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. ? ?
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