Cao Shuyan, Ye Leping, Wu Ying, Mao Baiping, Chen Lanlan, Wang Xiudi, Huang Ping, Su Ying, Ge Ren-Shan
Center of Scientific Research, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, PR China.
Pharmacology. 2017;100(3-4):139-147. doi: 10.1159/000475531. Epub 2017 Jun 22.
Placenta secretes a large amount of progesterone and estradiol, which are critical for maintaining pregnancy. In human placenta, 3β-hydroxysteroid dehydrogenase 1 (HSD3B1) catalyzes pregnenolone to form progesterone, and aromatase (CYP19A1) catalyzes testosterone into estradiol. Fungicides display antifungal activities and are widely used to prevent fungal infections in agricultural plants. These chemicals include azoles, such as tebuconazole (TEB), triadimefon (TRI), and vinclozolin (VCZ) or organotins, such as tributyltin (TBT) and tetrabutyltin (TTBT). Fungicides may disrupt the activities of these 2 enzymes. In the present study, we investigated the effects of these fungicides on steroid production in a human placental cell line JEG-3 and on HSD3B1 and CYP19A1 activities. Of all fungicides tested at 100 µmol/L, only TBT inhibited pregnenolone-mediated progesterone production in JEG-3 cells by over 50%. Except TTBT, all other 4 fungicides inhibited testosterone-mediated estradiol production by over 50%. TBT was a moderate HSD3B1 inhibitor with a half maximal inhibitory concentration (IC50) of 45.60 ± 0.12 µmol/L. When pregnenolone was used to determine the mode of inhibition, TBT was a competitive inhibitor of HSD3B1. The IC50 values of TEB, TRI, VCZ, and TBT for CYP19A1 were 56.84 ± 0.13, 58.73 ± 0.14, 57.42 ± 0.171, and 4.58 ± 0.048 µmol/L, respectively. TEB, TRI, and VCZ were noncompetitive inhibitors of CYP19A1, while TBT was a competitive inhibitor of this enzyme. Therefore, they are endocrine disruptors.
胎盘分泌大量孕酮和雌二醇，它们对维持妊娠至关重要。在人胎盘中，3β-羟基类固醇脱氢酶1（HSD3B1）催化孕烯醇酮形成孕酮，芳香化酶（CYP19A1）催化睾酮转化为雌二醇。杀菌剂具有抗真菌活性，广泛用于预防农作物真菌感染。这些化学物质包括唑类，如戊唑醇（TEB）、三唑酮（TRI）和乙烯菌核利（VCZ），或有机锡类，如三丁基锡（TBT）和四丁基锡（TTBT）。杀菌剂可能会干扰这两种酶的活性。在本研究中，我们研究了这些杀菌剂对人胎盘细胞系JEG-3中类固醇生成以及对HSD3B1和CYP19A1活性的影响。在100µmol/L测试的所有杀菌剂中，只有TBT抑制JEG-3细胞中孕烯醇酮介导的孕酮生成超过50%。除TTBT外，其他4种杀菌剂均抑制睾酮介导的雌二醇生成超过50%。TBT是一种中度HSD3B1抑制剂，半数最大抑制浓度（IC50）为45.60±0.12µmol/L。当使用孕烯醇酮确定抑制模式时，TBT是HSD3B1的竞争性抑制剂。TEB、TRI、VCZ和TBT对CYP19A1的IC50值分别为56.84±0.13、58.73±0.14、57.42±0.171和4.58±0.048µmol/L。TEB、TRI和VCZ是CYP19A1的非竞争性抑制剂，而TBT是该酶的竞争性抑制剂。因此，它们是内分泌干扰物。
