T‐2 toxin downregulates LHCGR expression, steroidogenesis, and cAMP level in human cumulus granulosa cells

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.