Mechanisms of mutagenesis of metals & PAH/metal mixtures

金属诱变机制

• 批准号: 6578776
• 负责人: Kathleen Dixon
• 金额: $ 17.11万
• 依托单位: UNIVERSITY OF CINCINNATI
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-04-01 至 2003-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6578776
• 关键词: arsenic; carbopolycyclic compound; cell line; chemical carcinogenesis; chromium; environmental contamination; environmental toxicology; free radical oxygen; gene deletion mutation; genetically modified animals; glutathione; hazardous substances; intermolecular interaction; laboratory mouse; yeasts

DESCRIPTION (Taken from application) The long-range goal of this research is to understand the mechanisms of action of the carcinogenic metals/metalloids chromium and arsenic, and to determine the impact of these metals on the mutagenic activity of polycyclic aromatic hydrocarbons (PAH). Both metals are important contaminants at Superfund sites, and in many cases they exist in complex mixtures with PAHs. Exposure by inhalation to chromate compounds has been associated with the development of lung cancer, particularly in cigarette smokers. Exposure to arsenite in drinking water has been associated with the development of skin cancer, as well as internal cancers of the lung, liver, and bladder. Chromate has been shown to be mutagenic in a variety of test systems; in contrast, arsenite and arsenate have generally tested negative for mutagenesis. However, there is evidence that arsenic is clastogenic and it appears to enhance the mutagenic activity of other agents in co-exposures. During the previous grant period, we demonstrated that chromate induces oxidative damage to DNA in a process that involves intracellular glutathione(GSH)-mediated reduction of chromate (CrVI). Furthermore, the mutagenic specificity of chromate is consistent with oxidative DNA damage in yeast, mammalian cells and the lungs of transgenic mice. In this renewal application, we propose to characterize further the mutagenic potential and mutagenic specificity of chromate, particularly with respect to the induction of deletion mutations. In addition, we propose to expand our investigation of mechanisms of metal-induced mutagenesis to include the analysis of the mutagenic potential of arsenic. We are particularly interested in determining the activity of these metals as co-mutagens in combination with PAHs, because environmental exposures often involve complex mixtures of the two classes of carcinogenic compounds. We propose to test the following two hypotheses: 1) Arsenic and chromium function as mutagens by mechanisms involving interaction with intracellular GSH and generation of reactive oxygen species. 2) Arsenic and chromium act as co-mutagens by potentiating the mutagenic activity of PAHs We propose to address these hypotheses by investigating the mutagenic, and co-mutagenic potential with PAHs, of arsenic and chromium in yeast, mammalian cells, and transgenic mice.

描述（摘自应用程序） 这项研究的长期目标是了解其作用机制 致癌金属/类金属铬和砷，并确定 这些金属对多环芳烃致突变活性的影响 碳氢化合物（PAH）。这两种金属都是超级基金场地的重要污染物， 在许多情况下，它们与多环芳烃以复杂的混合物形式存在。曝光 吸入铬酸盐化合物与以下发展有关： 肺癌，尤其是吸烟者。砷暴露 饮用水与皮肤癌的发展有关， 以及肺癌、肝癌和膀胱癌。铬酸盐一直是 在各种测试系统中显示出致突变性;相反，亚砷酸盐和 砷酸盐通常对诱变测试为阴性。不过有 有证据表明砷具有致染色体断裂作用， 在共同暴露中的其他药剂的活性。在上一个资助期内，我们 证明铬酸盐在一个过程中诱导DNA氧化损伤， 涉及细胞内谷胱甘肽（GSH）介导的铬酸盐（CrVI）还原。 此外，铬酸盐的致突变特异性与 酵母、哺乳动物细胞和转基因小鼠肺中的氧化性DNA损伤 小鼠在此更新申请中，我们建议进一步表征 铬酸盐的致突变潜力和致突变特异性，特别是与 关于缺失突变的诱导。此外，我们建议 扩展我们对金属诱导突变机制的研究，包括 砷的潜在致突变性分析。我们特别 感兴趣的是确定这些金属作为共诱变剂的活性， 与多环芳烃结合，因为环境暴露往往涉及复杂的 两类致癌化合物的混合物。我们建议测试 以下两个假设：1）砷和铬作为诱变剂， 涉及与细胞内GSH相互作用和 活性氧物质。2)砷和铬作为共诱变剂， 加强多环芳烃的致突变活性，我们建议解决这些问题 通过研究致突变性和共致突变性， 多环芳烃，砷和铬在酵母，哺乳动物细胞和转基因小鼠。