90	Under Development

This AOP was last modified on May 26, 2024 20:39

Revision dates for related pages

Page	Revision Date/Time
Reduction, Testosterone synthesis in Leydig cells	September 16, 2017 10:14
Decrease, testosterone levels	May 24, 2024 12:27
Decrease, dihydrotestosterone (DHT) level	April 05, 2024 08:10
Decrease, androgen receptor activation	April 05, 2024 08:19
Altered, Transcription of genes by the androgen receptor	April 05, 2024 09:28
anogenital distance (AGD), decreased	December 22, 2022 05:18
Reduction, Testosterone synthesis in Leydig cells leads to Decrease, testosterone levels	May 01, 2024 16:10
Decrease, testosterone levels leads to Decrease, AR activation	April 05, 2024 09:18
Decrease, testosterone levels leads to Decrease, DHT level	October 19, 2023 08:31
Decrease, DHT level leads to Decrease, AR activation	April 05, 2024 08:48
Decrease, AR activation leads to Altered, Transcription of genes by the AR	April 05, 2024 08:50
Altered, Transcription of genes by the AR leads to AGD, decreased	May 11, 2020 07:04
Decrease, AR activation leads to AGD, decreased	December 22, 2022 05:20
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.

AOP Development Strategy

Context

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Strategy

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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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Type	Event ID	Title	Short name

KE	413	Reduction, Testosterone synthesis in Leydig cells	Reduction, Testosterone synthesis in Leydig cells
KE	1690	Decrease, testosterone levels	Decrease, testosterone levels
KE	1613	Decrease, dihydrotestosterone (DHT) level	Decrease, DHT level
KE	1614	Decrease, androgen receptor activation	Decrease, AR activation
KE	286	Altered, Transcription of genes by the androgen receptor	Altered, Transcription of genes by the AR

1688

anogenital distance (AGD), decreased

AGD, decreased

Relationships Between Two Key Events (Including MIEs and AOs)

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Title	Adjacency	Evidence	Quantitative Understanding

Reduction, Testosterone synthesis in Leydig cells leads to Decrease, testosterone levels	adjacent	High	Moderate
Decrease, testosterone levels leads to Decrease, DHT level	adjacent	Moderate	Low
Decrease, DHT level leads to Decrease, AR activation	adjacent	High	Moderate
Decrease, AR activation leads to Altered, Transcription of genes by the AR	adjacent	High	Moderate
Altered, Transcription of genes by the AR leads to AGD, decreased	adjacent	Moderate	Moderate

Decrease, testosterone levels leads to Decrease, AR activation	non-adjacent	Moderate	Moderate
Decrease, AR activation leads to AGD, decreased	non-adjacent

Network View

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Prototypical Stressors

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Name
Dibutyl phthalate
Bis(2-ethylhexyl) phthalate

Life Stage Applicability

The life stage for which the AOP is known to be applicable. More help

Life stage	Evidence
Foetal	High
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

The sex for which the AOP is known to be applicable. More help

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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Known Modulating Factors

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Quantitative Understanding

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Considerations for Potential Applications of the AOP (optional)

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References

List of the literature that was cited for this AOP. More help

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.