GSE193373
Gene expression profiling of Zebrafish larvae treated with bepridil
Purpose: Bepridil is a commonly used drug for angina pectoris and arrhythmia. However, its toxicity and other potential effects on embryonic development remain unknown. In this study, we revealed the physical and developmental toxicity of bepridil on zebrafish models and human myocardial H9c2 cells. Methods: The AB line zebrafish embryos were treated with different concentrations of bepridil at 24 hpf. The mRNA profiles of zebrafish larvae at 120 hpf in 0, 250, 750 and 1295 ng/mL bepridil groups were generated with deep sequencing, in triplicate, using Illumina sequencing platform (HiSeqTM 2500). RNA integrity was analyzed through the Agilent 2100 Bioanalyzer (Agilent Technologies, Santa Clara). The RNA integrity number = 7 was subjected to the following analysis. Genes with adjusted P-value < 0.05 and foldChange >2 were defined as differentially expressed genes (DEGs). Results: About 45 million sequence reads were mapped to the zebrafish genome in each group. The RNA-seq data confirmed that low-dose of bepridil treatment induced an obvious xenobiotic stimulus and drug catabolic process. The enriched DEGs of GO and KEGG workflow showed negative regulation of proteolysis and peptidase in 250 and 750 ng/mL bepridil groups, which eventually led to the metabolic disorders of lipids and a variety of essential amino acids. As a long-term acting calcium antagonist, bepridil caused partial changes (Generatio, 61/426) of calcium signaling channel in 120 hpf zebrafish larvae after 1295 ng/mL (LC10) treatment. However, the cardiac muscle contraction and adrenergic of cardiomyocytes were affected significantly in the same group. Besides, the overall DEGs were highly correlated to cell proliferation and differentiation of the zebrafish. In brief, the transcriptome results were similar to our in vivo phenotype data. The liver metabolism and cardiovascular function of zebrafish would be affected by bepridil during early embryonic development. Conclusions: Our study reveals the potential embryotoxicity of bepridil, a traditional antiarrhythmic drug, in zebrafish embryos. The transcriptomes of zebrafish larvae were progressed with biological replicates (n = 3) and generated through RNA-seq. Our results reveal the detailed biological and metabolic responses of bepridil to embryonic development, which has guiding significance for the clinical medication of prenatal heart patients. Overall design: Zebrafish larvae mRNA profiles of 120 hpf individuals in 0, 250, 750 and 1295 ng/mL bepridil treatment groups