Etude de l'expression des cytochromes P 450 aromatases comme marqueurs biologiques d'une perturbation endocrinienne chez le poisson

Abstract : The objective of this work was to study the effects of endocrine disrupting chernicals (EDCs) on brain and gonadal P45Oaromatase in fish in order to determine to which extent these genes or their products could be used as biomarkers of endocrine disruption in fish. We first developed methods to measure cypl9a and cypl9b mRNA and protein levels, as well as activity of brain and gonadal aromatase in zebrafish (Danio rerio). These methods allowed us to obtain relevant and original data on the expression of aromatases in this species. Next, we assessed the effects of several environmental pollutants and characterized the inhibitory potency of several pesticides using an in vitro assay based on brain and gonadal microsomal aromatase fiom rainbow trout (Oncorhynchus mykiss). Clotrimazole, an imidazole fùngicide used as a pharmaceutical, was found to be the most active substance among the tested pesticides. In vivo, we observed that various substances can perturb brain and gonadal aromatase and elicit tissue-specific responses. While androstadrienedione (a steroidal inhibitor of aromatase) inhibited aromatase activity in both brain and gonads without affecting cypl9 expression, the in vivo action of clotrimazole (characterized as an aromatase inhibitor in vitro) was more complex. The effects of this molecule differed depending on the target tissue and the concentration used for exposure. Moreover, the effects observed on the mRNA levels did not allow to predict the effects on the aromatase activity. Finally, we showed that some xenoestrogens are able to inhibit ovarian aromatase gene expression and at the same time to induce brain aromatase at the gene and protein level through an estrogen receptor (ER)-dependent mechanism. This demonstrates that measurement of cypl9b induction is a relevant biomarker of exposure to estrogenic compounds. Taken together, Our work provides new and relevant data concerning the effects and mechanisms of action of EDCs in fish, especially in female individuals. However, to determine the physiological and reproductive consequences of aromatase perturbation, M e r research is needed. Such knowledge is critical for establishing the use of these biomarkers in risk assessrnent of EDCs.
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Nathalie Hinfray. Etude de l'expression des cytochromes P 450 aromatases comme marqueurs biologiques d'une perturbation endocrinienne chez le poisson. Biologie animale. Université Paul Verlaine - Metz, 2006. Français. ⟨NNT : 2006METZ021S⟩. ⟨tel-01777250⟩

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