Development and Cross-Validation of a Zebrafish Quantitative Adverse Outcome Pathway Model on Aromatase Inhibition Leading to Reproductive Dysfunction

Summary

Adverse outcome pathway (AOP) has become a key component in next-generation risk assessment (NGRA), as AOPs provide mechanistic and causal basis for linking toxicological responses across multiple levels of biological organization, thus allowing utilization of new approach methodologies (NAMs) to support prioritization, classification, and hazard assessment of chemicals. Quantitative AOPs (qAOPs) further allow estimation of points of departure (PODs) along a cascade of toxicological events and prediction of final adverse outcome(s) based on early key events. The present study developed a zebrafish-based qAOP model for an OECD-endorsed AOP linking aromatase inhibition to reproductive dysfunction (AOPWiki, AOP no. 25). The model was built based on newly generated laboratory data from a prototypical aromatase inhibitor propiconazole (PRO) and further challenged by another chemical tebuconazole (TEB) to evaluate the model’s performance and applicability. We found that female and male zebrafish have different effects to establish AOP after exposure to PRO and qAOP was expanded and applied to cross-species prediction with fathead minnow. During the environmentally relevant concentrations of PRO and TEB for 21 days, aromatase CYP19, vitellogenin, and steroidogenesis were affected significantly, and the reproduction of zebrafish significantly decreased. The present study aimed to expand the mechanism of aromatase and assembled quantitative AOP in zebrafish and further linked with in vitro, which extended aromatase inhibitor-mediated reproductive dysfunction as a demonstrative case of published qAOP model in fathead minnow Pimephales promelas (AOPWiki, AOP no. 25).