GENOTOXICITY OF CHROMIUM COMPOUNDS

铬化合物的遗传毒性

• 批准号: 6043506
• 负责人: Anatoly Zhitkovich
• 金额: $ 21.44万
• 依托单位: BROWN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-08-01 至 2002-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6043506
• 关键词: DNA damage; adduct; autoradiography; carcinogen testing; chemical carcinogen; chemical carcinogenesis; chromium; cysteine; glutamates; glutathione; histidine; human genetic material tag; hypoxanthine phosphoribosyltransferase; mutagen testing; mutagens; neoplasm /cancer genetics; nucleic acid sequence; polymerase chain reaction; tissue /cell culture; transfection /expression vector

DESCRIPTION: Exposure to hexavalent chromium compounds has been established to present a significant cancer risk to human respiratory system. Induction of DNA lesions and subsequently, mutations is generally considered to be responsible for the initiation of Cr(VI)-dependent carcinogenic process. Cr(VI) compounds have been shown to be mutagenic to bacterial and mammalian cells, however, the nature of underlying DNA modifications have not yet been characterized. Reductive conversion of Cr(VI) to Cr(III) accompanied by the formation of intermediate Cr(V/VI) forms and radical byproducts is required for the induction of genotoxic effects. Recent data showed that a major form of DNA adducts formed in Cr(VI)-exposed cells is represented by crosslinks composed of intracellular amino acids or glutathione bridged to DNA by Cr(III). Cysteine, histidine and glutamic acid were predominant amino acids found crosslinked to DNA. Subsequent in vitro studies demonstrated that these ternary adducts are formed by binding of Cr(III)-amino acid complexes to DNA. In preliminary experiments some amino acid-Cr(III) adducts exhibited mutagenic activity. On the basis of these data Dr. Zhitkovich hypothesized that a significant portion of Cr(VI) genotoxicity results from reactions of its final reductive metabolite, Cr(III). In order to obtain evidence supporting this hypothesis, a number of experiments aimed at studying formation of Cr(III) adducts and their mutagenic potential will be carried out. Mutagenicity of the in vitro formed Cr(III)- and amino acids/glutathione-Cr(III)-DNA adducts will be investigated in human cells using a shuttle vector approach. Involvement of Cr(III) in the DNA adduction in vivo will be studied in mammalian cells following their exposure to Cr(VI) or particulate Cr(III) compounds. In addition, the role of nucleotide excision repair in the removal of different Cr(III) adducts will also be analyzed. The results of the proposed work will help understand molecular mechanisms of Cr(VI) carcinogenicity by testing a Cr(III)-dependent pathway of DNA damage and mutagenicity of major adducts. Clarification of the genotoxic activity of intracellular Cr(III) may also have important public health implications considering the fact that human exposure frequently occurs to mixtures of Cr(VI) and Cr(III) forms while current risk assessment is based predominantly on the Cr(VI) levels.

描述：已确定暴露于六价铬化合物 对人体呼吸系统有很大的致癌风险。 感应 DNA损伤和随后的突变通常被认为是 负责启动Cr（VI）依赖性致癌过程。 Cr（VI）化合物对细菌和哺乳动物具有致突变性 然而，在细胞中，潜在的DNA修饰的性质还没有被发现。 表征了 将Cr（VI）还原转化为Cr（III）， 需要形成中间Cr（V/VI）形式和自由基副产物 用于诱导遗传毒性效应。 最近的数据显示， 在Cr（VI）暴露的细胞中形成的DNA加合物的形式表示为 由细胞内氨基酸或谷胱甘肽组成的交联， Cr（III）的DNA。 半胱氨酸、组氨酸和谷氨酸占优势 发现与DNA交联的氨基酸。 随后的体外研究 证明这些三元加合物是通过结合 Cr（III）-氨基酸复合物与DNA的结合。 在初步实验中， 酸-Cr（III）加合物具有致突变活性。 根据这些 Zhitkovich博士假设Cr（VI）的很大一部分 遗传毒性由其最终还原代谢物的反应产生， Cr（III）。 为了获得支持这一假设的证据， 旨在研究Cr（III）加合物的形成及其 将进行致突变潜力试验。 体外致突变性 形成的Cr（III）-和氨基酸/谷胱甘肽-Cr（III）-DNA加合物将被 使用穿梭载体方法在人类细胞中研究。 参与 将在哺乳动物细胞中研究Cr（III）在体内DNA加合中的作用 在暴露于Cr（VI）或颗粒状Cr（III）化合物之后。 在 此外，核苷酸切除修复在去除不同的 还将分析Cr（III）加合物。 拟议工作的结果 将有助于了解Cr（VI）致癌性的分子机制， 检测Cr（III）依赖性DNA损伤途径和主要 加合物 阐明细胞内Cr（III）的遗传毒性活性 考虑到以下事实， 人类经常接触Cr（VI）和Cr（III）形式的混合物 而目前的风险评估主要基于Cr（VI）水平。