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Aop: 344

AOP 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 Do not cite


This AOP was last modified on September 08, 2020 14:50

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Revision dates for related pages

Page Revision Date/Time
Decrease, androgen receptors (AR) activation April 10, 2019 05:24
Decreased, Transcription of genes by AR August 07, 2020 06:53
Antagonism, Androgen receptor May 17, 2020 10:54
increase, retained nipples in males May 11, 2020 10:07
Antagonism, Androgen receptor leads to Decrease, AR activation May 11, 2020 07:39
Antagonism, Androgen receptor leads to nipple retention (NR) male May 11, 2020 10:24
Decrease, AR activation leads to Decreased, Transcription of genes by AR May 11, 2020 06:50
Decreased, Transcription of genes by AR leads to nipple retention (NR) male 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.

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 26 Antagonism, Androgen receptor Antagonism, Androgen receptor
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 1786 increase, retained nipples in males nipple retention (NR) male

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 Decreased, Transcription of genes by AR adjacent Moderate Moderate
Decreased, Transcription of genes by AR leads to nipple retention (NR) male adjacent Moderate Low
Antagonism, Androgen receptor leads to nipple retention (NR) male non-adjacent Moderate Low

Network View

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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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Quantitative Understanding

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Considerations for Potential Applications of the AOP (optional)

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References

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