Indirect Genotoxicity in Metal Carcinogenesis

金属致癌过程中的间接遗传毒性

基本信息

批准号：
9913735
负责人：
Anatoly Zhitkovich
金额：
$ 36.56万
依托单位：
BROWN UNIVERSITY
依托单位国家：
美国
项目类别：
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/9913735
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

项目摘要

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.

项目概要各种癌基因和抑癌基因的突变以及其他基因组重排是人类癌症的主要原因。肺部肿瘤的突变负担特别高。尽管癌症的发展依赖于多种遗传事件，但许多人类肺癌在标准测定中，致癌物被测试为非致突变性。我们目前对这方面的了解还很缺乏看似非诱变致癌物造成基因损伤的原因对公共健康产生负面影响行动并阻止及早发现此类危险化学品。金属是重要的金属之一一组广泛存在的致癌物，大部分无致突变性，包括导致肺癌的镍（镍）。镍是一种大量的工业金属，每天都有数百万人吸入镍。工人。这种金属也是一种常见的环境污染物，在化石形成过程中大量释放燃料燃烧、城市垃圾焚烧和许多其他过程。 Ni 含量 > 50% 超级基金有毒网站。在这个项目中，我们将测试一个概念上新颖的假设，即 Ni(II) 会破坏独特的生化过程和由此产生的代谢功能障碍导致总体遗传改变和人类肺细胞的癌变。我们的主要假设将在三个方面进行检验互补的目标。拟议的研究将确定 (1) Ni(II) 引起的变化的机制在细胞代谢物中，(2) Ni(II) 改变导致的初始和继发性遗传异常 ATR 激酶的代谢和保护功能，以及 (3) Ni 诱导代谢的重要性致瘤细胞转化功能障碍。预计完成拟议工作建立一种主要人类致癌物间接遗传毒性的新机制。这个机制可适用于具有特定化学反应性的其他非致突变致癌物。这项目还应提供癌症风险建模所需的有价值的机制信息低剂量镍暴露并确定开发潜在化学预防方法的目标。