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Aop: 305

Title

A descriptive phrase which references both the Molecular Initiating Event and Adverse Outcome.It should take the form “MIE leading to AO”. For example, “Aromatase inhibition leading to reproductive dysfunction” where Aromatase inhibition is the MIE and reproductive dysfunction the AO. In cases where the MIE is unknown or undefined, the earliest known KE in the chain (i.e., furthest upstream) should be used in lieu of the MIE and it should be made clear that the stated event is a KE and not the MIE. More help

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

The user responsible for managing the AOP entry in the AOP-KB and controlling write access to the page by defining the contributors as described in the next section. More help

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 Do not cite	Under Development	1.90	Included in OECD Work Plan

This AOP was last modified on December 22, 2022 05:23

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
anogenital distance (AGD), decreased	December 22, 2022 05:18
Altered, Transcription of genes by AR	November 04, 2020 11:11
5α-reductase, inhibition leads to Decrease, DHT level	April 18, 2019 19:54
Decrease, AR activation leads to AGD, decreased	December 22, 2022 05:20
Decrease, DHT level leads to Decrease, AR activation	February 02, 2021 05:50
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.

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)

An AO is a specialized KE that represents the end (an adverse outcome of regulatory significance) of an AOP. More help

Type	Event ID	Title	Short name

MIE

1617

5α-reductase, inhibition

KE	1613	Decrease, dihydrotestosterone (DHT) level	Decrease, DHT level
KE	1614	Decrease, androgen receptors (AR) activation	Decrease, AR activation
KE	286	Altered, Transcription of genes by AR	Altered, Transcription of genes by 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

5α-reductase, inhibition leads to Decrease, DHT level	adjacent	High	High
Decrease, DHT level leads to Decrease, AR activation	adjacent

Decrease, AR activation leads to AGD, decreased

non-adjacent

Network View

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Prototypical Stressors

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Name
Finasteride

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

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

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.