This AOP is licensed under a Creative Commons Attribution 4.0 International License.
Androgen receptor (AR) antagonism leading to short anogenital distance (AGD) in male (mammalian) offspring
Point of Contact
- Terje Svingen
|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 Do not cite||Under Development||1.90||Included in OECD Work Plan|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 June 04, 2021 16:32
|Antagonism, Androgen receptor||November 05, 2020 06:19|
|Decrease, androgen receptors (AR) activation||April 10, 2019 05:24|
|decrease, transcription of genes by AR||August 30, 2019 04:19|
|decrease, male anogenital distance||June 09, 2020 12:07|
|Antagonism, Androgen receptor leads to Decrease, AR activation||May 11, 2020 07:39|
|Antagonism, Androgen receptor leads to short male AGD||August 07, 2020 05:12|
|Decrease, AR activation leads to decrease, transcription of genes by AR||November 02, 2020 08:12|
|decrease, transcription of genes by AR leads to short male AGD||May 11, 2020 07:37|
|Finasteride||November 29, 2016 18:42|
|Flutamide||November 29, 2016 18:42|
This AOP links Androgen receptor antagonism 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).
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, including differentiation of the levator ani/bulbocavernosus (LABC) muscle complex in male fetuses. 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 antagonism of the AR in target cells of the primitive perineal region, which leads to inactivation of the AR and failure to properly masculinize the perineum/LABC complex. In this instance, the local levels of testosterone or DHT may be normal, but prevented from binding the AR.
Summary of the AOP
Molecular Initiating Events (MIE)
Key Events (KE)
Adverse Outcomes (AO)
|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||1687||decrease, transcription of genes by AR||decrease, transcription of genes by AR|
|AO||1688||decrease, male anogenital distance||short male AGD|
Relationships Between Two Key Events (Including MIEs and AOs)
|Antagonism, Androgen receptor leads to Decrease, AR activation||adjacent||High||High|
|Decrease, AR activation leads to decrease, transcription of genes by AR||adjacent||High||Moderate|
|decrease, transcription of genes by AR leads to short male AGD||adjacent||Moderate||Low|
|Antagonism, Androgen receptor leads to short male AGD||non-adjacent||Moderate||Low|
Life Stage Applicability
Overall Assessment of the AOP
Domain of Applicability
Essentiality of the Key Events
Considerations for Potential Applications of the AOP (optional)
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.