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ToxSci Advance Access published online on October 11, 2006
Toxicological Sciences, doi:10.1093/toxsci/kfl132
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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 August 15, 2006
Accepted October 3, 2006

Reproductive and Developmental Toxicology

TCDD-Induced Alterations in Gene Expression Profiles of the Developing Mouse Paw Do Not Influence Morphological Differentiation of This Potential Target Tissue

Jeffrey C. Bemis 1 1, Napoleon F. Alejandro 2 1, Daniel A. Nazarenko 3, Andrew I. Brooks 4, Raymond B. Baggs 5, and Thomas A. Gasiewicz 1 *

1 University of Rochester Medical Center, Department of Environmental Medicine, Rochester NY, 14642
2 University of Rochester Medical Center, Department of Environmental Medicine, Rochester NY, 14642; Current Affiliations: NFA - Boehringer Ingleheim, Ridgefield, CN, 06877
3 Fulcrum Pharma Developments, Inc., Morrisville, NC, 27560
4 University of Rochester Medical Center, Department of Environmental Medicine, Rochester NY, 14642; Current Affiliations: AIB - Rutgers University, Piscataway, NJ, 08854
5 University of Rochester Medical Center, Department of Environmental Medicine, Rochester NY, 14642; University of Rochester Medical Center, Department of Pathology, Rochester NY, 14642; Current Affiliations: RBB - Oregon State University, Corvallis, OR, 97331

* To whom correspondence should be addressed.
Thomas A. Gasiewicz, E-mail: tom_gasiewicz{at}urmc.rochester.edu


  Abstract

The Aryl-hydrocarbon Receptor (AhR) is a ligand-dependent transcription factor that mediates the toxicity of certain halogenated aromatic hydrocarbons including 2,3,7,8-tetra-chlorodibenzo-p-dioxin (TCDD). These compounds are potent developmental toxicants that can alter gene expression and disrupt processes of proliferation and differentiation. It has not yet been determined which tissues during development are most sensitive to these compounds, nor which genes are directly associated with the toxicities. We developed a transgenic mouse model to delineate the temporal and spatial context of transcriptionally active AhR by utilizing a Dioxin Responsive Element (DRE)-linked LacZ reporter system. The present study focuses on the pattern of TCDD-induced transgene expression localized to the footpad and digits of the paws between gestational days (GD) 13 and 18. Paw morphology was evaluated at several developmental stages following TCDD exposure. Gene expression profiles acquired by microarray technology were evaluated in the paws of fetuses exposed at GD14.5. The results showed that TCDD exposure in utero induced LacZ expression in the developing paws. This expression appeared to be localized to the mesenchymal cell layer. Gross morphological changes were not observed in the paws prior to or after birth following TCDD exposure in utero. However, significant alterations in gene expression profiles in the developing paws were observed at 24 hours following TCDD exposure in utero. These results indicate that the developing paw is a target tissue of TCDD in terms of altered gene expression, further validating the use of this AhR responsive reporter gene transgenic mouse model in studying AhR ligand mediated responsiveness. However, the linkage of these changes to detectable biological outcomes in the paw remains unclear.

1These authors contributed equally to this work.


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