Mechanism of carcinogenesis in female reproductive organs induced by environmental estrogens

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Chemical pollutant has some potential to alter estrogenic responses, and therefore its presence in the environment may be of concern for reproductive health. It may be involved with the increased incidence rates of breast cancer and endometrial cancer in most countries worldwide. Carcinogenesis is a multistage process, consisting of initiation, promotion, and progression phases. The tumor-initiation process starts DNA damage, leading to irreversible gene alteration. The tumor-promotion process requires sustained exposure to agents that stimulate the growth.Salsolinol (Sal) is an endogenous metabolite of alcohol, generated by condensation reaction of dopamine with acetaldehyde, a major ethanol metabolite. Sal induced DNA damage including 8-oxo-7,8-dihydro-2'-deoxyguanosine formation in the presence of Cu(II) or Fe(III)EDTA. Catalase and metal-specific chelators inhibited SAL-induced DNA damage, suggesting the involvement of H2O2 and transition metals. SAL induced proliferation in estrogen-sensitive breast cancer MCF-7 cells, and the proliferation was inhibited by 4-hydroxytamoxifen, suggesting the involvement of estrogen receptor. In addition, SAL increased estrogen-independent mammary epithelial MCF-10A cells, and the proliferation was inhibited by an antioxidant N-acetylcysteine, suggesting that ROS may participate in proliferation of MCF-10A cells via EGFR activation. We demonstrated that SAL induces oxidative DNA damage and mammary cell proliferation, which may play important roles in tumor initiation and promotion of multistage breast cancer development in relation to alcohol drinking. Furthermore, we have revealed that plant polyphenol procyanidin B2(Free Radic. Biol. Med. 39, 1041-1049, 2005), air pollutant 3-nitrobenzanthrone (Free Radic. Biol. Med. 40, 1242-1249, 2006), and hair dye components ortho-phenylenediamine (Mutat. Res. 607, 184-191, 2006) have the DNA damaging abilities.