CHROMIUM III GENOTOXICITY--DIRECT AND INDIRECT PATHWAYS

三价铬遗传毒性——直接和间接途径

• 批准号: 6054480
• 负责人: Diane M Stearns
• 金额: $ 2.35万
• 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/6054480
• 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：本提案是R29 FIRST奖项的重新提交， 其标题已适当地从《联合国海洋法公约》 铬（III）的共突变性。 这份意见书也是从 北方亚利桑那大学文理学院 申请人最近（一九九七年八月）获委任为香港中文大学助理教授， 部 化学。 上一次提交的材料来自达特茅斯 学院 总的目标是阐明铬的作用机理 铬是一种工业上常用的重金属， 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，然而，这 一项提案假设铬（III）与铬（VI）有关 诱发癌症，因为它是铬的细胞内代谢产物 （六）。 铬（III）对人体健康的不利影响尚不清楚， (III)的化合物被用作膳食补充剂，然而， 研究者强调，考虑的重点应该是细胞内 Cr（III）而不是一般的Cr（III）暴露。 有强烈 这些迹象表明，这样的声明是非常恰当的。 的具体目标 这一建议，然后阐明直接和间接途径铬 （三）诱发DNA损伤和突变。 为了测试Cr（III）是否 负责Cr-DNA加合物的形成，不同的加合物将 合成并通过MR光谱学和其他技术检查，包括 X射线晶体学 也就是说，将构建一个知识库， 合成的Cr-DNA加合物和用于检测Cr-DNA加合物的该信息 在用Cr（III）和Cr（VI）处理的培养细胞中形成。 在第二 一系列实验旨在测试假设，C（III）导致 通过形成Cr-DNA加合物直接损伤细胞， 通过抑制修复间接损伤DNA，细胞生物学研究将 进行。 这与生物无机化学方法形成对比， 第一系列实验。 具体而言，CHO细胞，正常和缺陷 在核苷酸切除修复的不同步骤中， (III)复合物和DNA为基础的病变测量（铬-DNA加合物，链 断裂、交联和碱不稳定位点）。 进行比较时 基因毒素模型。 在第三个系列的实验中， 并评估生物可利用Cr（III）的共致突变性。 染色体 将测量变化和hgprt突变以评估直接影响， 还将进行与已知遗传毒素的联合治疗， 评价共致突变性。 希望从这些研究中获得的知识 探索铬（III）遗传毒性的途径将有助于 了解Cr（VI）的致癌能力，以及 摄入生物可利用的Cr（III）营养补充剂对人类的风险。