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: 7134100
• 负责人: KENT D SUGDEN
• 金额: $ 28.05万
• 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 2011-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7134100
• 关键词: DNA damage; DNA repair; ascorbate; carcinogenesis; carcinogens; cell line; chemical structure function; chromium; crosslink; cytotoxicity; drug metabolism; electron spin resonance spectroscopy; environment related neoplasm /cancer; environmental exposure; environmental toxicology; gel mobility shift assay; gene mutation; genetic transcription; glutathione; guanine; high performance liquid chromatography; mass spectrometry; metal metabolism; oxidation; vitamin metabolism

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）：六价氧化态的铬、铬酸盐或 Cr(VI) 是已知的人类致癌物。人类接触这种致癌物发生在使用铬的职业中以及主要来自人为的环境来源。尽管美国做出了保护和回收利用的努力，但每年仍有超过 20,000 吨铬被释放到环境中，其中超过 5000 吨铬作为大气排放。 Cr(VI) 排放到环境中的现象无处不在，导致 ATSDR 将这种金属列为 20 种高度优先减排有毒物质之一。虽然 Cr(VI) 被认为是一种有毒的 DNA 损伤剂，但 DNA 损伤和产生的 DNA 损伤的机制仍然未知。我们最近在体外和细胞系统中发现了 DNA 中几个新的“进一步氧化”鸟嘌呤损伤，这些损伤是由 Cr(VI) 处理引起的。这些病变已在细胞系统中表现出许多与 Cr 诱导的肺癌病理相关的相同生物效应。基于这些发现，我们建议检验以下假设：“铬酸盐接触会导致 DNA 中形成进一步氧化的鸟嘌呤损伤子集，最终导致癌症的细胞事件”。我们用来检验这个假设的方法是： 1) 我们将测试铬酸盐对一组模型、DNA 修复缺陷的细胞系的选择性毒性，并确定出现的氧化损伤的范围，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细胞系并确定这种细胞内还原剂调节是否影响相对病变分布，3) 我们建议鉴定铬氧化 DNA 形成 DNA 还原剂、DNA 氨基酸和 DNA 蛋白质的潜力交联，4) 我们建议确定这些交联对突变、DNA 修复和基因转录等细胞功能的影响。这项研究的最终结果将是对 Cr(VI) 引起的氧化 DNA 损伤形成损害关键细胞过程的损伤过程的基本见解。这项研究还将有助于识别 Cr(VI) 暴露的新生物标志物，并提出可以分析多态性和突变的修复基因。