ToxSci Advance Access originally published online on August 12, 2009
Toxicological Sciences 2009 112(1):221-228; doi:10.1093/toxsci/kfp180
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Automated Dose-Response Analysis of the Relative Hepatic Gene Expression Potency of TCDF in C57BL/6 Mice
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* Department of Biochemistry & Molecular Biology
National Food Safety & Toxicology Center
Center for Integrative Toxicology
Gene Expression in Development and Disease Initiative
¶ Quantitative Biology Initiative, Michigan State University, East Lansing, Michigan 48824
|| The Dow Chemical Company, Midland, Michigan 48674
1 To whom correspondence should be addressed at Department of Biochemistry & Molecular Biology, Michigan State University, 501 Biochemistry Building, Wilson Road, East Lansing, MI 48824-1319. Fax: 517-353-9334. E-mail: tzachare{at}msu.edu.
Received May 6, 2009; accepted July 28, 2009
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Abstract |
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Toxic equivalency factors (TEFs) are assigned to dioxin-like chemicals based on relative potency (REP) values of individual adaptive and toxic responses compared to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Agilent 4x44K oligonucleotide microarrays were used to examine the hepatic gene expression potency of 2,3,7,8-tetrachlorodibenzofuran (TCDF), relative to TCDD with complementary histopathology, TCDD and TCDF tissue level analysis, and ethoxyresorufin-O-deethylase (EROD) assay data. Immature ovariectomized C57BL/6 mice were gavaged with 0.03, 0.1, 0.3, 1, 3, 10, 30, or 100 µg/kg TCDD, the World Health Organization TEF-adjusted doses (10 x TCDD dose) of TCDF (0.3, 1, 3, 10, 30, 100, or 300 µg/kg), or sesame oil vehicle and killed at 72 h. Two thousand two hundred eighty-eight and 1347 genes were differentially expressed (P1(t) > 0.90) at one or more doses by TCDD and TCDF, respectively. Automated dose-response modeling (ToxResponse Modeler) identified a total of 1027 and 837 genes with either a sigmoidal, exponential, linear, Gaussian, or quadratic dose-response relationship 72 h after treatment in TCDD and TCDF, respectively. Two hundred seventy genes exhibited a sigmoidal TCDD-induced dose-response (ED50s from 0.08 to 42.2 µg/kg) compared to only 179 sigmoidal responsive genes (ED50s from 0.74 to 299.9 µg/kg) elicited by TCDF. Of the 1027 TCDD dose-responsive genes, 654 were not examined further due to the lack of a dose response elicited by TCDF. Of the 373 genes that exhibited a TCDD and TCDF dose response, REPs were calculated for the 83 genes that exhibited comparable sigmoidal curve shapes and slopes. The median REP for these 83 genes was 0.10, with a maximum REP of 0.56 and a minimum of 0.01. REPs of 0.04 were also calculated for EROD and increase in relative liver weight (RLW) at 72 h. Collectively, the lower number of TCDF-induced genes compared to TCDD and the 0.04 REPs for EROD activity and increased RLW are not consistent with the TEF of 0.10 for the hepatotoxicity of TCDF in C57BL/6 mice at 72 h.
Key Words: TCDD; TCDF; TEF; microarray; liver; mouse; temporal; dose response.