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ToxSci Advance Access originally published online on September 16, 2009
Toxicological Sciences 2009 112(1):245-256; doi:10.1093/toxsci/kfp191
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© The Author 2009. Published by Oxford University Press on behalf of the Society of Toxicology. For permissions, please email: journals.permissions@oxfordjournals.org.
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/2.5/uk/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Dioxin-Dependent and Dioxin-Independent Gene Batteries: Comparison of Liver and Kidney in AHR-Null Mice

Paul C. Boutros*,1, Kirsten A. Bielefeld{dagger}, Raimo Pohjanvirta{ddagger} and Patricia A. Harper{dagger},§

* Bioinformatics & Biocomputing Platform, Ontario Institute for Cancer Research, Toronto M5G 0A3 Canada {dagger} Developmental & Stem Cell Biology Program, Hospital for Sick Children, Toronto, Ontario M5G 1X8 Canada {ddagger} Department of Food and Environmental Hygiene, University of Helsinki, Helsinki, Finland 00014 § Department of Pharmacology and Toxicology, University of Toronto, Toronto, Ontario M5S 1A8 Canada

1 To whom correspondence should be addressed at Ontario Institute for Cancer Research; MaRS Centre, South Tower; 101 College Street, Suite 800, Toronto, Ontario, Canada M5G 0A3. E-mail: Paul.Boutros{at}utoronto.ca.

Received June 8, 2009; accepted August 8, 2009


  Abstract

The aryl hydrocarbon receptor (AHR) is a widely expressed ligand-dependent transcription factor that mediates cellular responses to dioxins and other planar aromatic hydrocarbons. Ahr-null mice are refractory to the toxic effects of dioxin exposure. Although some mechanistic aspects of AHR activity are well understood, the tissue specificity of AHR effects remains unclear, both during development and following administration of exogenous ligands. To address the latter issue, we defined and compared transcriptional responses to dioxin exposure in the liver and kidney of wild-type and Ahr-null adult C57BL/6J mice treated with either 2,3,7,8-tetrachlorodibenzo-p-dioxin or corn-oil vehicle. In both tissues, essentially all effects of dioxin on hepatic mRNA levels were mediated by the AHR. Although 297 genes were altered by dioxin exposure in the liver, only 17 were changed in the kidney, including a number of well-established AHR target genes. Ahr genotype had a large effect in both tissues, profoundly remodeling both the renal and hepatic transcriptomes. Surprisingly, a large number of genes were affected by Ahr genotype in both tissues, suggesting the presence of a basal AHR gene battery. Alterations of the renal transcriptome in Ahr-null animals were associated with perturbation of specific functional pathways and enrichment of specific DNA motifs. Our results demonstrate the importance of intertissue comparisons, highlight the basal role of the AHR in liver and kidney, and support a role in development or normal physiology.

Key Words: aryl hydrocarbon receptor; dioxin; TCDD; microarray; kidney; liver.


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