This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Arsenic, a recognized environmental toxicant targets the human skin and long-term exposure to arsenic principally through drinking water has been correlated with increased risk to skin cancer. In this pilot study, we propose to investigate the time course alteration in genome-wide expression profiles of keratinocyte cell line to chronic exposure concentrations of arsenic trioxide. We hypothesize that in chronically exposed arsenic trioxide treated cells over a time course of two weeks, mimicking keratinocyte differentiation, toxic insult by arsenic trioxide will cause alterations in gene expression leading to carcinogenesis. In the first year, we have focused on identifying and prioritizing genes known to interact with arsenic that may influence an individual's susceptibility to arsenic-induced skin lesions. Thus the following objective was to determine the functional impact of the location of single nucleotide polymorphisms (SNPs) on genes known to interact with arsenic. We have integrated data on over 1,400 genes curated in the Comparative Toxicogenomics Database and known to interact with arsenic with gene-centric data from the Environmental Genome Project and the Entrez dbSNP. Our data integration approach classed over 13,400 SNPs by associated functional impacts: frame shift, missense, nonsense and synonymous. Furthermore, we identified subsets of SNPs in the base excision DNA repair pathway such as XRCC1, hOGG1 and APEX1, that may influence individual susceptibility to arsenic-induced skin lesions. In the second year, the aberrations in the expression of functionally-defined arsenic-interacting genes in response to chronic exposures to arsenic will be determined.
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