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

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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