Mechanism of carcinogenesis in female reproductive organs induced by environmental estrogens

化学污染物有可能改变雌激素反应，因此它在环境中的存在可能会对生殖健康造成影响。这可能与乳腺癌和子宫内膜癌在全球大多数国家的发病率增加有关。癌变是一个多阶段的过程，包括起始、促进和进展三个阶段。肿瘤启动过程启动DNA损伤，导致不可逆的基因改变。促进肿瘤的过程需要持续接触刺激生长的物质。沙龙醇(Salsolinol，SAL)是酒精的内源性代谢物，由多巴胺与主要的乙醇代谢物乙醛缩合反应生成。在铜(II)或铁(III)EDTA存在下，SAL可引起DNA损伤，包括8-氧-7，8-二氢-2‘-脱氧鸟苷的形成。过氧化氢酶和金属特异性螯合剂可抑制SAL诱导的DNA损伤，提示过氧化氢和过渡金属参与其中。SAL可诱导雌激素敏感的乳腺癌MCF-7细胞增殖，4-羟基三苯氧胺可抑制其增殖，提示雌激素受体参与了该作用。此外，SAL可增加雌激素非依赖性乳腺上皮MCF-10A细胞的增殖，并被抗氧化剂N-乙酰半胱氨酸抑制，提示ROS可能通过EGFR激活参与MCF-10A细胞的增殖。我们证明SAL可诱导DNA氧化损伤和乳腺细胞增殖，这可能在与饮酒有关的肿瘤发生和促进多期乳腺癌的发生中起重要作用。此外，我们还揭示了植物多酚原花青素B2(Free Radic.比奥尔。地中海医院。39,1041-1049,2005)，空气污染物3-硝基苯甲酮(自由拉迪克)。比奥尔。地中海医院。40,1242-1249,2006)和染发剂成分邻苯二胺(Mutat.第607、184-191、2006)具有DNA损伤能力。

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.