斑马鱼作为药物心脏毒性早期评估的快速模型系统

Zonghao Lin , Xinru Wei , Yuanzheng Wei , Zongyu Miao , Huixin Ye , Meihui Wu , Xiangying Liu , Lei Cai , Chuqin Yu
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引用次数: 0

摘要

目的斑马鱼药物心脏毒性评价存在指标不系统、灵敏度低等问题。方法选择四种不同浓度的典型心脏毒性药物(多柔比星、5-氟尿嘧啶、布洛芬和利多卡因)作用于斑马鱼胚胎。用体视显微镜观察和记录各组斑马鱼的死亡、心脏畸形、心率、血流量和静脉-大动脉窦(SV-BA)距离。使用斑马鱼行为记录仪对药物治疗后斑马鱼的行为变化进行计数和分析。结果 4种药物均能不同程度地降低斑马鱼胚胎的心率和血流速度,增加斑马鱼胚胎的SV-BA距离,减少斑马鱼胚胎的活动行为,对斑马鱼的心脏功能有不同程度的抑制作用。在筛选出的 12 个只在心脏表达的基因中,只有 CMLC1 在斑马鱼心脏有较高的特异性表达。结论与传统的心脏毒性评价指标(心率、血流速度和SV-BA距离)相比,选集是一种更快、更灵敏的方法。斑马鱼的心脏特异性表达基因较少,不适合仅根据循环 mRNA 的心脏特异性表达来评估心脏毒性。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Zebrafish as a rapid model system for early cardiotoxicity assessment of drugs

Objective

There 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.

Methods

Four 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.

Results

All 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.

Conclusion

Ethology 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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