AOP key event relationship report: Linking androgen receptor antagonism with nipple retention

In rat developmental and reproductive toxicity studies, nipple/areola retention (NR) in male offspring is a biomarker for reduced androgen signaling during development. This is because nipples normally regress in male rats in response to androgen signaling during critical stages of development. NR is thus included as a mandatory endpoint in several OECD test guidelines for assessment of chemicals, particularly as a readout for anti-androgenic effects relevant for reproductive toxicity. With the growing interest in developing Adverse Outcome Pathways (AOPs) to aid in chemical risk assessment, a more pragmatic approach has been proposed, whereby essential units of knowledge could be developed independently of complete AOPs, not least emergent key event relationships (KERs). Herein, we have developed a KER linking "androgen receptor antagonism" and "increased areola/nipple retention". The KER is based on a literature review conducted in a transparent semi-systematic manner in peer-reviewed databases with pre-defined inclusion criteria. Twenty-seven papers were included for development of the KER. The results support a qualitative relationship between the two key events (KEs) with a high weight of evidence; i.e., a causal relationship between androgen receptor (AR) antagonism and nipple retention in male rats exists.