Genotoxicity of Chromium Compounds

描述（由申请方提供）：六价铬（Cr）化合物的致癌活性已通过实验和流行病学研究确定。在几十种职业中发现了人类对Cr（VI）的暴露，并在居住在Cr排放工业源和Cr处置场附近的人群中检测到。Cr（VI）是一种主要的空气污染物和超级基金污染物。Cr（VI）暴露细胞中DNA损伤的主要形式是稳定的Cr（III）形式与DNA磷酸盐反应产生的丰富的Cr-DNA加合物。我们已经发现，一些Cr-DNA加合物在人体细胞复制过程中具有致突变性。三元DNA加合物含有庞大的配体，如谷胱甘肽或抗坏血酸，诱导最强的致突变反应。我们还确定，铬（III）依赖性反应是负责形成致突变DNA损伤的还原激活过程中的铬（VI）的主要生物还原剂，半胱氨酸和抗坏血酸。其他数据表明，Cr（III）-DNA加合物形成的生物学后果受到DNA错配修复系统状态的强烈影响。我们建议阐明的机制，错配修复依赖诱导应激信号和形成的遗传改变铬（VI）暴露的细胞。将进行实验以鉴定通过DNA错配修复识别并激活遗传毒性反应的特定Cr-DNA加合物。这项工作的结果应该提供一个更好的理解的分子基础的Cr（VI）致癌作用，个别Cr-DNA加合物的重要性，并发现新的功能的错配修复识别的DNA骨架修饰。鉴定最有效的遗传毒性Cr-DNA加合物和控制细胞对Cr（VI）反应的关键途径可用于开发有用的暴露生物标志物和个体对不良健康影响的易感性。

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.