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ToxSci Advance Access originally published online on August 24, 2005
Toxicological Sciences 2005 88(1):231-241; doi:10.1093/toxsci/kfi301
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© The Author 2005. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please email: journals.permissions@oupjournals.org

Toxicogenomic Profile of 2,3,7,8-Tetrachlorodibenzo-p-Dioxin in the Murine Fetal Heart: Modulation of Cell Cycle and Extracellular Matrix Genes

E. A. Thackaberry*, Z. Jiang{dagger}, C. D. Johnson{ddagger}, K. S. Ramos§ and M. K. Walker,1

* College of Pharmacy, University of New Mexico Health Sciences Center, Albuquerque, New Mexico 87131; {dagger} Department of Biocomputing, University of New Mexico Health Sciences Center, Albuquerque, New Mexico 87131; {ddagger} Ambion, Inc. The RNA Company, Austin, Texas 78744; § Department of Biochemistry and Molecular Biology, Center for Genetics and Molecular Medicine, University of Louisville Health Sciences Center, Louisville, Kentucky 40292; Department of Cell Biology and Physiology, University of New Mexico Health Sciences Center, Albuquerque, New Mexico 87131

Received July 21, 2005; accepted August 22, 2005

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) and similar environmental contaminants have been demonstrated to be potent cardiovascular teratogens in developing piscine and avian species. In the present study, we investigated the effects of TCDD on gene expression during murine cardiovascular development. C57Bl6N pregnant mice were dosed with 1.5, 3.0, or 6.0 µg TCDD/kg on gestational day (GD) 14.5, and microarray analysis was used to characterize the global changes in fetal cardiac gene expression on GD 17.5. TCDD significantly altered expression of a number of genes involved in xenobiotic metabolism, cardiac homeostasis, extracellular matrix production/remodeling, and cell cycle regulation. Interestingly, while the AhR-responsive genes Cyp1A1, Cyp1B1, Ugt1a6, and Ahrr, were all induced by TCDD in the fetal murine heart, other AhR-responsive genes, Cyp1a2, Nqo1, and Gsta1, were not. Quantitative real-time polymerase chain reactions confirmed the changes in expression of several G1/S-type cyclins and extracellular matrix–related genes. These results demonstrate the global changes in cardiac gene expression that result from TCDD exposure of the fetal murine heart and implicate genes involved in cell cycle and extracellular matrix regulation in TCDD-induced cardiac teratogenicity and functional deficits.

Key Words: TCDD; aryl hydrocarbon receptor; microarray; heart development; cell cycle.


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