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ToxSci Advance Access published online on July 27, 2008
Toxicological Sciences, doi:10.1093/toxsci/kfn149
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© The Author 2008. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org
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Abnormal Liver Development and Resistance to 2,3,7,8-Tetrachlorodibenzo-p-dioxin Toxicity in Mice Carrying a Mutation in the DNA Binding Domain of the Aryl Hydrocarbon Receptor

Maureen K. Bunger*, Edward Glover*, Susan M. Moran*, Jacqueline A. Walisser*, Garet P. Lahvis*,{dagger},{ddagger}, Erin L. Hsu*,{dagger} and Christopher A. Bradfield*,{dagger},§

* McArdle Laboratory for Cancer Research {dagger} Molecular and Environmental Toxicology Center {ddagger} Departments of Surgery and Psychology University of Wisconsin School of Medicine and Public Health

§ To whom correspondence should be addressed: Christopher A. Bradfield, Ph.D., McArdle Laboratory for Cancer Research, 1400 University Avenue, Madison, WI 53706, Phone: (608)-262-024, Fax: (608)-262-2824, Email: bradfield{at}oncology.wisc.edu

Received July 16, 2008; revision received July 16, 2008; accepted July 18, 2008


  Abstract

The Aryl Hydrocarbon Receptor (AHR) is known for its role in the adaptive and toxic responses to a large number of environmental contaminants, as well as its role in hepatovascular development. The classical AHR pathway involves ligand binding, nuclear translocation, heterodimerization with the AHR nuclear translocator (ARNT), and binding of the heterodimer to dioxin response elements, thereby modulating the transcription of an array of genes. The AHR has also been implicated in signaling events independent of nuclear localization and DNA binding, and it has been suggested that such pathways may play important roles in the toxicity of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Here, we report the generation of a mouse model that expresses an AHR protein capable of ligand binding, interactions with chaperone proteins, functional heterodimerization with ARNT, and nuclear translocation, but is unable to bind dioxin response elements. Using this model, we provide evidence that DNA binding is required AHR-mediated liver development, as Ahrdbd/dbd mice exhibit a patent ductus venosus, similar to what is seen in Ahr-/- mice. Furthermore, Ahrdbd/dbd mice are resistant to TCDD-induced toxicity for all endpoints tested. These data suggest that DNA binding is necessary for AHR-mediated developmental and toxic signaling.

Key Words: Aryl Hydrocarbon Receptor; dioxin; TCDD; ductus venosus.


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