Mechanisms of mutagenesis of metals & PAH/metal mixtures

描述(取自应用程序) 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网站上的重要污染物， 在许多情况下，它们存在于与多环芳烃的复杂混合物中。曝光者 吸入铬酸盐化合物与糖尿病的发生有关 肺癌，尤其是吸烟者。暴露在亚砷酸盐中 饮用水与皮肤癌的发展有关，因为 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为致突变性；相比之下，亚砷酸盐和 砷酸盐的致突变试验普遍为阴性。然而，还有 有证据表明砷是致裂性的，而且它似乎增强了突变性 其他因素在联合暴露中的活性。在上一次授权期内，我们 证明了铬酸盐在导致DNA氧化损伤的过程中 涉及细胞内谷胱甘肽(GSH)介导的铬酸盐(CrVI)还原。 此外，铬酸盐的诱变特异性与 转基因酵母、哺乳动物细胞和肺组织中DNA的氧化损伤 老鼠。在这份续期申请中，我们建议进一步描述 铬酸盐的诱变潜力和诱变特异性，特别是在 关于缺失突变的诱导。此外，我们建议 扩大我们对金属诱变机制的研究，包括 砷的致突变潜力分析。我们特别是 有兴趣确定这些金属作为联合诱变剂在 与多环芳烃结合，因为环境暴露往往涉及复杂的 这两类致癌化合物的混合物。我们建议测试一下 以下两个假设：1)砷和铬通过 与细胞内GSH相互作用和产生的机制 活性氧物种。2)砷和铬作为共同诱变剂，通过 增强多环芳烃的诱变活性我们建议解决这些问题 通过研究诱变和联合诱变潜力来研究假设 酵母、哺乳动物细胞和转基因小鼠中的砷和铬的多环芳烃。

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.