UDP-glucuronosyltransferase Activities toward Sex Hormones in the Adult Male Rat Administered Bisphenol A

内分泌干扰物对雄性动物生殖器官的各种不良影响已有报道。我们发现，给予内分泌干扰物双酚A(1 mg/2天，连续2周或4周)后，成年雄性Wistar大鼠肝微粒体中UDP-葡萄糖醛酸基转移酶对双酚A、睾酮和雌二醇的激活活性显著降低。但雌性大鼠经双酚A处理4周后，其转移酶活性仍未受到抑制。众所周知的内分泌干扰物己烯雌酚也有同样的作用，但对异丙基苯酚对UDP-葡萄糖醛酸基转移酶的性激素活性没有影响。与抗雌激素三苯氧胺联合给药可抑制双酚A对转移酶活性的抑制。Western blotting分析表明，该药可降低大鼠肝微粒体中葡萄糖醛酸化双酚A的UGT2B1的含量。Northern印迹分析还表明，双酚A处理组大鼠肝脏中UGT2B1mRNA的表达水平明显下降。这些对UDP-葡萄糖醛酸基转移酶活性、UGT2B 1蛋白和UGT2I3 1mRNA表达的抑制在雌性大鼠中没有发生。结果表明，双酚A处理降低了成年雄性大鼠UGT2B 1和其他介导性激素葡萄糖醛酸化的UGT亚型的mRNA表达，这表明抑制葡萄糖醛酸化作用可能破坏了内分泌平衡。

Various adverse effects of endocrine disruptors on the reproductive organs of male animals have been reported. We found that UDP-glucuronosyltransferase activines towards bisphenol A, testosterone and estradiol were significantly decreased in liver microsomes prepared from adult male Wistar rats administered the endocrine disruptor bisphenol A (1 mg/2 days for 2 or 4 weeks). However, suppression of the transferase activities was not observed in female rats even after bisphenol A-treatment for 4 weeks. Diethylstilbestrol, which is well known as an endocrine disruptor, had the same effects, but p-cumylphenol had no effect on UDP-glucuronosyltransferase activities towards sex hormones. Co-administration with an antiestrogen, tamoxifen, inhibited the suppression of the transferase activities by bisphenol A. Western blotting analysis showed that the content of UGT2B1, which glucuronidates bisphend A, was decreased in the rat liver microsomes by the treatment. Northern blotting analysis also indicated that UGT2B1 mRNA in the liver was decreased by bisphenol A treatment. These suppressions of UDP-glucuronosyltmnsferase activities, UGT2B 1 protein and UGT2I3 1 mRNA expression did not occur in female rats.The results indicate that bisphenol A treatment reduces the mRNA expression of UGT2B 1 and other UGT isoforms mediating glucuronidation of sex hormones in adult male rats, and this suggests that endocrine balance may be disrupted by suppression of glucuronidation.