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ToxSci Advance Access published online on May 13, 2008
Toxicological Sciences, doi:10.1093/toxsci/kfn095
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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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2,3,7,8-Tetrachlorodibenzo-p-dioxin Exposure Prevents Cardiac Valve Formation in Developing Zebrafish

Vatsal Mehta*, Richard E. Peterson*,{dagger} and Warren Heideman*,{dagger},1

* Molecular and Environmental Toxicology Center {dagger} Pharmaceutical Sciences Division, School of Pharmacy, University of Wisconsin, Madison, Wisconsin 53705

1 To whom correspondence should be addressed: School of Pharmacy, University of Wisconsin, 777 Highland Avenue, Madison, WI 53705-2222, Fax: (608) 265-3316, E-mail: wheidema{at}wisc.edu

Received March 8, 2008; revision received April 21, 2008; accepted April 23, 2008


  Abstract

Cardiovascular malformations are one of the most common congenital birth defects observed in humans. Defects in cardiac valves disrupt normal blood flow. Zebrafish are an outstanding experimental model for studying the effects that environmental contaminants have on developmental processes. Previous research has shown that 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) causes blood regurgitation in the heart and reduces peripheral blood flow in embryonic zebrafish, suggesting some form of valve failure. To test this we used video microscopy to examine valve function and structure in developing zebrafish exposed to TCDD. TCDD exposure produced blood regurgitation at both the atrioventricular (AV) and bulboventricular (BV) junctions. In marked contrast to control embryos exposed to the vehicle dimethyl sulfoxide (DMSO), embryos exposed to TCDD failed to form valve leaflets as the heart matured. In addition, while TCDD did not block initial formation of the bulbus arteriosus, we found that TCDD exposure prevented the normal growth and development of this portion of the outflow tract. TCDD altered the localization of endothelial cells at the AV and BV junctions and altered the localized expression of mRNAs bmp4 and notch1b normally associated with the nascent valves. Taken together, our results demonstrate that while TCDD does not prevent the initial specification of the presumptive valve locations, TCDD exposure produces severe alterations in valve development, leading to blood regurgitation and failing circulation in the developing zebrafish.

Key Words: zebrafish; 2,3,7,8-tetrachlorodibenzo-p-dioxin; heart; blood regurgitation; atrio-ventricular valve; bulbo-ventricular valve.


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