Mitochondrial dynamics disruption: Unraveling Dinotefuran's impact on cardiotoxicity

Exposure to pesticides has been associated with several cardiovascular complications in animal models. Neonicotinoids are now the most widely used insecticide globally, while the impact of neonicotinoids on cardiovascular function and the role of mitochondrial dynamics in neonicotinoids-induced cardiotoxicity is unclear. In the present study, Xenopus laevis tadpoles were exposed to environmental related concentrations (0, 5, and 50 μg/L) of typical neonicotinoid dinotefuran, with two enantiomers, for 21 days. We evaluated the changes in heart rate and cardiomyocyte apoptosis in exposed tadpoles. Then, we performed the transcriptome, metabolomics, transmission electron microscopy (TEM), and protein immunoblot to investigate the potential adverse impact of two enantiomers of dinotefuran on cardiotoxicity associated with mitochondrial dynamics. We observed changes in heart rate and increased cardiomyocyte apoptosis in exposed tadpoles, indicating that dinotefuran had a cardiotoxic effect. We further found that the cardiac contractile function pathway was significantly enriched, while the glucose metabolism-related pathways were also disturbed significantly. TEM observation revealed that the mitochondrial morphology of cardiomyocytes in exposed tadpoles was swollen, and mitophagy was increased. Mitochondria fusion was excessively manifested in the enhanced mitochondrial fusion protein. The mitochondrial respiratory chain was also disturbed, which led to an increase in ROS production and a decrease in ATP content. Therefore, our results suggested that dinotefuran exposure can induce cardiac disease associated mitochondrial disorders by interfering with the functionality and dynamics of mitochondria. In addition, both two enantiomers of dinotefuran have certain toxicity to tadpole cardiomyocytes, while R-dinotefuran exhibited higher toxicity than S-enantiomer, which may be attributed to disparities in the activation capacities of the respiratory chain.