Oxidative Mechanisms of Arsenic-induced Carcinogenesis

砷诱发癌变的氧化机制

• 批准号: 6891568
• 负责人: Ke Jian Liu
• 金额: $ 35.5万
• 依托单位: UNIVERSITY OF NEW MEXICO
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-05-03 至 2007-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6891568
• 关键词: DNA damage; SDS polyacrylamide gel electrophoresis; arsenic; biological signal transduction; chemical carcinogenesis; chemical related neoplasm /cancer; electron spin resonance spectroscopy; environmental exposure; epidermal growth factor; free radical oxygen; genetically modified animals; growth factor receptors; keratinocyte; laboratory mouse; oxidative stress; peroxidation; polymerase chain reaction; skin neoplasms; superoxides; western blottings

DESCRIPTION (provided by applicant): Arsenic exposure is strongly associated with keratinocytic tumors, both basal and squamous cell carcinomas. Despite this strong epidemiological evidence, little is known of the mechanisms of arsenic induced tumorigenesis in keratinocytes. Arsenic is defined as a complete carcinogen with both DNA damaging and tumor promoting capabilities, yet the underlying mechanisms of arsenic-induced carcinogenesis remain unclear. Recent studies indicate that arsenic exposure results in the generation of reactive oxygen species (ROS) and oxidative stress; however, there are substantial gaps in our knowledge on the potential significance of ROS generation and arsenic toxicity. Specifically not known are: 1) the exact nature of the reactive species generated by arsenic exposure, 2) the relationship between the transforming or carcinogenic potential of different forms of arsenic and ROS generation, and 3) the relationship between distinct ROS species and DNA damage or modulation of signaling pathways. Identifying the specific reactive oxygen specie(s) responsible for arsenic-induced carcinogenesis is critically important because reactive oxygen and nitrogen species consist of several unique and distinctively different specific reactive intermediates. This is because the patterns of both DNA damage, and the activation of specific signal transduction pathways are highly dependant upon the exact nature of the specific reactive oxygen species involved. We hypothesize that the formation and chemical nature of ROS, and therefore the pathways of ROS-induced cell damage, signaling and hence carcinogenesis, are strongly dependent upon the exact nature of the arsenic species. To test this hypothesis, we will: 1) Identify and quantitate superoxide and the resulting specific reactive species generated by exposure to inorganic arsenic and its major organic metabolites in human keratinocytes and in vivo measurement of ROS production in the skin of hairless mice; 2) Determine lipid peroxidation, protein oxidation, and oxidative DNA damage following exposure to different arsenic compounds; 3) Determine the mutagenic effect, and signal transduction associated with ROS generation following exposure to each form of arsenic. Overall, the proposed experiments will provide a fundamental understanding of the role of superoxide and the resulting oxidative stress in the underlying mechanisms contributing to tumor promotion and skin carcinogenesis by arsenic.

描述（由申请人提供）：砷暴露与基底和鳞状细胞癌的角质形成细胞肿瘤密切相关。尽管有强有力的流行病学证据，但对砷诱导的角质形成细胞的肿瘤发生的机制知之甚少。砷被定义为具有DNA损伤和肿瘤促进能力的完整致癌物，但是砷诱导的致癌作用的潜在机制尚不清楚。最近的研究表明，砷暴露会导致活性氧（ROS）和氧化应激的产生。但是，我们对ROS产生和砷毒性的潜在意义的知识存在很大的差距。具体不知道的是：1）砷暴露产生的反应性物种的确切性质，2）不同形式的砷和ROS产生的转化或致癌潜力之间的关系，以及3）不同的ROS物种与DNA损害之间的关系或信号通路的调制。识别负责砷诱导的癌变的特定活性氧体非常重要，因为活性氧和氮物种由几种独特和独特的特定反应性中间体组成。这是因为DNA损伤的模式以及特定信号转导途径的激活高度依赖于所涉及的特定活性氧的确切性质。我们假设ROS的形成和化学性质，因此ROS诱导的细胞损伤的途径，信号传导及其癌变，在很大程度上取决于砷物种的确切性质。为了检验这一假设，我们将：1）识别和定量超氧化物以及通过暴露于人角质形成细胞中的无机砷及其主要有机代谢产生的特定反应性物种，以及在无毛小鼠皮肤中的ROS产生的体内测量； 2）确定暴露于不同砷化合物后的脂质过氧化，蛋白质氧化和氧化性DNA损伤； 3）确定暴露于每种形式的砷后与ROS产生相关的诱变作用，并确定与ROS产生相关的信号转导。总体而言，提出的实验将对超氧化物的作用以及由此产生的氧化应激在促进肿瘤促进和砷的皮肤致癌作用的基本理解。