Isoniazid causes heart looping disorder of zebrafish embryo by inducing oxidative stress

Abstract

The cardiotoxicity of isoniazid on zebrafish embryos and its underlying mechanism remained unclear. Here, we exposed zebrafish embryos at 4 hours post fertilization to different levels of isoniazid and recorded the morphology and number of malformed and dead embryos under the microscope. The high concentration of isoniazid group showed more malformed and dead embryos compared with low dose of isoniazid group and control group. Besides, the morphology of heart and its alteration were visualized using the transgenic zebrafish (cmlc2: GFP) and confirmed by in situ hybridization. The negative effects of isoniazid on the developing heart were characterized by lower heart rate and more heart looping disorders. Mechanistically, PCR showed decreased expression of heart-specific transcription factors exposed to isoniazid. Oxidative stress was induced by Isoniazid in cardiomyocytes, mediated by decreased activity of CAT and SOD, which could be rescued by ROS scavenger. In conclusion, we demonstrated that isoniazid lead to heart looping disturbance by downregulating cardiac specific transcription factors and inducing cardiomyocytes apoptosis.