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ToxSci Advance Access published online on November 1, 2007
Toxicological Sciences, doi:10.1093/toxsci/kfm272
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© The Author 2007. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

In utero and lactational 2,3,7,8-tetrachlorodibenzo-p-dioxin exposure: Effects on fetal and adult cardiac gene expression and adult cardiac and renal morphology

Andrea C. Aragon*, Phillip G. Kopf*, Matthew J. Campen{ddagger}, Janice K. Huwe§ and Mary K. Walker*,{dagger},1

* College of Pharmacy, University of New Mexico Health Sciences Center, Albuquerque, NM 87131 {dagger} Department of Cell Biology and Physiology, University of New Mexico Health Sciences Center, Albuquerque, NM 87131 {ddagger} Lovelace Respiratory Research Institute, Albuquerque, NM 87108 § Biosciences Research Laboratory, Agricultural Research Station, United States Department of Agriculture, Fargo, North Dakota 58105

1 Corresponding Author: Mary K. Walker, MSC09 5360, 2703 Frontier NE, Suite 220, College of Pharmacy, University of New Mexico, Albuquerque, NM 87131-5691, Phone: 505-272-0580, Fax: 505-272-0704, mwalker{at}salud.unm.edu

Received September 19, 2007; revision received October 26, 2007; accepted October 29, 2007


  Abstract

The mouse heart is a target of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) during fetal development, and microarray analysis demonstrates significant changes in expression of cardiac genes involved in extracellular matrix (ECM) remodeling. We tested the hypothesis that developmental TCDD exposure would disrupt cardiac ECM expression and be associated with changes in cardiac morphology in adulthood. In one study, time-pregnant C57BL/6 mice were dosed with corn oil or 1.5, 3.0, or 6.0 µg TCDD/kg on gestation day (GD) 14.5 and sacrificed on GD 17.5, when changes in fetal cardiac mRNA expression were analyzed using quantitative PCR. TCDD induced mRNA expression of genes associated with ECM remodeling (matrix metalloproteinase 9 and 13, preproendothelin-1), cardiac hypertrophy (atrial natriuretic peptide, ß-myosin heavy chain, osteopontin), and aryl hydrocarbon receptor (AHR) activation (cytochrome P4501A1, AHR repressor). Further, all TCDD-induced changes required the AHR since gene expression was not altered in AHR knockout fetuses. In a second study, time-pregnant mice were treated with corn oil or 6.0 µg TCDD/kg on GD 14.5, and male offspring were assessed for changes in cardiac gene expression and cardiac and renal morphology at 3 mo. All TCDD-induced changes in cardiac gene expression observed fetally, except for preproET-1, remained induced in the hearts of adult male offspring. Adult male offspring of TCDD-exposed dams also displayed cardiac hypertrophy, decreased plasma volume, and mild hydronephrosis. These results demonstrate that in utero and lactational TCDD exposure alters cardiac gene expression and cardiac and renal morphology in adulthood, which may increase the susceptibility to cardiovascular dysfunction.

Author e-mail addresses: acaragon{at}salud.unm.edu, pkopf{at}salud.unm.edu, mcampen{at}lrri.org, Janice.Huwe{at}ars.usda.gov, mwalker{at}salud.unm.edu


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