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GENE EXPRESSION PROFILING OF NORMAL HUMAN BRONCHIAL EPITHELIAL CELLS EXPOSED TO TRIVALENT ARSENICALS AND DIMETHYLTHIOARSINIC ACID
Citation:
CHILAKAPATI, J., K. WALLACE, H. REN, M. FRICKE, K. BAILEY, W. O. WARD, C. CORTON, J. T. CREED, AND K. T. KITCHIN. GENE EXPRESSION PROFILING OF NORMAL HUMAN BRONCHIAL EPITHELIAL CELLS EXPOSED TO TRIVALENT ARSENICALS AND DIMETHYLTHIOARSINIC ACID. Presented at Society of Toxicology’s 47th Annual Meeting, Seattle, WA, March 16 - 20, 2008.
Impact/Purpose:
To investigate, in human bronchial epithelial (BEAS2B) cells, the effects of inorganic arsenic (iAsIII), monomethylarsonous acid (MMAIII), dimethylarsinous acid (DMAIII) and dimethylthioarsinic acid (DMTA), a sulfur-containing dimethyl arsenic metabolite.
Description:
Lung is a major target for arsenic carcinogenesis in humans. However, the carcinogenic mode of action of arsenicals is unknown. We investigated, in human bronchial epithelial (BEAS2B) cells, the effects of inorganic arsenic (iAsIII), monomethylarsonous acid (MMAIII), dimethylarsinous acid (DMAIII) and dimethylthioarsinic acid (DMTA), a sulfur-containing dimethyl arsenic metabolite. Cells were exposed to 3, 15 µM-iAsIII; 0.3, 1 µM-MMAIII; 0.2, 1 µM-DMAIII; 0.2, 0.9 µM-DMTA as non-cytotoxic and minimally cytotoxic (~20%) concentrations based on neutral red uptake assays after 24 h of culture. Total RNA was isolated and gene expression analysis conducted using Affymetrix® Human Genome 133 Plus 2.0 arrays. Differentially expressed genes (DEG) were determined using a one-way ANOVA (p≤0.05) by Rosetta Resolver®, a Benjamini-Hochberg FDR multiple testing correction (<0.05) and a ± 1.5 fold change cut-off. For all compounds except DMTA, >90% of DEG altered in the low concentration were also changed at the high concentration. iAsIII showed the highest number of DEG at both concentrations (2708 and 123, high and low, respectively). 1749, 420 and 120 DEG were unique to the high concentrations of iAsIII, MMAIII and DMAIII, respectively. Ingenuity Pathway AnalysisTM revealed p53 signaling (E2F1& 2, SERPIN), and cell cycle related genes (cyclinD1) were altered by the high concentrations of DMTA, MMAIII and iAsIII. Oxidative stress (DUSP1, GPX2, NQO1) and NFκB signaling (TLR4, NFκB) pathways were changed in the high concentrations of MMAIII and iAsIII. Additional pathway analysis will better define the biological effects of arsenicals that will aid in creating a better risk assessment model for arsenical-induced lung cancer.