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Use of the HepaRG Cell Line to Assess Potential Human Hepatotoxicity of ToxCast™ Chemicals
Citation:
NELSON, G. M., M. Mennecozzi, H. Ren, W. O. Ward, B. N. CHORLEY, I. Shah, J. W. ALLEN, M. Whelan, AND C. CORTON. Use of the HepaRG Cell Line to Assess Potential Human Hepatotoxicity of ToxCast™ Chemicals. Presented at Society of Toxicology (SOT) Annual Meeting, San Francisco, CA, March 11 - 15, 2012.
Impact/Purpose:
The HepaRG cell line is a promising model system for predicting human hepatotoxicity in part because ofthe greater capacity to metabolize chemicals than other cell models. We hypothesized that this cell line would be a relevant model for toxicity testing ofindustrial chemicals.
Description:
The HepaRG cell line is a promising model system for predicting human hepatotoxicity in part because of the greater capacity to metabolize chemicals than other cell models. We hypothesized that this cell line would be a relevant model for toxicity testing of industrial chemicals. Gene expression profiles were used to predict changes in xenobiotic-activated transcription factors. Approximately 20 chemicals that have been evaluated in high throughput assays as part of the ToxCast™ screening program are under investigation. Initial studies examined the gene expression response to the fungicide vinclozolin, a rodent liver carcinogen. Three separate preparations of differentiated HepaRG cells were exposed for 72 hr with either DMSO or one of six concentrations of vinclozolin ranging from 7.8-250 uM. RNA expression was analyzed using Illumina Human HT-12v4 bead chips. The gene expression data were normalized by Illumina Genome Studio, and differentially expressed genes were identified by CyberT. The doses of 250, 125 and 63 uM resulted in 404, 258, and 65 genes altered, respectively. No genes were significantly altered at doses below 63 uM. Ingenuity Pathways Analysis (IPA) indicated that a nurnber of pathways were altered including metabolism of androgen/estrogen, xenobiotics and fatty acids. Genes associated with dose-dependent AHR (CYP1A1, CYPIA2, CYP1BI) and PPARaipha (ACADM, ACADVL, CPT1A, ECH1) activation were identified. These findings overlap with changes observed after vinclozolin exposure in cell models as part of the ToxCast™ screening program including HepG2 transcription factor screening and nuclear receptor marker gene evaluation in human primary hepatocytes. Future research with additional ToxCast ™ chemicals will help to determine the strengths and weaknesses of the HepaRG cell line as a model for human hepatotoxicity. (This abstract does not reflect EPA policy).