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ToxSci Advance Access published online on September 7, 2006
Toxicological Sciences, doi:10.1093/toxsci/kfl100
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© The Author 2006. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org
Received July 12, 2006
Accepted September 1, 2006

Systems Toxicology

Comparative Toxicogenomic Analysis of the Hepatotoxic Effects of TCDD in Sprague Dawley Rats and C57BL/6 Mice

Darrell R. Boverhof 1, Lyle D. Burgoon 1, Colleen Tashiro 2, Bonnie Sharratt 2, Brock Chittim 2, Jack R. Harkema 3, Donna L. Mendrick 4, and Timothy R. Zacharewski 1 *

1 Department of Biochemistry and Molecular Biology, National Food Safety and Toxicology Center, Michigan State University, East Lansing MI, USA, 48824; Center for Integrative Toxicology, National Food Safety and Toxicology Center, Michigan State University, East Lansing MI, USA, 48824
2 Wellington Laboratories Inc., Guelph ON, CANADA, N1G 3M5
3 Department of Pathobiology and Diagnostic Investigation, National Food Safety and Toxicology Center, Michigan State University, East Lansing MI, USA, 48824; Center for Integrative Toxicology, National Food Safety and Toxicology Center, Michigan State University, East Lansing MI, USA, 48824
4 Gene Logic Inc., Gaithersburg MD, USA, 20879

* To whom correspondence should be addressed.
Timothy R. Zacharewski, E-mail: tzachare{at}msu.edu


  Abstract

In an effort to further characterize conserved and species-specific mechanisms of TCDD-mediated toxicity, comparative temporal and dose-response microarray analyses were performed on hepatic tissue from immature, ovariectomized Sprague Dawley rats and C57BL/6 mice. For temporal studies, rats and mice were gavaged with 10 or 30µg/kg of TCDD, respectively, and sacrificed after 2, 4, 8, 12, 18, 24, 72 or 168 hrs while dose-response studies were performed at 24hrs. Hepatic gene expression profiles were monitored using custom cDNA microarrays containing 8,567 (rat) or 13,361 (mouse) cDNA clones. Affymetrix data from male rats treated with 40µg/kg TCDD were also included to expand the species comparison. In total, 3,087 orthologous genes were represented in the cross-species comparison. Comparative analysis identified 33 orthologous genes that were commonly regulated by TCDD as well as 185 rat-specific and 225 mouse-specific responses. Functional annotation using Gene Ontology identified conserved gene responses associated with xenobiotic/chemical stress and amino acid and lipid metabolism. Rat-specific gene expression responses were associated with cellular growth and lipid metabolism while mouse-specific responses were associated with lipid uptake/metabolism and immune responses. The common and species-specific gene expression responses were also consistent with complementary histopathology, clinical chemistry, hepatic lipid analyses and reports in the literature. These data expand our understanding of TCDD-mediated gene expression responses and indicate that species-specific toxicity may be mediated by differences in gene expression which may help explain the wide range of species sensitivities and will have important implications in risk assessment strategies.


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