Genotoxicity of Chromium Compounds

铬化合物的遗传毒性

• 批准号: 9215672
• 负责人: Anatoly Zhitkovich
• 金额: $ 36.56万
• 依托单位: BROWN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-08-01 至 2020-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9215672
• 关键词: Biological; Biological Markers; Carcinogens; Cells; Chromatin; Chromium; Chromium Compounds; Coupled; DNA; DNA Adducts; DNA Binding; DNA Damage; DNA Double Strand Break; DNA Modification Process; DNA Repair; DNA Repair Gene; DNA lesion; DNA sequencing; Dangerousness; Data; Dose; Environmental Exposure; Excision; Exposure to; Generations; Genetic; Genetic Markers; Genetic Predisposition to Disease; Genetic Transcription; Genome; Genomic Segment; Genomics; Household; Human; In Vitro; Individual; Injury; Knowledge; Lead; Location; Malignant Neoplasms; Maps; Mediating; Metabolism; Metals; Minor; Mismatch Repair; Modeling; Molecular; Monitor; Nucleotide Excision Repair; Occupational; Occupational Exposure; Plasmids; Population; Process; Production; Property; Public Health; Publishing; Reaction; Recruitment Activity; Risk Assessment; Series; Shuttle Vectors; Site; Spottings; Superfund; Testing; Toxic effect; Toxicology; Transcription-Coupled Repair; Vertebral column; Water Supply; Work; Workplace; adduct; biomarker development; biomarker identification; carcinogenicity; chromatin immunoprecipitation; chromium hexavalent ion; cytotoxic; cytotoxicity; design; drinking water; endonuclease; experimental study; genotoxicity; high risk; improved; inorganic phosphate; novel; nuclease; public health relevance; repaired; response; superfund site; toxic metal; vector

 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.

 描述（由申请人提供）： 六价铬 [Cr(VI)] 是一种强效人类致癌物，在美国超过 50 万人的工作场所中发现。由于数百万美国家庭的饮用水和许多超级基金有毒地点的饮用水中都存在这种金属，因此六价铬的环境暴露也构成了重大的公共卫生问题。 Cr(VI) 的细胞内还原导致多种 DNA 损伤的形成，包括多种形式的 Cr-DNA 加合物。我们之前发现 Cr-DNA 结合是 Cr(VI) 及其主要生物还原剂直接代谢产生的所有诱变和基因毒性效应的原因。 Cr-DNA 加合物的遗传毒性是出乎意料的，因为它们的双链体扭曲特性非常弱，反映了 Cr 原子与 DNA 磷酸基团的连接。 Cr(VI) 还会导致剧毒、致癌的 DNA 双链断裂 (DSB)，这种断裂在环境相关的 Cr(VI) 剂量下即可检测到，且修复效果较差。该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 Cr-DNA 加合物的有毒 DNA 修复形成 DSB 的机制。拟议的研究旨在确定触发有毒 DNA 修复和 DSB 形成的 Cr-DNA 损伤的特定形式，表征 DNA 链切割中涉及的核酸酶活性，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可以帮助识别六价铬暴露的毒理学重要生物标志物和高风险基因组位点，可用于监测暴露人群的遗传损伤。