Building an adverse outcome pathway network for estrogen-, androgen- and steroidogenesis-mediated reproductive toxicity

Abstract

Introduction: Adverse Outcome Pathways (AOPs) can support both testing and assessment of endocrine disruptors (EDs). There is, however, a need for further development of the AOP framework to improve its applicability in a regulatory context. Here we have inventoried the AOP-wiki to identify all existing AOPs related to mammalian reproductive toxicity arising from disruption to the estrogen, androgen, and steroidogenesis modalities. Core key events (KEs) shared between relevant AOPs were also identified to aid in further AOP network (AOPN) development.Methods: A systematic approach using two different methods was applied to screen and search the entire AOP-wiki library. An AOPN was visualized using Cytoscape. Manual refinement was performed to remove AOPS devoid of any KEs and/or KERs.Results: Fifty-eight AOPs relevant for mammalian reproductive toxicity were originally identified, with 42 AOPs included in the final AOPN. Several of the KEs and KE relationships (KERs) described similar events and were thus merged to optimize AOPN construction. Sixteen sub-networks related to effects on hormone levels or hormone activity, cancer outcomes, male and female reproductive systems, and overall effects on fertility and reproduction were identified within the AOPN. Twenty-six KEs and 11 KERs were identified as core blocks of knowledge in the AOPN, of which 19 core KEs are already included as parameters in current OECD and US EPA test guidelines.Discussion: The AOPN highlights knowledge gaps that can be targeted for further development of a more complete AOPN that can support the identification and assessment of EDs.

Enhanced identification of endocrine disruptors through integration of science-based regulatory practices and innovative methodologies: The MERLON Project

“…Due to the central role steroid hormones play in reproductive development and function, it is not surprising that many adverse effects induced by EDCs may occur through the estrogenic, androgenic, or steroidogenic (EAS) modalities ( ECHA/EFSA et al , 2018 ; OECD, 2018 ). This background knowledge is also why most attention has been paid to these modalities over recent decades of EDC-induced reproductive toxicity and why the emerging AOPN for reproductive toxicity in the AOP-wiki includes several adverse outcomes (AOs) known to be mediated through EAS disruption ( Wiklund et al , 2023 ; Zilliacus et al , 2024 ). Notably, however, this does not exclude the involvement of other modalities such as, for example, retinoid signalling.…”