ToxSci Advance Access originally published online on January 5, 2005
Toxicological Sciences 2005 84(2):368-377; doi:10.1093/toxsci/kfi073
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Heart Malformation Is an Early Response to TCDD in Embryonic Zebrafish
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* Molecular and Environmental Toxicology Center, University of Wisconsin, Madison, Wisconsin 53705; Developmental Biology Laboratory, Cardiovascular Research Center, Massachusetts General Hospital, Charlestown, Massachusetts 02129; Department of Medicine, Harvard Medical School, Boston, Massachusetts 02115; and School of Pharmacy, University of Wisconsin, Madison, Wisconsin 53705
Received October 29, 2004; accepted December 22, 2004
The zebrafish (Danio rerio) has become an attractive vertebrate model for studying developmental processes, and is emerging as a model system for studying the mechanisms by which toxic compounds perturb normal development. When exposed to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) shortly after fertilization, zebrafish embryos exhibit pericardial edema and reduced blood flow by 72 h post fertilization (hpf). To better understand the progression of dioxin toxicity in zebrafish, we have examined the effects of TCDD on heart development. At 72 hpf, TCDD-treated embryos exhibited altered looping, with the atria positioned distinctly posterior to the ventricles, contrary to the looping of control hearts, where the two chambers lied side by side. Moreover, the ventricles in dioxin-exposed hearts became more compact, and the atria elongated in comparison to controls. These defects are not secondary to pericardial edema because they were observed when edema formation was suppressed with osmotic support. In addition to morphological changes, TCDD produced functional deficits in the developing hearts, including blood regurgitation and a striking ventricular standstill that became prevalent by 120 hpf. We also assessed the effect of TCDD on the heart size using stereological measurements, which demonstrated significant reduction in heart tissue volume at 72 hpf. Perhaps our most significant finding was a decrease in the total number of cardiomyocytes in TCDD-exposed embryos by 48 hpf, one day prior to observable effects on peripheral blood flow. We conclude that the developing heart is an important target for TCDD in zebrafish.
Key Words: 2,3,7,8-tetrachlorodibenzo-p-dioxin; TCDD toxicity; zebrafish; heart; development.
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