This AOP is licensed under a Creative Commons Attribution 4.0 International License.

Aop: 344

Title

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Androgen receptor (AR) antagonism leading to nipple retention (NR) in male (mammalian) offspring

Short name

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AR antagonism leading to NR

Graphical Representation

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Authors

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Sofie Christiansen; National Food Institute, Technical University of Denmark, Kongens Lyngby, 2800 Denmark

Louise Ramhøj; 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 Do not cite	Under Development	1.108	Included in OECD Work Plan

This AOP was last modified on February 06, 2023 05:16

Revision dates for related pages

Page	Revision Date/Time
Decrease, androgen receptors (AR) activation	April 10, 2019 05:24
Altered, Transcription of genes by AR	November 04, 2020 11:11
Antagonism, Androgen receptor	June 15, 2022 06:17
Nipple retention (NR), increased	January 11, 2023 05:53
Antagonism, Androgen receptor leads to Decrease, AR activation	May 11, 2020 07:39
Antagonism, Androgen receptor leads to nipple retention, increased	January 11, 2023 06:22
Decrease, AR activation leads to Altered, Transcription of genes by AR	May 11, 2020 06:50
Altered, Transcription of genes by AR leads to nipple retention, increased	May 11, 2020 10:24

Abstract

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This AOP links Androgen receptor antagonism during fetal life with nipple retention (NR) in male rat offspring. NR, measured around 2 weeks post partum, is a marker for feminization of male rat fetuses and is associated with general feminization of male offspring. Although NR is not a directly applicable measure in humans (male humans normally retain two nipples), it is nevertheless considered an ‘adverse outcome’ in OECD test guidelines; NR measurements are mandatory in specific tests for developmental and reproductive toxicity in chemical risk assessment (TG 443, TG 421/422, TG 414).

The AR is a nuclear receptor involved in the transcriptional regulation of various target genes during development and adulthood across species. Its main ligand is testosterone and dihydrotestosterone (DHT). 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 normal masculinization of the developing fetus, and AR action in male rats signals the nipple anlagen to regress, leaving males with no nipples.

The key events in this pathway is antagonism of the AR in target cells of the nipple anlagen, which leads to inactivation of the AR and failure to suppress development of the nipples. In this instance, the local levels of testosterone or DHT may be normal, but prevented from binding the AR.

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

MIE

Antagonism, Androgen receptor

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

1786

Nipple retention (NR), increased

nipple retention, increased

Relationships Between Two Key Events (Including MIEs and AOs)

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Title	Adjacency	Evidence	Quantitative Understanding

Antagonism, Androgen receptor leads to Decrease, AR activation	adjacent	High
Decrease, AR activation leads to Altered, Transcription of genes by AR	adjacent	Moderate	Moderate
Altered, Transcription of genes by AR leads to nipple retention, increased	adjacent	Moderate	Low

Antagonism, Androgen receptor leads to nipple retention, increased

non-adjacent

Moderate

Low

Network View

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Prototypical Stressors

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Life Stage Applicability

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Taxonomic Applicability

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Sex Applicability

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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

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