TCDD induces valve defects in the developing embryonic zebrafish heart and inhibits heart regeneration in the adult

Embryonic zebrafish exhibit structural and functional defects in the heart following exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). These include reduced numbers of cardiac myocytes, reduced cardiac output, altered looping of cardiac chambers, and ventricular standstill. Anecdotal evidence suggests that TCDD induces blood regurgitation at heart valve junctions and valve failure. To test this hypothesis, high-speed imaging was done to follow blood flow across valve junctions. TCDD exposure produced blood regurgitation at both the atrio-ventricular (AV) and the bulbo-ventricular (BV) junctions and prevented valve leaflet formation. TCDD did not block the initial formation of the bulbus arteriosus, but prevented its further development. TCDD exposure reversed the restriction of endothelial cells at the AV and BV junctions as indicated by the expression of bmp4 and notch1b. These results suggest that TCDD does not prevent the initial specification of presumptive valve locations, but later produces severe alterations in valve development. This leads to blood regurgitation and failed peripheral circulation. TCDD exposure prevented heart regeneration in the adult zebrafish following surgical resection of the apex of the ventricle. In the absence of wounding, TCDD caused no gross morphological defects in the adult heart, suggesting TCDD specifically inhibits the regenerative response. The injured heart was sensitive to TCDD exposure only when fish were exposed to TCDD one day prior to injury, and the heart regenerated fully when fish were exposed to TCDD any time after injury. A primary characteristic of the failed regeneration response was the continued presence of a blood clot at the site of injury that was not replaced by new myocardial tissue. In addition, TCDD exposure caused decreased cell proliferation in the epicardial layer and increased scar tissue at the wound. Together, these results contribute towards our understanding of the mechanism by which developmental processes in the embryonic and adult zebrafish heart are inhibited following exposure to TCDD.