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AOP: 344
Title
Androgen receptor (AR) antagonism leading to nipple retention (NR) in male (mammalian) offspring
Short name
Graphical Representation
Point of Contact
Contributors
- Terje Svingen
- Evgeniia Kazymova
Coaches
- Judy Choi
OECD Information Table
OECD Project # | OECD Status | Reviewer's Reports | Journal-format Article | OECD iLibrary Published Version |
---|---|---|---|---|
1.108 | Under Development |
This AOP was last modified on May 26, 2024 20:39
Revision dates for related pages
Page | Revision Date/Time |
---|---|
Decrease, androgen receptor activation | April 05, 2024 08:19 |
Altered, Transcription of genes by the androgen receptor | April 05, 2024 09:28 |
Antagonism, Androgen receptor | April 05, 2024 08:04 |
Nipple retention (NR), increased | January 11, 2023 05:53 |
Antagonism, Androgen receptor leads to Decrease, AR activation | April 05, 2024 08:53 |
Antagonism, Androgen receptor leads to nipple retention, increased | January 11, 2023 06:22 |
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 nipple retention, increased | May 11, 2020 10:24 |
Abstract
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.
AOP Development Strategy
Context
Strategy
Summary of the AOP
Events:
Molecular Initiating Events (MIE)
Key Events (KE)
Adverse Outcomes (AO)
Type | Event ID | Title | Short name |
---|
MIE | 26 | Antagonism, Androgen receptor | Antagonism, Androgen receptor |
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 |
AO | 1786 | Nipple retention (NR), increased | nipple retention, increased |
Relationships Between Two Key Events (Including MIEs and AOs)
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 the AR | adjacent | Moderate | Moderate |
Altered, Transcription of genes by the AR leads to nipple retention, increased | adjacent | Moderate | Low |
Antagonism, Androgen receptor leads to nipple retention, increased | non-adjacent | Moderate | Low |