Indirect Genotoxicity in Metal Carcinogenesis

项目摘要 各种癌基因和肿瘤抑制基因的突变以及其他基因组重排 是人类癌症的主要原因。肺肿瘤具有特别高的突变负担。 尽管癌症的发展依赖于多种遗传事件，但许多人的肺 致癌物在标准试验中被测试为非诱变性的。我们目前缺乏关于 看似非诱变性致癌物造成遗传损伤的原因对公众健康产生负面影响 行动，并排除早期发现这类危险化学品。金属是一种重要的 一组广泛存在的致癌物，大部分无诱变性，包括导致肺癌的镍 （Ni）.镍是一种大容量的工业金属，每天有数百万人吸入镍。 工人这种金属也是一种常见的环境污染物，在化石燃料开采过程中大量释放。 燃料燃烧、城市垃圾焚烧和许多其他过程。发现Ni为> 50%， 超级基金有毒网站。在这个项目中，我们将测试一个概念新颖的假设，Ni（II）破坏了一个 独特的生物化学过程和由此产生的代谢功能障碍导致总的遗传改变 以及人类肺细胞的癌变。我们的主要假设将在三个方面得到检验 互补的目标。拟开展的研究将确定（1）Ni（II）诱导变化的机制 在细胞代谢产物中，（2）由Ni（II）改变的 ATR激酶的代谢和保护功能，以及（3）镍诱导的代谢的重要性 致瘤细胞转化功能障碍。预计拟议工作完成后， 建立了一种主要人类致癌物间接遗传毒性的新机制。这一机制 可适用于具有特定化学反应性的其他非致突变致癌物。的 项目还应提供一个有价值的机制信息，需要为癌症风险建模， 低剂量镍暴露，并确定潜在的化学预防方法的发展目标。

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.