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Genomic-wide analysis of BEAS-2B cells exposed to Trivalent Arsenicals and Dimethylthioarsinic acid
Citation:
Chilakapati, J., K. WALLACE, H. Ren, M. FRICKE, K. BAILEY, W. Ward, J. Creed, AND K. T. KITCHIN. Genomic-wide analysis of BEAS-2B cells exposed to Trivalent Arsenicals and Dimethylthioarsinic acid. TOXICOLOGY. Elsevier Science Ltd, New York, NY, 268(1-2):31-39, (2010).
Impact/Purpose:
The major goal of this study was to investigate the biological effects for different chemical forms of arsenic in human bronchial epithelial cells (BEAS-2B). The second major goal of this study was to determine the dose-response relationship of arsenic and its metabolites in this cellular experimental system.
Description:
Lung is a major target for arsenic carcinogenesis in humans by both oral and inhalation routes. However, the carcinogenic mode of action of arsenicals is unknown. We investigated the effects of inorganic arsenic (iAsIII), monomethylarsonous acid (MMAIII), dimethylarsinous acid (DMAIII) and dimethylthioarsinic acid (DMTA), a sulfur-containing dimethyl arsenic metabolite in human bronchial epithelial (BEAS-2B) cells. Cells were exposed to 3, 15 )..I.M-iAsIII; 0.3, I )..I.M-MMAIII; 0.2, I )..I.M-DMAIII; 0.2, 0.9 )..I.M-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 :s 0.05) by Rosetta Resolver®, a Benjamini-Hochberg FDR (false discovery rate) multiple testing correction «0.05) followed by a Scheffe's post hoc test, and a ±1.5 fold change cut-off. For all compounds except DMTA, >90% ofDEG altered in the low concentration were also changed at the high concentration. iAslII 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 iAslII, MMAIII and DMAIII, respectively. Ingenuity Pathway Analysis™ revealed p53 signaling (E2Fl& 2, SERPIN), and cell cycle related genes (cyclinD 1) were altered by the high concentrations of DMTA, MMAIII and iAslII. Oxidative stress (DUSPI, GPX2, NQOl) and NFKB signaling (TLR4, NFkB) pathways were changed in the high concentrations of MMAIII and iAsIII. These findings will better define the biological effects of arsenicals that will aid in creating a better risk assessment model for arsenical-induced lung cancer.
