Abstract
ObjectiveThere are some problems in the evaluation of drug cardiotoxicity in zebrafish, such as unsystematic indicators and weak sensitivity. This study aims to explore the advantages and disadvantages of various evaluation methods in rapid cardiotoxicity assessment, and to identify and establish representative and highly sensitive evaluation indicators. MethodsFour typical cardiotoxic drugs (Doxorubicin, 5-Fluorouracil, Ibuprofen and Lidocaine) with different concentrations were selected to act on zebrafish embryos. The death, cardiac malformation, heart rate, blood flow and sinus venosus-bulbus arteriosus (SV-BA) distance of zebrafish in each group were observed and recorded by stereo microscopy. The behavioral changes of zebrafish after drug treatment were counted and analyzed using a zebrafish behavior recorder. Adult zebrafish were used to screen the cardiotoxic expressed genes, and the spatiotemporal expression stability and concentration-dose dependence of the specifically highly expressed genes were studied. ResultsAll the 4 drugs can reduce the heart rate and blood flow velocity of zebrafish embryos to varying degrees, increase the SV-BA distance of zebrafish embryos, reduce the activity behavior of zebrafish embryos, and have different degrees of inhibitory effects on the cardiac function of zebrafish. Among the selected 12 genes expressed only in the heart, one and only CMLC1 showed high specific expression in the heart of zebrafish. However, doxorubicin did not affect the expression of CMLC1 gene in a concentration-dose dependent manner, and the other three drugs could significantly induce the up-regulation of CMLC1 gene expression. ConclusionEthology is a faster and more sensitive method than the traditional cardiotoxicity evaluation indicators (heart rate, blood flow velocity, and SV-BA distance). Zebrafish have a small number of highly heart-specific expressed genes and are not suitable for assessing cardiotoxicity based solely on heart-specific expression of circulating mRNA.
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