Metabolic activation of endocrine-disruptors in animal body

本研究考察了内分泌干扰物的代谢激活。用人乳腺癌细胞系MCF-7进行报告细胞试验，估计雌激素活性。在NADPH存在的情况下，与肝微粒体孵育后，我们发现了一些非雌激素性的雌激素产生活性。作为雌激素，我们通过筛选2-硝基芴、反式二苯乙烯、联苯、二苯基甲烷、二苯、2,2 -二苯基丙烷、苄基丙酮、苯乙烯低聚物、二苯胺、二苯基砜、偶氮苯、芘、氯菊酯、邻苯二甲酸二甲酯和查尔酮的代谢物的雌激素活性来检测它们。这些雌激素在体内和体外转化为它们的羟基化活性代谢物。羟基化作用由肝微粒体细胞色素P450 2B1或1A1介导。2. 双酚A、芴、芘、ddt和部分有机磷杀虫剂具有抗雄激素活性。倍硫磷亚砜与大鼠肝脏制剂孵育后也表现出活性。3. 四溴双酚A是一种阻燃剂，具有甲状腺激素活性。部分多氯联苯在细胞色素P450体系羟基化后也表现出活性。4. 反式二苯乙烯、2-硝基芴和倍硫磷在大鼠体内表现出内分泌干扰作用。5. 雄性金鱼在含有反式二苯乙烯、二苯基或2-硝基芴（5 × 10^<-6> M）的水中饲养5天后，血液中卵黄原蛋白水平明显升高。这些羟基化化合物在保持水中被检测到。这些事实表明，这些雌激素在哺乳动物和鱼类中被激活为雌激素。

The metabolic activation of endocrine disrupters was examined in this study.1. Estrogenic activity was estimated by the reporter assay using human breast cancer cell line MCF-7. We found some proestrogens which were not estrogenic and produced their activities after the incubation with liver microsomes in the presence of NADPH. As proestrogens, we detected 2-nitrofluorene, trans-stilbene, biphenyl, diphenylmethane, dibenzyl, 2, 2-diphenylpropane, benzylideneacetone, styrene oligomers, diphenylamine, diphenylsulfone, azobenzene, pyrene, permethrin, dimethylphthalate and chalchone by screening the estrogenic activities of their metabolites. 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. 2. Bisphenol A, fluorene, pyrene, DDTs and some organophosphorus insecticides exhibited antiandrogenic activity. Fenthion sulfoxide also exhibited the activity after incubation with rat liver preparations. 3. Tetrabromobisphenol A, a flame retardant, exhibited thyroid hormonal activity. Some PCBs also exhibited the activity after the hydroxylation by cytochrome P450 system. 4. Trans-Stilbene, 2-nitrofluorene and fenthion showed endocrine-disrupting actions in vivo in rats. 5. When male goldfish were kept in the water containing trans-stilbene, diphenyl or 2-nitrofluorene (5x10^<-6> M) for five days, the vitellogenin level in blood was markedly increased. These hydroxylated compounds were detected in keeping water. These facts suggest that these proestrogens were activated to estrogens in mammals and fish.