Carbamazepine induces hepatotoxicity in zebrafish by inhibition of the Wnt/β-catenin signaling pathway
Carbamazepine induces hepatotoxicity in zebrafish by inhibition of the Wnt/β-catenin signaling pathway
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DOI：
10.1016/j.envpol.2021.116688
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发表时间：
2021-02-18
影响因子：
8.9
通讯作者：
Lu, Huiqiang
中科院分区：
文献类型：
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作者：
Bai, Zhonghui;Jia, Kun;Lu, Huiqiang
随着药物滥用的日益严重，卡马西平随城市污水排入水生环境，对水生生物造成潜在危害。本文利用斑马鱼这一水生脊椎动物模型，对CBZ的肝毒性进行了综合评价。幼虫暴露于0.07、0.13和0.26 mmol/L的CBZ，暴露时间为72 hpf~144 hpf;成虫暴露于0.025、0.05和0.1 mmol/L的CBZ，暴露时间为28 d。结果表明，CBZ对仔、成虫的肝脏有明显的毒性作用。油红O染色显示CBZ暴露引起幼虫和成虫肝脏中严重的脂质积累。此外，CBZ暴露通过TUNEL染色促进肝细胞凋亡，这是由ROS含量升高引起的。随后，暴露组中与Wnt通路相关的基因下调表明CBZ通过Wnt/β-连环蛋白信号通路抑制肝脏发育。总之，CBZ通过促进脂质积聚、产生过量ROS和抑制斑马鱼Wnt/β-连环蛋白信号通路诱导严重肝毒性。结果揭示了CBZ诱导的斑马鱼肝毒性的发生，并阐明了其作用机制，这可能说明了与CBZ暴露相关的环境问题。(C)2021爱思唯尔有限公司版权所有。
As drug abuse has become increasingly serious, carbamazepine (CBZ) is discharged into the aquatic environment with municipal sewage, causing potential harm to aquatic organisms. Here, we utilized zebrafish, an aquatic vertebrate model, to comprehensively evaluate the hepatotoxicity of CBZ. The larvae were exposed to 0.07, 0.13, and 0.26 mmol/L CBZ from 72 hpf to 144 hpf, and the adults were exposed to 0.025, 0.05, and 0.1 mmol/L CBZ for 28 days. The substantial changes were observed in the size and histopathology of livers, indicating that CBZ induced severe hepatoxicity in the larvae and adults. Oil red O staining demonstrated CBZ exposure caused severe lipid accumulation in the livers of both larvae and adults. Furthermore, CBZ exposure facilitated hepatocyte apoptosis through TUNEL staining, which was caused by rising ROS content. Subsequently, down-regulation of genes related to the Wnt pathway in exposure groups indicated that CBZ inhibited the development of liver via the Wnt/beta-catenin signaling pathway. In conclusion, CBZ induced severe hepatotoxicity by promoting lipid accumulation, generating excessive ROS production, and inhibiting the Wnt/beta-catenin signaling pathway in zebrafish. The results reveal the occurrence of CBZ-induced hepatotoxicity in zebrafish and clarify its mechanism of action, which potentially illustrate environmental concerns associated with CBZ exposure. (C) 2021 Elsevier Ltd. All rights reserved.