Azole fungicides are detected in the aquatic environment and can inhibit enzymatic activities of cytochrome P450 (CYP). This thesis aims to characterize the mechanism of action of the pharmaceutical clotrimazole on testicular steroidogenesis in zebrafish using a network of functional genes along the brain-pituitary-gonad axis and to evaluate the effect of clotrimazole on spermatogenesis. We show that clotrimazole is able to affect steroidogenesis differently in vitro and in vivo (i) the exposure of testicular explants in vitro leads to inhibition of the synthesis of 11-ketotestosterone, showing a direct action on the testis, and (ii) in vivo exposure increases the transcript levels of genes involved in steroidogenesis. An integrative approach of gene expression measurements along the pituitary-gonad axis highlights a mechanism of biological compensation, with a critical role of the Fsh/FshR pathway in mediating the effects of clotrimazole on testicular steroidogenesis. Finally, effects on spermatogenesis were observed in vivo following chronic exposure to clotrimazole, with an increase in gonado-somatic index as well as in number of Leydig cells. These observations are consistent with measurements at molecular level. Taken together, these data show the interest of an integrative approach. This work raises further concerns, primarily on the study of the functional impact of clotrimazole on reproduction, including male and female studies.
