Genotoxicity of Chromium Compounds

铬化合物的遗传毒性

• 批准号: 7253891
• 负责人: Anatoly Zhitkovich
• 金额: $ 30.97万
• 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 2009-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7253891
• 关键词: 1-Phosphatidylinositol 3-Kinase; Accounting; Air Pollutants; Apoptosis; Apoptotic; Base Pair Mismatch; Binding; Biological; Biological Assay; Biological Markers; Carcinogen exposure; Carcinogens; Caspase; Cell Cycle; Cell Death; Cells; Characteristics; Chromium Compounds; Chronic; Complex; Critical Pathways; Cysteine; Cytogenetics; DNA; DNA Adducts; DNA Damage; DNA Interstrand Crosslinking; DNA biosynthesis; Data; Development; Dose; Epidemiologic Studies; Event; Exhibits; Exposure to; Frequencies; Genes; Genetic; Genetic Recombination; Glutathione; Goals; Grant; Growth; Health; Histidine; Human; In Vitro; Individual; Induction of Apoptosis; Ligands; Lung; Lung Neoplasms; MSH2 gene; MSH6 gene; Malignant - descriptor; Measures; Mediating; Microsatellite Repeats; Mismatch Repair; Mismatch Repair Gene Inactivation; Modification; Molecular; Mutagenesis; Mutation; Nuclear; Occupational Groups; Occupations; Oligonucleotides; Oxidants; Pathway interactions; Phenotype; Plasmids; Play; Population; Predisposition; Production; Proteins; Reaction; Repair Complex; Resistance; Role; Signal Transduction; Sister Chromatid Exchange; Site; Source; Stress; System; TP53 gene; Testing; Toxic effect; Variant; Vertebral column; Work; ascorbate; base; biological adaptation to stress; carcinogenesis; carcinogenicity; chromium hexavalent ion; exposed human population; gene induction; genotoxicity; homologous recombination; human H2AX protein; inorganic phosphate; recombinational repair; repaired; research study; response; size; uptake

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）化合物的致癌活性已通过实验和流行病学研究得到证实。在数十种职业中发现了人类接触六价铬的情况，并且在居住在铬排放工业源和铬处置场附近的人群中也发现了这种情况。 Cr(VI) 是一种主要空气污染物，也是超级基金污染物。 Cr(VI) 暴露细胞中 DNA 损伤的主要形式是稳定 Cr(III) 形式与 DNA 磷酸盐反应中产生的丰富的 Cr-DNA 加合物。我们发现一些 Cr-DNA 加合物在人体细胞复制过程中具有诱变性。含有大配体（例如谷胱甘肽或抗坏血酸）的三元 DNA 加合物可诱导最强的诱变反应。我们还确定，Cr(III) 依赖性反应是在 Cr(VI) 的主要生物还原剂半胱氨酸和抗坏血酸还原激活过程中形成诱变 DNA 损伤的原因。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。我们建议阐明错配修复依赖性应激信号传导诱导机制以及 Cr(VI) 暴露细胞中遗传改变形成的机制。将进行实验来鉴定可被 DNA 错配修复识别并激活基因毒性反应的特定 Cr-DNA 加合物。这项工作的结果应该有助于更好地理解 Cr(VI) 致癌的分子基础、各个 Cr-DNA 加合物的重要性，并揭示错配修复在识别 DNA 主链修饰中的新功能。鉴定最有效的基因毒性 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生物标志物，用于暴露暴露和个体对不良健康影响的易感性。