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ToxSci Advance Access published online on February 16, 2005
Toxicological Sciences, doi:10.1093/toxsci/kfi116
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Toxicological Sciences © 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
Received November 11, 2004
Accepted February 9, 2005

Reproductive and Developmental Toxicology

Cardiovascular gene expression profiles of dioxin exposure in zebrafish embryos

Heather M. Handley-Goldstone 1*, Matthew W. Grow 2, and John J. Stegeman 1

1 Woods Hole Oceanographic Institution, Biology Department, Woods Hole MA 02543
2 Indiana University School of Medicine, Center for Medical Genomics, Indianapolis IN 46202; Massachusetts General Hospital, Cardiovascular Research Center, Charlestown MA

* To whom correspondence should be addressed.
Heather M. Handley-Goldstone, E-mail: hhandley{at}alum.mit.edu


  Abstract

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is a widespread environmental contaminant that causes altered heart morphology, circulatory impairment, edema, hemorrhage, and early life stage mortality in fish. TCDD toxicity is largely dependent upon the aryl hydrocarbon receptor, but understanding of the molecular mechanism of cardiovascular embryotoxicity remains incomplete. In order to identify genes potentially involved in cardiovascular impacts, we constructed custom cDNA microarrays consisting of 4,896 zebrafish adult heart cDNA clones and over 200 genes with known developmental, toxicological, and housekeeping roles. Gene expression profiles were obtained for 3-day old zebrafish following early embryonic exposure to either 0.5 or 5.0 nM TCDD. 516 clones were significantly differentially expressed (p-value < 0.005) under at least one treatment condition; 123 high-priority clones were selected for further investigation. CYP1A, CYP1B1, and other members of the AHR gene battery, were strongly and dose-dependently induced by TCDD. Importantly, altered expression of cardiac sarcomere components, including cardiac troponin T2 and multiple myosin isoforms, was consistent with the hypothesis that TCDD causes dilated cardiomyopathy. Observed increases in expression levels of mitochondrial energy transfer genes also may be related to cardiomyopathy. Other TCDD-responsive genes included fatty acid and steroid metabolism enzymes, ribosomal and signal transduction proteins, and 18 ESTs with no known protein homologs. As the first broad-scale study of TCDD-modulated gene expression in a non-mammalian system, this work provides an important perspective on mechanisms of TCDD toxicity.


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