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: 7795848
• 负责人: KENT D SUGDEN
• 金额: $ 24.69万
• 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 2012-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7795848
• 关键词: 8-Oxo-2' -Deoxyguanosine; Accounting; Acetylcysteine; Affect; Amino Acids; Antibodies; Base Excision Repairs; Biological; Biological Assay; Biological Markers; 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; Epidemiology; 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; Plasmids; Process; Proteins; Recycling; Reducing Agents; Relative (related person); Research; Research Personnel; Role; Shuttle Vectors; Site; Source; System; Testing; Toxic effect; United States; Variant; Water; XPA gene; analog; anthropogenesis; ascorbate; base; cancer initiation; 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.

描述（由申请人提供）：铬，铬酸盐或CR（VI）的六价氧化状态，是已知的人类致癌物。人类接触这种致癌物发生在镀铬的职业和主要是人为的环境来源中。尽管在美国进行了保护和回收工作，但每年以超过5000公吨的大气排放量向环境发布了超过20,000吨的铬。 CR（VI）排放到环境的无处不在，导致ATSDR列出了该金属作为降低排放量的前20个高优先级有毒剂之一。尽管CR（VI）作为有毒DNA损伤剂的建立良好，但DNA损伤的机制和产生的DNA病变仍然未知。我们最近确定了DNA中的几种新的“进一步氧化”的鸟嘌呤病变，这些鸟嘌呤病变是由CR（VI）从体外和细胞系统中引起的。这些病变已经证明了与CR诱导的肺癌病理相关的细胞系统中许多相同的生物学作用。基于这些发现，我们建议检验以下假设：“铬酸盐暴露会导致DNA中进一步氧化的鸟嘌呤病变的一部分，最终导致引起癌症的细胞事件。”我们将用来检验该假设的方法； 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为了形成DNA降低，DNA-氨基酸和DNA-蛋白交联，以及4）我们提出，确定这些交联对突变，DNA修复和基因转录的细胞功能的影响。这项研究的最终结果将是对CR（VI）造成的氧化性DNA损伤形成损害关键细胞过程的病变的基本见解。这项研究还将有助于鉴定CR（VI）暴露的新生物标志物，并建议对可以分析多态性和突变的修复基因。