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Our goals were to investigate whether environmentally relevant doses of T‐2 toxin can affect human ovarian granulosa cells' function and to reveal the potential mechanism of T‐2 toxin's action. Results showed that T‐2 toxin strongly attenuated luteinizing hormone/choriogonadotropin receptor (LHCGR) mRNA expression in follicle‐stimulating hormone (FSH)‐stimulated human cumulus granulosa cells. Addition of human chorionic gonadotropin was not able to elicit maximal response of ovulatory genes amphiregulin, epiregulin, and progesterone receptor. T‐2 toxin reduced mRNA levels of CYP19A1 and steroidogenic acute regulatory protein (STAR) and lowered FSH‐stimulated estradiol and progesterone production. Mechanistic experiments demonstrated that T‐2 toxin decreased FSH‐stimulated cyclic adenosine monophosphate (cAMP) production. Addition of total PDE inhibitor 3‐isobutyl‐1‐methylxanthine prevented T‐2 toxin's action on LHCGR, STAR, and CYP19A1 mRNA expression in FSH‐stimulated human cumulus granulosa cells. Furthermore, T‐2 toxin partially decreased 8‐bromoadenosine 3′5′‐cyclic monophosphate (8‐Br‐cAMP)‐stimulated LHCGR and STAR, but did not affect 8‐Br‐cAMP‐stimulated CYP19A1 mRNA expression in human cumulus granulosa cells. Overall, our data indicate that environmentally relevant dose of T‐2 toxin decreases steroidogenesis and ovulatory potency in human cumulus granulosa cells probably through activation of PDE, thus posing a significant risk for female fertility.

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Humans are exposed not only to single endocrine disruptors, but also to chemical mixtures that can adversely affect their reproductive health. Steroidogenesis in reproductive tissues is emerging as the key target of endocrine disruptor action. Here, we analyzed the effect of environmental chemical mixtures with estrogenic activity on steroidogenic processes in immature rat granulosa cells and whether the observed steroidogenic effects were mediated through estrogen receptors. Extracts from untreated wastewater were prepared by solid-phase extraction and silica gel fractionation. ER-CALUX assay showed that the polar fractions of wastewater exerted different levels of estrogenic activity. Exposure of immature granulosa cells to the polar fraction exerting 9 ng of 17β-estradiol equivalents per liter of water of estrogenic activity increased mRNA expression of the key enzymes of progesterone biosynthetic pathway Star and Hsd3b1, but did not alter the level of Cyp19a1 and Lhr. Addition of estrogen receptor inhibitor ICI 182 780 prevented the estrogenic mixture-induced increase in Hsd3b1, but not Star mRNA level in immature granulosa cells. These results indicate that the environmental chemical mixtures with estrogenic activity exert endocrine disrupting effects by augmenting the progesterone biosynthetic pathway in immature rat granulosa cells, which is an effect achieved in part through activation of the estrogen receptors.