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Mechanism of carcinogenesis in female reproductive organs induced by environmental estrogens

环境雌激素诱发女性生殖器官癌变的机制

基本信息

批准号：
17590511
负责人：
MURATA Mariko
金额：
$ 2.24万
依托单位：
Mie University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2005
资助国家：
日本
起止时间：
2005 至 2006
项目状态：
已结题

项目摘要

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.

化学污染物具有改变雌激素反应的潜力，因此其在环境中的存在可能会影响生殖健康。它可能与全球大多数国家乳腺癌和子宫内膜癌发病率的增加有关。癌变是一个多阶段的过程，包括起始、促进和进展阶段。肿瘤起始过程启动DNA损伤，导致不可逆的基因改变。促肿瘤过程需要持续暴露于刺激生长的药物中。猪毛菜醇（Salsolinol，Sal）是乙醇的内源性代谢产物，由多巴胺与乙醇的主要代谢产物乙醛缩合反应产生。Sal诱导DNA损伤，包括在Cu（II）或Fe（III）EDTA存在下形成8-氧代-7，8-二氢-2 '-脱氧鸟苷。过氧化氢酶和金属特异性螯合剂抑制SAL诱导的DNA损伤，表明H2 O2和过渡金属的参与。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SAL的增殖，提示SAL与雌激素受体有关。此外，SAL增加雌激素非依赖性乳腺上皮MCF-10A细胞的增殖，并且抗氧化剂N-乙酰半胱氨酸抑制增殖，表明ROS可能通过EGFR活化参与MCF-10A细胞的增殖。我们证明，SAL诱导氧化性DNA损伤和乳腺细胞增殖，这可能在肿瘤的发生和促进与饮酒有关的多阶段乳腺癌的发展中发挥重要作用。此外，我们已经发现，植物多酚原花青素B2（自由基。39，1041-1049，2005）、空气污染物3-硝基苯并蒽酮（Free Radic. 40，1242-1249，2006）和染发剂组分邻苯二胺（Mutat. Res. 607，184-191，2006）具有DNA损伤能力。