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

Toxicol Lett. 2020 May 15;324:1-11. doi: 10.1016/j.toxlet.2020.02.003. Epub 2020 Feb 5.

Abstract

α-asarone is a natural phenylpropene found in several plants, which are widely used for flavoring foods and treating diseases. Previous studies have demonstrated that α-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 α-asarone in zebrafish, especially the cardiotoxicity. Zebrafish embryos were exposed to different concentrations of α-asarone (1, 3, 5, 10, and 30 μM). Developmental toxicity assessments revealed that α-asarone did not markedly affect mortality and hatching rate. In contrast, there was a concentration-dependent increase in malformation rate of zebrafish treated with α-asarone. The most representative cardiac defects were increased heart malformation rate, pericardial edema areas, sinus venosus-bulbus arteriosus distance, and decreased heart rate. Notably, we found that α-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 α-asarone exposure. Further investigation addressing the mechanism indicated that α-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 α-asarone induced cardiotoxicity. These findings revealed the cardiac developmental toxicity of α-asarone, expanding our knowledge about the toxic effect of α-asarone on living organisms.

Keywords: Apoptosis; Cardiotoxicity; QT duration; T-wave; Zebrafish.

MeSH terms

  • Abnormalities, Drug-Induced / etiology*
  • Allylbenzene Derivatives
  • Animals
  • Anisoles / toxicity*
  • Apoptosis / drug effects*
  • Cardiotoxicity / etiology
  • Electrocardiography / drug effects*
  • Embryo, Nonmammalian / drug effects
  • Heart Defects, Congenital / chemically induced*
  • Mitochondria, Heart / drug effects*
  • Mitochondria, Heart / pathology
  • Zebrafish

Substances

  • Allylbenzene Derivatives
  • Anisoles
  • asarone