Genotoxicity of Chromium Compounds

描述(申请人提供)：实验和流行病学研究证实了六价铬化合物的致癌活性。在几十个职业中发现了人对铬(VI)的暴露，并在居住在铬排放源和铬处置场所附近的人口中发现了这一点。铬(Vl)是一种主要的空气污染物和超级基金污染物。在铬(VI)暴露的细胞中，DNA损伤的主要形式是稳定的铬(III)与DNA磷酸盐反应生成丰富的铬-DNA加合物。我们发现，几种铬-DNA加合物在人体细胞复制过程中具有致突变性。含有体积较大的配体的三元DNA加合物，如谷胱甘肽或抗坏血酸，可诱导最强的突变反应。我们还确定了在铬(VI)的主要生物还原剂半胱氨酸和抗坏血酸还原活化铬(VI)的过程中，依赖于铬(III)的反应是造成突变DNA损伤的原因。更多的数据表明，铬(III)-DNA加合物形成的生物学后果强烈地受到DNA错配修复系统状态的影响。我们建议阐明在铬(VI)暴露的细胞中，错配修复依赖的压力信号诱导和遗传改变形成的机制。将进行实验，以确定特定的铬-DNA加合物，这些加合物可被DNA错配修复识别并激活遗传毒性反应。这项工作的结果将有助于更好地理解铬(VI)致癌的分子基础，单个铬-DNA加合物的重要性，并揭示错配修复在识别DNA骨架修饰方面的新功能。确定最有效的遗传毒性铬-DNA加合物和控制细胞对铬(VI)反应的关键途径可用于开发有用的暴露和个体对不利健康影响的易感性的生物标志物。

DESCRIPTION (provided by applicant): Carcinogenic activity of hexavalent chromium (Cr) compounds is firmly established by experimental and epidemiological studies. Human exposure to Cr(VI) is found in several dozen occupations and detected in populations residing in the vicinity of Cr-emitting industrial sources and Cr disposal sites. Cr(Vl) is a major air pollutant and a Superfund contaminant. The major form of DNA damage in Cr(VI)-exposed cells is abundant Cr-DNA adducts generated in the reactions of stable Cr(III) form with DNA phosphates. We have found that several Cr-DNA adducts were mutagenic during replication in human cells. Ternary DNA adducts containing bulky ligands, such as glutathione or ascorbate, induced the strongest mutagenic responses. We also determined that Cr(III)-dependent reactions were responsible for the formation of mutagenic DNA damage during reductive activation of Cr(VI) by its major biological reducers, cysteine and ascorbate. Additional data have shown that biological consequences of the formation of Cr(III)-DNA adducts are strongly influenced by the status of DNA mismatch repair system. We propose to elucidate the mechanisms of mismatch repair-dependent induction of stress signaling and formation of genetic alterations in Cr(VI)- exposed cells. Experiments will be performed to identify specific Cr-DNA adducts that are recognized by DNA mismatch repair and activate genotoxic responses. The results of this work should provide a greater understanding of molecular basis of Cr(VI) carcinogenesis, the importance of individual Cr-DNA adducts and uncover new functions of mismatch repair in recognition of DNA backbone modifications. Identification of the most potent genotoxic Cr-DNA adducts and critical pathways controlling cellular responses to Cr(VI) can be used in the development of useful biomarkers of exposure and individual susceptibility to adverse health effects.