α-asarone induces cardiac defects and QT prolongation through mitochondrial apoptosis pathway in zebrafish

alpha-asarone is a natural phenylpropene found in several plants, which are widely used for flavoring foods and treating diseases. Previous studies have demonstrated that alpha-asarone has many pharmacological functions, while some reports indicated its toxicity. However, little is known about its cardiovascular effects. This study investigated developmental toxicity of alpha-asarone in zebrafish, especially the cardiotoxicity. Zebrafish embryos were exposed to different concentrations of alpha-asarone (1, 3, 5, 10, and 30 mu M). Developmental toxicity assessments revealed that alpha-asarone did not markedly affect mortality and hatching rate. In contrast, there was a concentration-dependent increase in malformation rate of zebrafish treated with alpha-asarone. The most representative cardiac defects were increased heart malformation rate, pericardial edema areas, sinus venosusbulbus arteriosus distance, and decreased heart rate. Notably, we found that alpha-asarone impaired the cardiac function of zebrafish by prolonging the mean QTc duration and causing T-wave abnormalities. The expressions of cardiac development-related key transcriptional regulators tbx5, nkx2.5, hand2, and gata5 were all changed under alpha-asarone exposure. Further investigation addressing the mechanism indicated that alpha-asarone triggered apoptosis mainly in the heart region of zebrafish. Moreover, the elevated expression of puma, cyto C, afap1, caspase 3, and caspase 9 in treated zebrafish suggested that mitochondrial apoptosis is likely to be the main reason for alpha-asarone induced cardiotoxicity. These findings revealed the cardiac developmental toxicity of aasarone, expanding our knowledge about the toxic effect of alpha-asarone on living organisms.