ABERRATIONS IN GENE EXPRESSION IN ARSENIC-TREATED HUMAN EPIDERMAL CELLS Arsenic (As) is recognized as an environmental toxicant of global public health concern and leading cause of toxicity and carcinogenicity in humans exposed to it. Arsenic targets the human skin and longterm 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 human keratinocytes exposed to chronic concentrations of arsenic trioxide. We hypothesize that in keratinocytes chronically exposed to arsenic trioxide over a time course of two weeks, mimicking keratinocyte differentiation, toxic insult by arsenic trioxide will cause alterations in gene expression leading to carcinogenesis. Our hypothesis is based on observed global transcriptional alterations in normal human epithelial keratinocytes (hEp) treated with arsenic for 2, 5, 8 or 14 days. We have shown that chronic exposure to arsenic trioxide (As2O3) has a differential effect on the genotoxicity and cytotoxicity of keratinocytes.
The specific aims of our investigation are to: (1) Evaluate chronic toxicity of arsenic trioxide to keratinocytes;(2) Elucidate the global alterations in gene expression of culture cells that have been chronically exposed to arsenic trioxide;and (3) Analyze the gene expression changes during the differentiation of keratinocytes into squamous cells at day 2, day 5, day 8 and day 14. Low-level long-term (chronic) human exposure to arsenic is what happens in arsenic endemic areas. The long-term goal of the proposed research is to understand the contribution of the epidermal cellular elements of the skin, namely basal keratinocytes and squamous cells to skin cancer. Our approach will allow us to identify potential pathways that are part of the initial response to chronic arsenic exposure. It will also provide us with a better picture of how these molecular pathways change as the cells adapt to arsenic toxicity during exposure (2-14 days). The significance of our pilot study is that skin cells chronically exposed arsenic trioxide under laboratory conditions provide an experimental model to understand the mechanism of arsenic-induced carcinogenesis.
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