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

公众对扰乱环境的内分泌化学品对生殖和健康的危害已引起了令人震惊的关注。生殖毒物被认为不仅通过扰乱内分泌，而且还通过直接损害生殖器官来发挥其毒性。事实上，许多致癌物质表现出生殖毒性。因此，这些化学物质可能通过DNA损伤表现出生殖毒性。在本研究中，我们研究了各种环境化学物质引起的DNA氧化损伤与其致癌性和生殖毒性的关系。(1)阐明雌激素致癌的机制具有重要意义。在远低于其代谢产物邻苯二酚雌激素的浓度下，雌二醇促进雌激素依赖的MCF-7细胞的增殖，但不会造成DNA损伤。另一方面，儿茶酚雌激素在极低浓度下会引起DNA损伤。因此，儿茶酚雌激素似乎可以促进…。更多的是通过氧化DNA损伤在肿瘤的发生中发挥作用，而雌激素本身通过在雌激素诱导的癌变中促进细胞增殖来促进肿瘤的发生(Int.J.癌症，2001)。我们发现，大豆中含有的大豆苷元及其代谢物7，3‘，4’-三羟基异黄酮可能以类似的方式诱导致癌。(2)据报道，用于生产炸药的2，4，6-三硝基甲苯(TNT)会造成生殖毒性和癌症。TNT可致大鼠睾丸精子数显著减少，睾丸和附睾8-oxodG生成量增加。作为一种TNT代谢物，TNT会对标记的DNA片段造成氧化损伤，而TNT本身不会。这些发现表明，TNT通过其代谢物(Free Radic)介导的氧化DNA损伤而诱导生殖毒性。(见新闻稿件)。我们还发现甲苯可能以类似的方式引起生殖毒性(BBRC，1999)。综上所述，这些发现表明环境化学品可能通过氧化DNA损伤表现出生殖毒性和致癌作用。较少

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