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Temporal and dose-dependent hepatic gene expression patterns in mice provide new insights into TCDD-mediated hepatotoxicity. DR Boverhof1,4, LD Burgoon2,4, C, Tashiro5, B, Chittim5, JR Harkema3,4 and TR Zacharewski1,4. Dept of Biochemistry and Molecular Biology1, Dept of Pharmacology and Toxicology2, Dept of Pathobiology and Diagnostic Investigation3, Center for Integrative Toxicology4, Michigan State University, East Lansing MI, USA and Wellington Laboratories5, Guelph ON, CANADA. In an effort to further characterize the mechanisms of TCDD-mediated toxicity, including its carcinogenicity, comprehensive temporal and dose response microarray analyses were performed on hepatic tissue from immature ovariectomized C57BL/6 mice treated with TCDD. For temporal analysis, mice were gavaged with 30 µg/kg of TCDD or vehicle and sacrificed after 2, 4, 8, 12, 18, 24, 72 or 168 hours. Dose response mice were gavaged with 0, 0.001, 0.01, 0.1, 1, 10, 100 or 300 µg/kg of TCDD and sacrificed after 24 hours. Hepatic gene expression profiles were monitored using custom cDNA microarrays containing 13,361 cDNA clones. Gene expression analysis identified 443 and 315 features which exhibited a significant change at one or more doses or time points, respectively, as determined using an empirical Bayes approach. Functional gene annotation extracted from public databases associated gene expression changes with physiological processes such as oxidative stress and metabolism, differentiation, apoptosis, gluconeogenesis, and fatty acid uptake and metabolism. Complementary histopathology (H&E and Oil Red O stains), clinical chemistry (i.e. ALT, TG, FFA, cholesterol) and high resolution gas chromatography/mass spectrometry assessment of hepatic TCDD levels were also performed in order to phenotypically anchor changes in gene expression to physiological endpoints. Collectively, the data support a proposed mechanism for TCDD mediated hepatotoxicity, including fatty liver which involves mobilization of peripheral fat and inappropriate increases in hepatic uptake of fatty acids. Supported by NIEHS ES011271 |
