CHROMIUM(III) GENOTOXICITY--DIRECT AND INDIRECT PATHWAYS

铬(III)遗传毒性——直接和间接途径

• 批准号: 2896133
• 负责人: Diane M Stearns
• 金额: $ 8.59万
• 依托单位: NORTHERN ARIZONA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-04-15 至 2003-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2896133
• 关键词: CHO cells; DNA damage; DNA repair; N methyl N' nitro N nitrosoguanidine; adduct; animal genetic material tag; carcinogen testing; chemical carcinogen; chemical carcinogenesis; chromium; crosslink; dietary supplements; hypoxanthine phosphoribosyltransferase; mutagen testing; mutagens; neoplasm /cancer genetics; nucleic acid sequence; nutrition related tag; toxicology

DESCRIPTION: This proposal is a resubmission for an R29 FIRST award the title of which has been appropriately changed from investigations of the comutagenicity of Chromium (III)@. This submission has also been sent from the College of Arts and Sciences, Northern Arizona University where the applicant has recently (August 97) been appointed Assistant Professor in the Dept. of Chemistry. The previous submission originated from Dartmouth College. The overall goal is to elucidate the mechanism of chromium carcinogenesis since chromium, a common industrially used heavy metal has been implicated in the development of human cancers. Chromium (VI) is the form of chromium which is classified as a human carcinogen, however, this proposal hypothesises that chromium (III) is involved in chromium (VI) induced cancers since it is an intracellular metabolic product of chromium (VI). Chromium (III) is not clearl an adverse agent in human health and Cr (III) based compounds are used as dietary supplements, however the principal investigator emphasizes that, The point to consider should be intracellular Cr (III) rather than Cr (III) exposure in general. There are strong indications that such a statement is highly pertinent. The specific goal of this proposal is then to elucidate direct and indirect pathways of Cr (III)-induced DNA damage and mutation. To test whether Cr (III) is responsible for the formation of Cr-DNA adducts, different adducts will be synthesized and examined by MR spectroscopy, and other techniques including X-ray crystallography. That is, a knowledge base will be constructed for synthetic Cr-DNA adducts and this information used to detect Cr-DNA adducts formed in cultured cells treated with Cr (III) and Cr (VI). In a second series of experiments designed to test the hypothesis that C (III) causes direct damage in cells through the formation of Cr-DNA adducts an produces indirect DNA damage by inhibiting repair, cell biological studies wil be undertaken. This contrasts with the bioinorganic chemistry approach in the first series of experiments. Specifically, CHO cells, normal and deficient in different steps of nucleotide excision repair will be treated with Cr (III) complexes and DNA based lesions measured (Cr-DNA adducts, strand breaks, cross-links and alkali labile sites). Comparison will be made against model genotoxins. In a third series of experiments the mutagenicity and co-mutagenicity of bioavailable Cr (III) will be assessed. Chromosomal changes and hgprt mutation will be measured to assess direct effects, while combined treatments with known genotoxins will also be undertaken to evaluate co-mutagenicity. It is hoped that knowledge gained from these explorations of the pathways of Cr (III) genotoxicity will contribute to an understanding of the carcinogenic capacity of Cr (VI), and the potential risk to humans of ingesting bioavailable Cr (III) nutritional supplements.

描述：这项提案是重新提交的R29第一奖 其标题已从对 铬(III)的共致突变性。此提交也是从 北亚利桑那大学艺术与科学学院 申请人最近(九七年八月)获委任为该学院助理教授。 部门化学专业。之前提交的材料来自达特茅斯 上大学。总的目标是阐明铬的作用机制。 自从铬，一种工业上常用的重金属以来，癌症已经 与人类癌症的发展有关。铬(VI)是 铬的形式被归类为人类致癌物质，然而，这 建议假设铬(III)与铬(VI)有关 诱发癌症，因为它是铬在细胞内的代谢产物 (Vi)。铬(III)对人体健康没有明确的不良影响 (Iii)基础化合物用作膳食补充剂，但主要 研究人员强调，要考虑的点应该是细胞内 铬(III)，而不是一般的铬(III)暴露。有很强的 有迹象表明，这样的声明是高度相关的。的具体目标 这一建议是为了阐明铬的直接和间接途径 (3)诱发DNA损伤和突变。为了测试铬(III)是否 负责铬-DNA加合物的形成，不同的加合物将 由磁共振波谱合成和检测，以及其他技术，包括 X射线结晶学。也就是说，将为以下方面构建知识库 合成的铬-DNA加合物及其用于检测铬-DNA加合物的信息 在经铬(III)和铬(VI)处理的培养细胞中形成。一秒钟内 一系列旨在测试C(III)引起的假设的实验 通过形成铬-DNA加合物对细胞的直接损伤 通过抑制修复间接DNA损伤，细胞生物学研究将 承担了。这与生物无机化学方法在 第一系列实验。具体来说，CHO细胞，正常和缺陷 在不同的核苷酸切除修复步骤中会用铬处理 (Iii)测量的复合体和DNA基损伤(铬-DNA加合物、链 断裂、交联链和碱不稳定部位)。我们将进行比较 对抗模型基因毒素。在第三系列实验中，诱变性 并将评估生物可用铬(III)的共同致突变性。染色体 将测量变化和hgprt突变以评估直接影响，而 与已知基因毒素的联合治疗也将用于 评估共同致突变性。希望从这些活动中获得的知识 对铬(III)遗传毒性途径的探索将有助于 对铬(VI)致癌能力和潜在致癌能力的认识 摄取生物可利用的铬(III)营养补充剂对人类的风险。