University of Novi Sad, Faculty of Sciences, Department of Biology and Ecology, Novi Sad, Serbia.
University of Novi Sad, Faculty of Technical Sciences, Department of Environmental Engineering and Occupational Safety and Health, Novi Sad, Serbia.
Environ Toxicol. 2019 Jul;34(7):844-852. doi: 10.1002/tox.22752. Epub 2019 Apr 5.
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.
我们的目的是研究环境相关剂量的 T-2 毒素是否会影响人卵巢颗粒细胞的功能，并揭示 T-2 毒素作用的潜在机制。结果表明，T-2 毒素强烈抑制卵泡刺激素（FSH）刺激的人卵丘颗粒细胞中黄体生成素/绒毛膜促性腺激素受体（LHCGR）mRNA 的表达。添加人绒毛膜促性腺激素不能引起排卵基因 Amphiregulin、Epiregulin 和孕激素受体的最大反应。T-2 毒素降低了 CYP19A1 和类固醇生成急性调节蛋白（STAR）的 mRNA 水平，并降低了 FSH 刺激的雌二醇和孕酮的产生。机制实验表明，T-2 毒素降低了 FSH 刺激的环磷酸腺苷（cAMP）的产生。添加总 PDE 抑制剂 3-异丁基-1-甲基黄嘌呤可防止 T-2 毒素对 FSH 刺激的人卵丘颗粒细胞中 LHCGR、STAR 和 CYP19A1 mRNA 表达的作用。此外，T-2 毒素部分降低了 8-溴环磷酸腺苷（8-Br-cAMP）刺激的 LHCGR 和 STAR，但不影响 8-Br-cAMP 刺激的人卵丘颗粒细胞中 CYP19A1 mRNA 的表达。总的来说，我们的数据表明，环境相关剂量的 T-2 毒素可能通过激活 PDE 降低人卵丘颗粒细胞中的类固醇生成和排卵能力，从而对女性生育能力构成重大风险。
