AUTHOR=Zilliacus Johanna , Draskau Monica K. , Johansson Hanna K. L. , Svingen Terje , Beronius Anna 

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

JOURNAL=Frontiers in Toxicology

VOLUME=Volume 6 - 2024

YEAR=2024

URL=https://www.frontiersin.org/journals/toxicology/articles/10.3389/ftox.2024.1357717

DOI=10.3389/ftox.2024.1357717

ISSN=2673-3080

ABSTRACT=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. A systematic approach using two different methods was applied to screen and search the entire AOP-wiki library. Fifty-eight relevant AOPs were identified and visualized in an AOPN using Cytoscape. Manual refinement involving the removal of AOPs devoid of any KEs and/or KERs resulted in the inclusion of 42 AOPs 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. 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.