OHTA Shigeru Hiroshima Univ.Sch.Med.Professor, 医学部, 教授 (60160503)
WATANABE Hiromitu Dept.Cancer Res.Hiroshima Univ.Professor, 原爆放射能医学研究所, 教授 (00034653)
ARIZONO Koji Faculty of Environmental and Symbiotic Sciences Prefectural University of Kumamoto, Professor, 環境共生学部, 教授 (70128148)
SUGIHARA Kazumi Hiroshima Univ.Sch.Med.Research Associate, 医学部, 教務員 (20271067)
YOSHIHARA Shin'ichi Hiroshima Univ.Sch.Med.Assoc.Prof., 医学部, 助教授 (00037607)
|Budget Amount *help
¥12,300,000 (Direct Cost: ¥12,300,000)
Fiscal Year 2000: ¥2,100,000 (Direct Cost: ¥2,100,000)
Fiscal Year 1999: ¥10,200,000 (Direct Cost: ¥10,200,000)
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.