Genotoxicity of Chromium Compounds

 描述(申请人提供)：六价铬[Cr(VI)]是一种强烈的人类致癌物质，在美国超过50万人的工作场所中发现。环境中暴露于铬(VI)也是一个重大的公共卫生问题，因为这种金属存在于数百万美国家庭的饮用水中和许多超级基金的有毒场所。细胞内铬(VI)的还原导致多种DNA损伤的形成，包括几种形式的铬-DNA加合物。我们以前已经发现，由于铬(VI)与其主要生物还原剂直接代谢而产生的所有诱变和遗传毒性效应都是由铬-DNA结合引起的。铬-DNA加合物的遗传毒性是意想不到的，因为它们非常弱的双链扭曲特性反映了铬原子与DNA磷酸基团的结合。铬(VI)还会引起毒性很大的、致癌的DNA双链断裂(DSB)，在与环境相关的铬(VI)剂量下可以检测到，而且修复效果很差。这项应用建立在我们之前发表的发现和新的初步数据的基础上，旨在研究通过铬-DNA加合物的毒性DNA修复形成DSB的机制。这些研究的目的是识别引起毒性DNA修复和DSB形成的特定形式的铬-DNA损伤，表征参与DNA链切割的核酸酶活性，并确定DNA断裂和DNA修复过程的基因组“宿主点”。这项工作的成功完成有助于确定铬(VI)暴露的重要毒理学生物标记物和可用于监测暴露人群遗传损害的高风险基因组位置。

 DESCRIPTION (provided by applicant): Hexavalent chromium [Cr(VI)] is a potent human carcinogen found in the workplace of more than 0.5 million individuals in the US. Environmental exposure to Cr(VI) also represents a significant public health concern due to the presence of this metal in drinking water for millions of US households and at many Superfund toxic sites. Intracellular reduction of Cr(VI) results in the formation of a wide assortment of DNA lesions, including several forms of Cr-DNA adducts. We have previously found that Cr-DNA binding was responsible for all mutagenic and genotoxic effects generated by direct metabolism of Cr(VI) with its main biological reducers. The genotoxicity of Cr-DNA adducts was unexpected considering their very weak duplex-distorting properties reflecting attachment of Cr atom to the DNA phosphate group. Cr(VI) also causes very toxic, cancer-promoting DNA double-strand breaks (DSB) that is detectable at environmentally relevant Cr(VI) doses and poorly repaired. This application, which is built on our previously published findings and new preliminary data, is designed to investigate a mechanism of DSB formation via toxic DNA repair of Cr-DNA adducts. The proposed studies aim to identify specific forms of Cr-DNA damage that trigger toxic DNA repair and DSB formation, characterize nuclease activities involved in DNA strand cleavage and determine genomic "host-spots" for DNA breakage and DNA repair processes. A successful completion of this work can help identify toxicologically important biomarkers of Cr(VI) exposure and high-risk genomic sites that can be used for monitoring of genetic damage in exposed populations.