Modeling Azole Fungicides' Endocrine Disruption: A Physiologically Based Kinetic Model of the Hypothalamus-Pituitary-Gonads Axis (PBK-TD) in Zebrafish 1,2,3LY T-K., 3Chadili E., 4 Le Menach K., 4Budzinski H., 3Hinfray N., 1,2Beaudouin R. 1Toxicologie Expérimentale et Modélisation (TEAM), Ineris, Verneuil-en-Halatte, France. Email: tu-ky.ly@ineris.fr 2 Stress Environnementaux et Biosurveillance des milieux aquatiques (UMR-I 02 Sebio), Ineris, Verneuil-en-Halatte, France. 3Ecotoxicologie des Substances et des Milieux (ESMI), Ineris, Verneuil-en-Halatte, France. 4Physico- et Toxico-Chimie de l'environnement (LPTC, UMR 5805 CNRS), Université de Bordeaux, Talence, France. This work aims to develop a physiologically based kinetic model, linked to a mechanistic toxicodynamic model of the hypothalamic–pituitary–gonadal (HPG) axis in zebrafish (PBK-HPG model), that could link the dose to adverse effects and be used for risk assessment of endocrine disruptors (ED). It was applied to two ED-suspected azole fungicides: prochloraz (PCZ) and imazalil (IMZ), both known for their aromatase inhibition potency. The proposed PBK-HPG model comprises twelve compartments representing diverse tissues and adapts to various exposure scenarios. It considers vitellogenin (VTG) and steroid hormones (estradiol, testosterone, 11-ketotestosterone), focusing on key aspects such as brain feedback loops, liver VTG synthesis, and gonadal steroid hormone synthesis. Model predictions were compared to original data from OECD TG229 and a time-dependent measurement of steroid concentrations. The model accurately predicted internal concentrations of PCZ and IMZ in key organs. It faithfully replicated the HPG axis baseline physiological conditions. Simulations of PCZ and IMZ effects on the HPG axis showed good results. Overall, the model was able to reproduce all the different experimental conditions. To conclude, our model provides valuable insights into the kinetics of the HPG axis, offering an understanding of the mechanism underlying the impact of azole fungicides on the HPG axis in zebrafish. The novel PBK-HPG model holds promise for integration into a quantitative adverse outcome pathway framework, offering a comprehensive approach for assessing the toxic effects of ED. 

Key words

PBK-TD Model, qAOP, Endocrine Disruption, Azole Fungicides, Zebrafish