AOP Report: An Upstream Network for Reduced Androgen Signaling Leading to Altered Gene Expression of Androgen Receptor-Responsive Genes in Target Tissues.

Adverse outcome pathways (AOPs) can aid with chemical risk assessment by providing plausible links between chemical activity at the molecular level and effect outcomes in intact organisms. Because AOPs can be used to infer causality between upstream and downstream events in toxicological pathways, the AOP framework can also facilitate increased uptake of alternative methods and new approach methodologies to help inform hazard identification. However, a prevailing challenge is the limited number of fully developed and endorsed AOPs, primarily due to the substantial amount of work required by AOP developers and reviewers. Consequently, a more pragmatic approach to AOP development has been proposed where smaller units of knowledge are developed and reviewed independent of full AOPs. In this context, we have developed an upstream network comprising key events (KEs) and KE relationships related to decreased androgen signaling, converging at a nodal KE that can branch out to numerous adverse outcomes (AOs) relevant to androgen-sensitive toxicological pathways. Androgen signaling represents an extensively studied pathway for endocrine disruption. It is linked to numerous disease outcomes and can be affected by many different endocrine-disrupting chemicals. Still, pathways related to disrupted androgen signaling remain underrepresented in the AOP-wiki, and endorsed AOPs are lacking. Given the pivotal role of androgen signaling in development and function across vertebrate taxa and life stages of both sexes, this upstream AOP network serves as a foundational element for developing numerous AOPs. By connecting the upstream network with various downstream AOs, encompassing different species, it can also facilitate cross-species extrapolations for hazard and risk assessment of chemicals. Environ Toxicol Chem 2024;43:2329-2337. © 2024 The Author(s). Environmental Toxicology and Chemistry published by Wiley Periodicals LLC on behalf of SETAC.