Isoniazid causes heart looping disorder in zebrafish embryos by the induction of oxidative stress

Jie Ni,Yimei Shu,Kangjie Shen,Jingwen Cheng,Xiaojie Wan,Fang Wang,Yeqin Sha,Xiyi Wei,Yuxiang Dong,Hongye Wang,Yihai Liu

doi:10.1186/s40360-020-0399-2

Jie Ni, Yimei Shu + Show 9 more

Open Access

https://doi.org/10.1186/s40360-020-0399-2

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Abstract

BackgroundThe cardiotoxicity of isoniazid on zebrafish embryos and its underlying mechanism is unclear.MethodsHere, we exposed zebrafish embryos at 4 h post-fertilization to different levels of isoniazid and recorded the morphology and number of malformed and dead embryos under the microscope.ResultsThe high concentration of isoniazid group showed more malformed and dead embryos than the low concentration of isoniazid group and control group. The morphology of the heart and its alteration were visualized using 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 when exposed to isoniazid. Oxidative stress was induced by isoniazid in cardiomyocytes, mediated by decreased activities of catalase and superoxide dismutase, which were rescued by scavengers of reactive oxygen species.ConclusionIn conclusion, this study demonstrated that isoniazid led to heart looping disturbance by the downregulation of cardiac-specific transcription factors and induction of cardiomyocyte apoptosis.

Highlights

The cardiotoxicity of isoniazid on zebrafish embryos and its underlying mechanism is unclear
We observed that isoniazid disturbed the cyclization process during heart development of zebrafish embryos and caused congenital cardiac malformation
It was mediated by inducing oxidative stress and cardiomyocytes apoptosis and alleviation of oxidative stress can protect cardiac development under the exposure to isoniazid

Summary

Introduction

The cardiotoxicity of isoniazid on zebrafish embryos and its underlying mechanism is unclear. One common side effect is liver damage, as approximately 20% of patients have increased AST (aspartate aminotransferase) and ALT (alanine aminotransferase) levels in the blood after administration of isoniazid [8] and. Isoniazid is regarded as a Pregnancy Category C drug by the Food and Drug Administration [12], some studies have demonstrated potential toxic effects to a fetus. Zhang et al discovered that isoniazid affects liver development in zebrafish embryos and causes liver injury by the construction of fabp10a:mcherry transgenic zebrafish [13]. The abnormal development of the nervous system, skull bone, and cartilage in a zebrafish embryo due to isoniazid has been demonstrated in vitro and in vivo [14]. There is no definitive report in regard to whether isoniazid has toxic effects on the developing heart of a zebrafish embryo

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