PBK-TD modelling of the gonadotropic axis: Case study with two azole fungicides in female zebrafish

Endocrine disruptors (EDs) can disrupt the gonadotropic axis, which consists of the Hypothalamus-Pituitary-Gonads (HPG), notably by altering aromatase (cyp19a), a key enzyme regulating the endocrine system and reproductive function in fish. The effects of EDs can be predicted by integrating both toxicokinetic (TK) and toxicodynamic (TD) processes in order to relate adverse outcomes to external exposures. In this study, we developed a physiologically based kinetic-toxicodynamic model to simulate the disruption of the HPG axis (PBK-TD, hereafter named PBK-HPG) in female zebrafish exposed to either of two aromatase inhibitors, imazalil or prochloraz. The model was calibrated using Bayesian methods and supported by novel experimental data, including measurements of vitellogenin, 17β-estradiol, and 11-ketotestosterone levels, along with in vivo monitoring of the cyp19a1a gene in transgenic cyp19a1a-GFP ebrafish. Seamless integration of a PBK model within a TD model of the HPG-axis, provided the link between external exposure and internal levels of imazalil and prochloraz in key organs, allowing for mechanistic predictions of their inhibitory effects on gonadal aromatase. Our PBK-HPG model accurately predicted both baseline homeostasis and the effects of aromatase inhibition, with all endocrine endpoints including reproductive disruption, i.e., decreased egg production, falling within a twofold range of both experimental and literature data. Therefore, our PBK-HPG model could further support the development of a mechanistic qAOP with TK considerations. The model offers significant potential for improving environmental risk assessments of EDs and possibly other stressors across species.