AOP report: Adverse outcome pathway network for developmental androgen signaling inhibition leading to increased nipple/areola retention in male offspring.

In murine species such as laboratory mice and rats, the number of nipples is a sexually dimorphic trait, with males typically not expressing nipples. This is an androgen-sensitive trait, with regression of the nipple anlagen dictated by high androgen levels during development. Nipple/areola retention (NR) in male rodents is thus considered a sensitive marker of disrupted androgen signaling during development and used to identify chemicals with antiandrogenic effects. Here, we have developed an adverse outcome pathway network for NR induced by reduced androgen signaling during critical developmental life stages. The network integrates three adverse outcome pathways covering (a) inhibited testosterone production, (b) reduced conversion to dihydrotestosterone, and (c) direct androgen receptor antagonism. It supports the regulatory application of NR as a measure of endocrine disruption relevant for human health and the use of NR as an indicator of antiandrogenicity in mammals and other vertebrates in the environment. It presents key events and key event relationships that can be leveraged to enhance the use of new approach methodologies, enhancing predictive toxicology and assessment of endocrine disruptors.