Genotoxicity of Chromium Compounds

铬化合物的遗传毒性

• 批准号: 6917117
• 负责人: Anatoly Zhitkovich
• 金额: $ 32.69万
• 依托单位: BROWN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-09-22 至 2008-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6917117
• 关键词: DNA damage; DNA repair; adduct; apoptosis; ascorbate; autoradiography; carcinogen testing; cell population study; chemical carcinogen; chemical carcinogenesis; chemical related neoplasm /cancer; chromium; cysteine; cysteine endopeptidases; gene induction /repression; gene targeting; glutathione; histidine; human genetic material tag; mutagen testing; mutagens; neoplasm /cancer genetics; nucleic acid sequence; p53 gene /protein; posttranslational modifications; tissue /cell culture; transfection /expression vector

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.

描述（由申请人提供）：六价铬（CR）化合物的致癌活性由实验和流行病学研究牢固确定。在数十名职业中发现了人类对CR（VI）的接触（VI），并在居住在CR发出工业来源和CR处置地点附近的人群中发现。 CR（VL）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损伤的主要形式是在稳定Cr（III）与DNA磷酸盐的反应中产生的丰富的Cr-DNA加合物。我们发现，在人类细胞复制过程中，几种CR-DNA加合物是诱变的。含有大量配体的三元DNA加合物，例如谷胱甘肽或抗坏血酸，诱导了最强的诱变反应。我们还确定，CR（III）依赖性反应是导致其主要生物还原剂，半胱氨酸和抗坏血酸的CR（VI）还原性激活过程中诱变DNA损伤的形成。其他数据表明，CR（III） - DNA加合物形成的生物学后果受DNA不匹配修复系统状态的强烈影响。我们建议阐明不匹配修复依赖性诱导应力信号传导的机制，以及CR（VI）暴露细胞中遗传改变的形成。将进行实验，以识别通过DNA错配修复并激活遗传毒性反应识别的特定CR-DNA加合物。这项工作的结果应提供对CR（VI）癌变的分子基础，单个CR-DNA加合物的重要性以及发现不匹配修复的新功能在识别DNA骨架修饰方面的新功能。可以使用最有效的遗传毒性CR-DNA加合物和控制对CR（VI）的细胞反应的关键途径，用于开发有用的暴露生物标志物和个人对不良健康影响的敏感性。