Oxidative DNA Lesion Formation from Chromate Exposure

铬酸盐接触导致 DNA 氧化损伤的形成

• 批准号: 7436224
• 负责人: KENT D SUGDEN
• 金额: $ 24.98万
• 依托单位: UNIVERSITY OF MONTANA
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-08-07 至 2011-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7436224
• 关键词: 8-Oxo-2' -Deoxyguanosine; Accounting; Acetylcysteine; Affect; Amino Acids; Antibodies; Base Excision Repairs; Biological; Biological Assay; Biological Markers; Buthionine Sulfoximine; Carcinogens; Cell Line; Cell Survival; Cell model; Cell physiology; Cells; Chromates; Chromium; DNA; DNA Damage; DNA Repair; DNA Repair Gene; DNA lesion; DNA-Binding Proteins; DNA-protein crosslink; Data; Electron Spin Resonance Spectroscopy; Environment; Escherichia coli; Event; Exposure to; Fibroblasts; Gel; Genetic Polymorphism; Genetic Transcription; Genomics; Glutathione; Growth; Guanine; High Pressure Liquid Chromatography; Human; In Vitro; Lead; Lesion; Link; Malignant Neoplasms; Malignant neoplasm of lung; Mass Spectrum Analysis; Measures; Metabolism; Metals; Metric; Modeling; Molecular Weight; Mus; Mutation; Nature; Nuclear Extract; Nucleotide Excision Repair; Occupational Exposure; Occupations; Pathology; Pathway interactions; Personal Satisfaction; Plasmids; Process; Proteins; Range; Recycling; Reducing Agents; Relative (related person); Research; Research Personnel; Role; Shuttle Vectors; Site; Source; System; Testing; Thinking; Toxic effect; United States; Variant; Water; XPA gene; analog; anthropogenesis; ascorbate; base; chromium hexavalent ion; crosslink; dehydroascorbate; exposed human population; gene repair; genotoxicity; guanidinohydantoin; insight; novel; oxidation; oxidative DNA damage; repaired; spiroiminodihydantoin

DESCRIPTION (provided by applicant): The hexavalent oxidation state of chromium, chromate or Cr(VI), is a known human carcinogen. Human exposure to this carcinogen occurs in chrome-utilizing occupations and from environmental sources that are primarily anthropogenic. Despite conservation and recycling efforts in the United States, over 20,000 metric tons of chromium is released to the environment every year with over 5000 metric tons as atmospheric emissions. The ubiquity of Cr(VI) emissions to the environment has led the ATSDR to list this metal as one of the top 20 high priority toxic agents for emission reduction. While Cr(VI) is well-established as a toxic DNA damaging agent, the mechanism(s) of DNA damage and the DNA lesions that are produced are still unknown. We have recently identified of several new "further oxidized" guanine lesions in DNA that arise from Cr(VI) treatment from both in vitro and cellular systems. These lesions have demonstrated many of the same biological effects in cell systems that are associated with pathologies of Cr-induced lung cancers. Based on these findings, we propose to test the hypothesis that "chromate exposure leads to the formation of a subset of further oxidized guanine lesions in DNA that are ultimately responsible for the cellular events that give rise to cancer". The approach that we will use to test this hypothesis will be; 1) We will test the selective toxicity of chromate towards a set of model, DNA-repair deficient, cell lines and determine the spectrum of oxidized lesions that arise, 2) we will determine how modulation of intracellular reduction potential may affect chromate sensitivity in these cell lines and determine whether this intracellular reductant modulation effects the relative lesion distribution, 3) we propose to identify the potential for oxidation of DNA by chromium to form DNA-reductant, DNA-amino acid and DNA-protein crosslinks, and 4) we propose to determine the effect that these crosslinks have on cellular function with regard to mutations, DNA repair and gene transcription. The end result of this study will be a fundamental insight into the process by which oxidative DNA damage caused by Cr(VI) forms lesions that impair critical cellular processes. This research will also serve to identify novel biomarkers of Cr(VI) exposure and suggest repair genes that can be analyzed for polymorphisms and mutations.

说明(申请人提供)：铬、铬酸盐或六价铬(VI)的六价氧化状态，是已知的人类致癌物质。人类接触这种致癌物发生在利用铬的职业和主要是人为的环境来源。尽管美国采取了保护和回收的努力，但每年仍有超过20,000公吨的铬被释放到环境中，其中超过5,000公吨是大气排放。铬(VI)对环境的排放无处不在，导致ATSDR将这种金属列为前20名优先减排的有毒物质之一。虽然铬(VI)是一种公认的毒性DNA损伤剂，但其损伤机制(S)及其引起的DNA损伤仍不清楚。我们最近在DNA中发现了几个新的“进一步氧化”的鸟嘌呤损伤，这些损伤是由体外和细胞系统的铬(VI)处理引起的。这些损伤在细胞系统中表现出许多与铬诱导肺癌的病理相关的相同的生物学效应。基于这些发现，我们建议检验这一假设，即“铬酸盐暴露导致DNA中进一步氧化的鸟嘌呤损伤的子集的形成，这最终导致导致癌症的细胞事件”。我们将用来检验这一假说的方法是；1)我们将测试铬酸盐对一系列DNA修复缺陷模型细胞的选择性毒性，并确定出现的氧化损伤的光谱；2)我们将确定细胞内还原电位的调节如何影响这些细胞系中的铬酸盐敏感性，并确定这种细胞内还原剂调节是否影响相对损伤的分布；3)我们建议确定铬氧化DNA形成DNA还原剂、DNA-氨基酸和DNA-蛋白质交联物的可能性；以及4)我们建议确定这些交联物对细胞功能的影响，包括突变、DNA修复和基因转录。这项研究的最终结果将是对铬(VI)引起的氧化DNA损伤形成损害关键细胞过程的根本洞察。这项研究还将用于识别暴露于铬(VI)的新生物标记物，并建议可以分析多态和突变的修复基因。