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Metabolism and endocrine disrupting action of environmental pollutants

环境污染物的代谢和内分泌干扰作用

基本信息

批准号：
11557199
负责人：
KITAMURA Shigeyuki
金额：
$ 7.87万
依托单位：
Hiroshima University School of Medicine
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B).
财政年份：
1999
资助国家：
日本
起止时间：
1999 至 2000
项目状态：
已结题

项目摘要

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.

本研究探讨了内分泌干扰物的代谢对雌激素活性的影响。用人乳腺癌细胞系MCF-7进行报告试验，用大鼠垂体瘤细胞系MTT/E-2进行生长试验，评价其雌激素活性。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。相反，与肝微粒体孵育可激活木犀草素A和甲氧氯胺。而p，p‘-DDT和o，p’-DDT的雌激素活性不受肝微体代谢的影响。2.我们发现了一些非雌激素的雌激素，并在代谢后产生了活性。作为雌激素，我们通过筛选代谢产物的雌激素活性，检测到了反式二苯乙烯、联苯、二苯甲烷、二苯基、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.在大鼠体内和体外，这些雌激素被转化为其羟化活性代谢物。羟化作用由肝微粒体细胞色素P450 2B1或1A1介导。4.反式二苯乙烯对小鼠无生殖毒性。但活性代谢产物反式-4，4‘-二羟基二苯乙烯对小鼠睾丸有毒性作用。5.雄性金鱼在含反式二苯乙烯(5×10~(-6)~(-6)M)的水中饲养5天后，血液中卵黄蛋白原水平显著升高。在养鱼池水中检测到反式-4-羟基二苯乙烯和反式-4，4‘-二羟基二苯乙烯为体内代谢产物。反式-二苯乙烯也被鱼的肝微体转化为这些羟化的代谢物。这一事实表明，反式二苯乙烯在鱼体内转化为活性代谢物。6.p，p‘-DDT和o，p’-DDT及其相关化合物对大鼠小脑细胞的神经毒性在1×10^&lt；-8&gt；-10^&lt；-7&gt；M。