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ToxSci Advance Access originally published online on March 30, 2005
Toxicological Sciences 2005 85(2):1048-1063; doi:10.1093/toxsci/kfi162
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Toxicological Sciences vol. 85 no. 2 © The Author 2005. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please email: journals.permissions@oupjournals.org

Temporal and Dose-Dependent Hepatic Gene Expression Patterns in Mice Provide New Insights into TCDD-Mediated Hepatotoxicity

Darrell R. Boverhof*,¶, Lyle D. Burgoon{dagger},¶, Colleen Tashiro||, Brock Chittim||, Jack R. Harkema{ddagger},¶, Donald B. Jump*,§ and Timothy R. Zacharewski*,¶,1

* Department of Biochemistry and Molecular Biology, Michigan State University, East Lansing Michigan; {dagger} Department of Pharmacology and Toxicology, Michigan State University, East Lansing Michigan; {ddagger} Department of Pathobiology and Diagnostic Investigation, Michigan State University, East Lansing Michigan; § Department of Physiology, Michigan State University, East Lansing Michigan; Center for Integrative Toxicology, Michigan State University, East Lansing Michigan; and || Wellington Laboratories Inc., Guelph Ontario, Canada

Received February 10, 2005; accepted March 22, 2005

In an effort to further characterize the mechanisms of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-mediated toxicity, 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 h. 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 h. Hepatic gene expression profiles were monitored using custom cDNA microarrays containing 13,362 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., alanine aminotransferase [ALT], triglyceride [TG], free fatty acids [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 end points. 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.

Key Words: TCDD; microarray; liver; mouse; temporal; dose response.


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