Cardiovascular gene expression profiles of dioxin exposure in zebrafish embryos

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 broadscale study of TCDD-modulated gene expression in a non-mammalian system, this work provides an important perspective on mechanisms of TCDD toxicity.