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DIFFERENTIAL TRANSCRIPTION FACTOR ACTIVATION AD GENE EXPRESSION PROFILES IN HUMAN VASCULAR ENDOTHELIAL CELLS ON EXPOSURE TO RESIDUAL OIL FLY ASH (ROFA) AND VANADIUM
Citation:
Nadadur, S. S. AND D L. Costa. DIFFERENTIAL TRANSCRIPTION FACTOR ACTIVATION AD GENE EXPRESSION PROFILES IN HUMAN VASCULAR ENDOTHELIAL CELLS ON EXPOSURE TO RESIDUAL OIL FLY ASH (ROFA) AND VANADIUM. Presented at Society of Toxicology 42nd Annual Meeting, Salt Lake City, Utah, March 9-13, 2003.
Description:
Differential transcription factor activation and gene expression profiles in human vascular endothelial cells on exposure to residual oil fly ash (ROFA) and vanadium.
Srikanth S. Nadadur and Daniel L. Costa, US EPA, ORD, NHEERL (ETD, Pulmonary Toxicology Branch), Research Triangle Park, NC 27711.
Endothelial cells that line the vascular tree serve as a selective thrombogenic barrier between blood components and tissues. Dysfunction of vascular permeability contributes to the pathogenesis of a wide range of diseases. Whether the vascular endothelial cells play any role in the observed cardiovascular effects of PM and/or its constituents is unclear. Acute injury to a cell on exposure to a toxicant can initiate a complex series of biological responses, which in turn link to transcriptional regulation of genes. Assessing the temporal and functional relationship of transcription factor activation and differential expression of genes could reveal novel interactions in the initiation and progression of acute injury. In this study primary cultures of human umbilical vein endothelial cells were exposed to saline, ROFA (1mg/ml) or vanadium (V) (1mM) for 20 minutes to investigate the immediate injury and or stress response. Differential activation of an array of 54 transcription factors was analyzed in the nuclear extracts of cells using Transcription Factor array (Panomics, Inc., Redwood City, CA) and the gene expression using human plastic microarray (Clontech, Palo Alto, CA). Analysis of Transcription factor regulation indicated exposure specific activation of AP-1, AP-2, EGR, E2F and p53 in ROFA and V exposed compared to saline exposed cells. Similarly, the gene expression data revealed exposure-specific differential expression in ~1200 genes. Around 700 genes were induced 5-20 fold and ~500 genes were suppressed (5-10 fold) due to ROFA or V exposure. Hierarchical clustering analysis on the gene expression data generated three unique gene clusters representing exposure-specific alteration in gene expression. Differential activation of transcription factors and regulation of downstream gene expression observed in this study suggests ROFA specific effects on endothelial cells in mediating PM toxicity. (This abstract does not reflect US EPA policy).