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Proteomic Analysis of Arsenic-Induced Oxidative Stress in Human Epidermal Keratinocytes
Citation:
GE, Y., M. E. BRUNO, K. WALLACE, W. M. WINNIK, AND K. BAILEY. Proteomic Analysis of Arsenic-Induced Oxidative Stress in Human Epidermal Keratinocytes. Presented at 18th Society of Environmental Toxicology and Chemistry Europe Annual Meeting, Warsaw, POLAND, May 25 - 29, 2008.
Impact/Purpose:
To get a better understanding of molecular basis and toxic modes of action of arsenic-induced oxidative stress, we have developed an integrated approach to analysis of protein expression changes in normal human epidermal keratinocytes (NHEKs) after 24 h exposure to low dosages of IAs (III), MMA (III), and DMA(III), with the aim of identifying proteins involved in oxidative stress during the early course of arsenic-induced carcinogenesis.
Description:
Chronic exposure to inorganic arsenic (IAs) has been associated with the development of several human cancers, including those found in the skin, lung, urinary bladder, liver, prostate and kidney. The precise mechanisms by which arsenic causes cancer are unknown. Defining the modes of action of arsenic carcinogenesis is further complicated by arsenic metabolism in humans and other species, which generates several methylated forms such as MMA and DMA that vary in their biological activities. Several modes of action have been proposed, with some of the strongest experimental evidence supporting roles involving the generation of oxidative stress, increased cell proliferation, genotoxicity, altered DNA repair and disruption of cell signaling. To get a better understanding of molecular basis and toxic modes of action of arsenic-induced oxidative stress, we have developed an integrated approach to cell treatment, protein sample preparation, protein expression profiling, antioxidant activity analysis and toxicity pathway identification. Using this integrated proteomic platform, we have studied the protein expression changes in normal human epidermal keratinocytes (NHEKs) after 24 h exposure to low dosages of IAs (III), MMA (III), and DMA(III), with the aim of identifying proteins involved in oxidative stress during the early course of arsenic-induced carcinogenesis. To our knowledge, this is the first study that provides a comprehensive protein expression profile of a target cell type exposed to environmentally-relevant concentrations of iAs(III), MMA(III) and DMA(III). In addition, the changes of oxidative stress pathways and their biological significance have also been characterized using this integrated proteomic approach.