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Evaluation of toxicity of environmental chemicals on the basis of their estrogenic activity and DNA-damaging ability and regional risk assessment

基于雌激素活性和DNA损伤能力的环境化学品毒性评价和区域风险评估

基本信息

批准号：
11794019
负责人：
KAWANISHI Shosuke
金额：
$ 7.68万
依托单位：
Mie University
依托单位国家：
日本
项目类别：
Grant-in-Aid for University and Society Collaboration
财政年份：
1999
资助国家：
日本
起止时间：
1999 至 2001
项目状态：
已结题

项目摘要

There has been an alarming concern among general public regarding the reproductive and health hazards of the endocrine disrupting environmental chemicals. Reproductive toxicants are considered to exert their toxicity through not only endocrine disruption but also direct damage to reproductive organs. In fact, a number of carcinogens exhibit reproductive toxicity. Thus, such chemicals may show reproductive toxicity through DNA damage. In the present study, we investigated the role of oxidative DNA damage induced by various environmental chemicals in relation to their carcinogenicity and reproductive toxicity. (1) It is important to clarify the mechanism of carcinogenesis induced by estrogens. Estradiol enhanced proliferation of estrogen-dependent MCF-7 cells at much lower concentrations than its metabolites, catechol estrogens, but did not cause DNA damage. On the other hand, catechol estrogens caused DNA damage at extremely low concentrations. Therefore, catechol estrogens appear to pl … More ay a role in tumor initiation through oxidative DNA damage, whereas estrogens themselves induce tumor promotion by enhancing cell proliferation in estrogen-induced carcinogenesis (Int. J. Cancer, 2001). We found that daidzein, contained in soy beans, and its metabolite, 7 ,3',4'-trihydroxyiosoflavone, may induce carcinogenesis in a similar manner. (2) 2,4,6-Trinitrotoluene (TNT), which is used to produce explosives, has been reported to cause reproductive toxicity and cancer. TNT administration to rats induced a dramatic decrease in the sperm number in the testis and an increase in 8-oxodG formation in the testis and epididymis. A TNT metabolite, induced oxidative damage to ^<32>P-labeled DNA fragments, while TNT itself did not. These findings suggest that TNT induces reproductive toxicity through oxidative DNA damage mediated by its metabolite (Free Radic. Res., in press). We also found that toluene may cause reproductive toxicity in a similar manner (BBRC, 1999). In conclusion, these findings suggest that environmental chemicals may exhibit reproductive toxicity and carcinogenicity through oxidative DNA damage. Less

公众对干扰内分泌的环境化学品对生殖和健康的危害感到担忧。生殖毒物被认为不仅通过干扰内分泌而且通过直接损害生殖器官来发挥其毒性。事实上，许多致癌物质都表现出生殖毒性。因此，这些化学品可能通过DNA损伤显示生殖毒性。在本研究中，我们调查了各种环境化学物质诱导的DNA氧化损伤与其致癌性和生殖毒性的关系。(1)阐明雌激素的致癌机制具有重要意义。雌激素在比其代谢产物儿茶酚雌激素低得多的浓度下增强雌激素依赖性MCF-7细胞的增殖，但不引起DNA损伤。另一方面，儿茶酚雌激素在极低浓度下引起DNA损伤。因此，儿茶酚雌激素似乎 ...更多信息可能通过氧化性DNA损伤在肿瘤起始中起作用，而雌激素本身通过增强雌激素诱导的癌发生中的细胞增殖来诱导肿瘤促进（Int. J. Cancer，2001）。我们发现大豆中含有的大豆苷元及其代谢产物7，3 '，4'-三羟基异黄酮可能以类似的方式诱导致癌作用。(2)2，4，6-三硝基甲苯（TNT），用于生产炸药，据报道会导致生殖毒性和癌症。TNT给药大鼠诱导睾丸中精子数量急剧减少，睾丸和附睾中8-oxodG形成增加。TNT的代谢产物会对13 <32>P标记的DNA片段造成氧化损伤，而TNT本身则不会。这些发现表明TNT通过其代谢物介导的氧化DNA损伤诱导生殖毒性（Free Radic.结果：印刷中）。我们还发现，甲苯可能以类似的方式导致生殖毒性（英国生物伦理委员会，1999年）。总之，这些研究结果表明，环境中的化学物质可能会通过氧化DNA损伤表现出生殖毒性和致癌性。少