Co-exposure to ketoconazole alters effects of bisphenol A in Danio rerio and H295R cells.

Chemicals are present in combination in ambient water, however toxicities of their mixtures are not well understood. This study investigated the effects of ketoconazole (KCZ) on the responses induced by bisphenol A (BPA) in zebrafish and in human adrenocarcinoma (H295R) cells. After exposure to BPA alone or mixed with KCZ for 21 d, egg production, relative tissue weights, sex hormone levels, cytochrome P450 (CYP)3a activity, and transcriptions of genes related to CYP metabolism, vitellogenesis, and steroidogenesis were determined in zebrafish. Male fish were more sensitive to the adverse effects of BPA than females, and the presence of KCZ potentiated the BPA-induced estrogenic responses in the male and anti-estrogenic responses in the female fish. In male zebrafish exposed to BPA, a significant reduction in egg number and relative gonad weight, an increase in 17β-estradiol (E2) to testosterone (T) ratio, and an upregulation of vtg, erα, and cyp19a genes were observed. Under KCZ, BPA exposure resulted in a significant downregulation of cyp3a65 and pxr genes and an increase in estrogenic responses in males. In female fish, anti-estrogenic effects, such as a decrease in E2 concentration, were observed following the combined exposure. These results indicate that KCZ could increase the toxicity of the chemicals that depend on the given CYP metabolism for their elimination or other crucial functions such as steroidogenesis. Co-exposure to BPA and KCZ in H295R cells also increased E2 and decreased T production. Release and presence of this azole compound warrant caution, because it could modify adverse effects of BPA.

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