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.