Indirect Genotoxicity in Metal Carcinogenesis

金属致癌过程中的间接遗传毒性

• 批准号: 10304906
• 负责人: Anatoly Zhitkovich
• 金额: $ 36.56万
• 依托单位: BROWN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-01-15 至 2024-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10304906
• 关键词: Alloys; Anabolism; Binding; Biochemical Process; Biological Assay; Biological Markers; Cancer Etiology; Cancer Model; Cancerous; Carcinogenicity Tests; Carcinogens; Cell Cycle; Cells; Chemicals; Chemoprevention; Chemopreventive Agent; Chromosome Fragile Sites; Chromosome abnormality; DNA; DNA Adducts; DNA Damage; DNA Sequence Alteration; DNA replication fork; Dangerousness; Dependence; Development; Dose; Early Diagnosis; Environment; Environmental Pollutants; Enzymes; Event; Exposure to; Fiber; Fossil Fuels; Genetic; Genome; Genomics; Genotoxic Stress; Goals; Human; Impairment; Incineration; Individual; Industrialization; Inhalation Exposure; Knowledge; Lung; Lung Neoplasms; Malignant Neoplasms; Malignant neoplasm of lung; Metabolic dysfunction; Metabolism; Metal Carcinogenesis; Metals; Methodology; Modeling; Molecular Abnormality; Municipalities; Mutagens; Mutation; Nickel; Occupational Exposure; Oncogenic; Pharmaceutical Preparations; Phenotype; Phosphotransferases; Play; Population; Predisposition; Process; Production; Public Health; RRM1 gene; RRM2 gene; Repression; Research; Ribonucleotide Reductase; Risk; Risk Assessment; Rodent; Role; S phase; Signal Transduction; Site; Source; Specificity; Stainless Steel; Structure; Superfund; Testing; Thymidylate Synthase; Tumor Suppressor Genes; Work; base; cancer risk; carcinogenicity; cell transformation; chromium hexavalent ion; epidemiologic data; experimental study; genotoxicity; improved; melanoma; novel; potential biomarker; tumorigenic; wasting

Project Summary Mutations in various oncogenes and tumor-suppressor genes as well as other genome rearrangements are a principal cause of human cancers. Lung tumors have especially high burdens of mutations. Despite this dependence of cancer development on multiple genetic events, many human lung carcinogens are tested as nonmutagenic in standard assays. Our current lack of knowledge about the causes of genetic damage by seemingly nonmutagenic carcinogens negatively impacts public health actions and precludes early detection of this class of dangerous chemicals. Metals is one important group of widespread carcinogens that are largely nonmutagenic, including lung cancer-causing nickel (Ni). Ni is a large-volume industrial metal with inhalation exposures occurring daily among millions of workers. This metal is also a common environmental pollutant that is abundantly released during fossil fuel burning, incineration of municipal waste and many other processes. Ni is found at > 50% of Superfund toxic sites. In this project, we will test a conceptually novel hypothesis that Ni(II) disrupts a unique biochemical process and the resulting metabolic dysfunction causes gross genetic alterations and cancerous transformation of human lung cells. Our main hypothesis will be tested in three complementary aims. The proposed studies will determine (1) mechanisms of Ni(II)-induced changes in cell metabolites, (2) initial and secondary genetic abnormalities resulting from Ni(II)-altered metabolism and protective functions of ATR kinase, and (3) importance of Ni-induced metabolic dysfunction in tumorigenic cell transformation. The completion of the proposed work is expected to establish a novel mechanism for indirect genotoxicity by a major human carcinogen. This mechanism can be applicable to other nonmutagenic carcinogens possessing a specific chemical reactivity. The project should also provide a valuable mechanistic information needed for modeling of cancer risks at low-dose Ni exposures and identify targets for development of potential chemopreventive approaches.

项目摘要 各种癌基因和肿瘤抑制基因以及其他基因组重排的突变 是人类癌症的主要原因。肺部肿瘤的突变负担特别高。 尽管癌症发展对多个遗传事件的依赖性，但许多人类肺 致癌物在标准测定中被测试为非溶剂。我们目前缺乏关于 看似非毒素致癌物造成遗传损害的原因，对公共卫生产生了负面影响 动作和排除了这类危险化学物质的早期发现。金属很重要 一组广泛的致癌物基本上是非毒素的，包括引起肺癌的镍 （ni）。 NI是一种大容量的工业金属，每天在数百万 工人。这种金属也是一种常见的环境污染物，化石期间大量释放 燃料燃烧，市政废物的焚化以及许多其他过程。 NI在> 50％ 超级基金有毒地点。在这个项目中，我们将检验一个概念上的新假设，即Ni（II）破坏了A 独特的生化过程和由此产生的代谢功能障碍会导致遗传改变 和人肺细胞的癌变转化。我们的主要假设将在三个 补充目标。拟议的研究将确定（1）Ni（ii）诱导的变化的机制 在细胞代谢产物中，（2）由Ni（II）改变的初始和次要遗传异常 ATR激酶的代谢和保护功能，以及（3）NI诱导的代谢的重要性 肿瘤细胞转化的功能障碍。预计拟议工作的完成 通过主要的人类致癌物建立一种新型的遗传毒性机制。这种机制 可以适用于具有特定化学反应性的其他非植物致癌物。这 项目还应提供对癌症风险建模所需的有价值的机械信息 低剂量NI暴露并确定用于发展潜在化学预防方法的靶标。