Metabolism and endocrine disrupting action of environmental pollutants

本研究探讨了内分泌干扰物代谢对雌激素活性的影响.通过使用人乳腺癌细胞系MCF-7的报告基因测定和使用大鼠垂体瘤细胞系MtT/E-2的生长测定来估计雌激素活性。当双酚A和壬基酚与大鼠肝微粒体在NADPH存在下孵育时，这些化合物的雌激素活性降低。与此相反，鹰嘴豆芽素A和甲氧滴滴涕被激活的肝微粒体孵育。而p，p '-DDT和o，p'-DDT的雌激素活性不受肝微粒体代谢的影响。2.我们发现一些前雌激素不是雌激素，而是在代谢后才产生活性。作为雌激素前体，通过筛选其代谢产物的雌激素活性，我们检测到了反式二苯乙烯、联苯、二苯甲烷、二苄基、2，2-二苯丙烷、亚苄基丙酮、苯乙烯、二苯胺、二苯砜、芘和查尔酮。3.这些前雌激素在大鼠体内和体外转化为它们的羟基化活性代谢产物。羟基化由肝微粒体细胞色素P450 2B 1或1A 1介导。4.反式芪在小鼠中未表现出生殖毒性。然而，活性代谢物反式-4，4 '-二羟基二苯乙烯可诱导小鼠睾丸毒性。5.雄性金鱼在含5×10^ M反式二苯乙烯的水中饲养<-6>5天后，血液中卵黄原蛋白水平显著升高。反式-4-羟基二苯乙烯和反式-4，4 '-二羟基二苯乙烯被检测为在鱼缸水保持鱼体内代谢物。反式芪也被转化为这些羟基化的代谢物的肝微粒体的鱼。这一事实表明，反式二苯乙烯在鱼中转化为活性代谢物。6. p，p '-DDT和o，p'-DDT及其有关化合物在1×10^-10 ^M范围内对大鼠小脑细胞有神经毒性<-8><-7>。

The effect of the metabolism of endocrine disruptors on the estrogenic activity was examined in this study.1. The estrogenic activity was estimated by the reporter assay using human breast cancer cell line MCF-7 and growth assay using rat pituitary tumor cell line MtT/E-2. When bisphenol A and nonylphenol were incubated with rat liver microsomes in the presence of NADPH, the estrogenic activities of these compounds were decreased. On the contrary, biochanin A and methoxychlor were activated by the incubation with liver microsomes. In contrast, the estrogenic activities of p, p'-DDT and o, p'-DDT were not effected by the liver microsomal metabolism. 2. We found some proestrogens which were not estrogenic and produced their activities after the metabolism. As proestrogens, we detected trans-stilbene, biphenyl, diphenylmethane, dibenzyl, 2, 2-diphenylpropane, benzylideneacetone, styrene, diphenylamine, diphenylsulfone, pyrene and chalchone by screening the estrogenic activities of their metabolites. 3. These proestrogens were converted to their hydroxylated active metabolites in vivo and in vitro in rats. The hydroxylation was mediated by liver microsomal cytochrome P450 2B1 or 1A1. 4. trans-Stilbene did not exhibit reproductive toxicity in mice. However, the active metabolite, trans-4,4'-dihydroxystilbene, induced the testicular toxicity in mice. 5. When male goldfish were kept in the water containing trans-stilbene(5×10^<-6> M)for five days, the vitellogenin level in blood was markedly increased. trans-4-Hydroxystilbene and trans-4,4'-dihydroxystilbene were detected as in vivo metabolites in the tank water kept the fish. trans-Stilbene was also converted to these hydroxylated metabolites by liver microsomes of the fish. This fact suggests that trans-stilbene was transformed to the active metabolites in the fish. 6. p, p'-DDT and o, p'-DDT, and their related compounds showed the neurotoxicity on rat cerebellum cells in the range of 1×10^<-8>-10^<-7>M.