Indirect Genotoxicity in Metal Carcinogenesis

项目摘要 多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。肺肿瘤的突变负担特别高。 尽管癌症的发展依赖于多种基因事件，但许多人类肺 在标准化验中，致癌物质被检测为无致突变性。我们目前对此缺乏了解 看似非致突变的致癌物造成的基因损伤对公众健康造成负面影响 行动，并阻止及早发现这类危险化学品。金属是一个重要的 一组广泛存在的致癌物，主要是无致突变性的，包括导致肺癌的镍 (NI)。镍是一种大量的工业金属，每天都会有数百万人吸入 工人们。这种金属也是一种常见的环境污染物，在化石过程中大量释放 燃料燃烧、城市垃圾焚烧和许多其他过程。NI出现在&gt；50%的 为有毒场所提供超级资金。在这个项目中，我们将测试一个概念上的新假设，即Ni(II)扰乱 独特的生化过程和由此导致的代谢功能障碍会导致严重的基因改变 以及人类肺细胞的癌变。我们的主要假设将在三年内得到检验 目标相辅相成。拟议的研究将确定(1)镍(II)诱导变化的机制 在细胞代谢产物中，(2)由镍(II)改变引起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)镍诱导代谢的重要性 致瘤细胞转化功能障碍。拟议工作的完成预计将 建立一种人类主要致癌物间接遗传毒性的新机制。这一机制 可适用于其他具有特定化学反应活性的非致突变致癌物质。这个 项目还应提供癌症风险建模所需的有价值的机械信息 低剂量镍暴露，并确定潜在化学预防方法的开发目标。

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.