Arsenic (As) is a well-documented human carcinogen. Environmental and occupational exposures to As-containing compounds are major public health issues. Understanding the mechanism of As-induced carcinogenesis is very important for early detection, for risk assessment, for establishment of an exposure standard, and for development of intervention and prevention strategies. While increasing evidence has linked arsenic exposure and generation of reactive oxygen species (ROS), we do not clearly understand the exact nature of the specific reactive species, the source and mechanism of ROS generation, the sequence of formation of different reactive species, and the specific species that are responsible for the arsenic-induced carcinogenesis. The goal of this proposal is to test the hypothesis that As-induced carcinogenesis is mediated by oxidative stress. To test this hypothesis, we will: (a) identify the molecular mechanism of As-induced ROS generation in cells with emphasis on 02.- radical generation since this radical is a precursor of other reactive oxygen species; (b) develop and apply an in vivo electron spin resonance (ESR) method for detection and identification of As-induced free radical generation in living animals; (c) determine oxidative stress, lipid peroxidation, protein oxidation, and oxidative DNA damage following As exposure in vivo; and (d) elucidate the role of oxidative stress in Cr(VI)-induced cell transformation and tumorigenesis. We will use As-treated HaCat cells to examine As-induced tumorigenesis in athymic nude mice and investigate the involvement of specific ROS species. We anticipate that As generates ROS, which cause activation of NF-KB and activator protein (AP-1) leading to tumorigenesis in nude mice. The methods used in the proposal are multi-disciplinary representing a combination of physical, chemical, and molecular approaches. The results obtained from this proposal will provide a fundamental understanding concerning the role of ROS in As-induced carcinogenesis. ? ?
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