ToxSci Advance Access published online on March 14, 2008
Toxicological Sciences, doi:10.1093/toxsci/kfn053
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Comparative Temporal Toxicogenomic Analysis of TCDD- and TCDF-Mediated Hepatic Effects in Immature Female C57BL/6 Mice
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* Department of Biochemistry & Molecular Biology
Center for Integrative Toxicology & National Food Safety & Toxicology Center, Michigan State University, East Lansing, MI 48824
The Dow Chemical Company, Midland, MI 48674
Corresponding Author: Tim Zacharewski, Michigan State University, Biochemistry & Molecular Biology, 501 Biochemistry Building, Wilson Road, East Lansing, MI 48824-1319, Fax: 517-353-9334, E-mail: tzachare{at}msu.edu
Received January 8, 2008; revision received March 4, 2008; accepted March 4, 2008
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Abstract |
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Temporal analyses were performed on hepatic tissue from immature female C57BL/6 mice in order to compare the gene expression profiles for 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and 2,3,7,8-tetrachlorodibzofuran (TCDF). Time course studies conducted with a single oral dose of 300 µg/kg TCDF or 30 µg/kg TCDD were used to compare differential gene expression on cDNA microarrays containing 13,361 features, representing 8,194 genes at 2, 4, 8, 12, 24, 72, 120 and 168 hrs. 195 genes were identified as differentially regulated by TCDF, of which 116 genes were in common with TCDD, with 109 exhibiting comparable expression profiles (correlation coefficients > 0.3). In general, TCDF was less effective in eliciting hepatic vacuolization, and differential gene expression compared to TCDD when given at an equipotent dose based on a toxic equivalence factor (TEF) of 0.1 for TCDF, especially after 72 hrs post administration. For example, the induction of Cyp1a1 mRNA by TCDF was weaker when compared TCDD. Moreover, TCDF induced less severe hepatocyte cytoplasmic vacuolization consistent with lower lipid accumulations which significantly subsided by 120 and 168 hrs when compared to TCDD. TCDF-elicited responses correlated with their hepatic tissue levels which gradually decreased between 18 and 168 hrs. Although both compounds elicited comparable gene expression profiles, especially at early time points, the TCDF responses were generally weaker. Collectively, these results suggest that the weaker TCDF responses could be attributed to differences in pharmacokinetics. However, more comprehensive dose-response studies are required at optimal times for each end point of interest in order to investigate the effect of pharmacokinetic differences on relative potencies that are important in establishing TEFs.
Key Words: TCDD; TCDF; Microarray; Liver; Mouse; Temporal.
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