Lenvatinib induces cardiac developmental toxicity in zebrafish embryos through regulation of Notch mediated-oxidative stress generation.
Lenvatinib induces cardiac developmental toxicity in zebrafish embryos through regulation of Notch mediated-oxidative stress generation.
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Lenvatinib 通过调节 Notch 介导的氧化应激产生来诱导斑马鱼胚胎的心脏发育毒性。
DOI：
10.1002/tox.23485
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发表时间：
2022
影响因子：
4.5
通讯作者：
Cao Zigang
中科院分区：
文献类型：
--
作者：
Liu Jieping;Huang Ling;Wan Mengqi;Chen Guilan;Su Meile;Han Fang;Liu Fasheng;Xiong Guanghua;Liao Xinjun;Lu Huiqiang;Li Wanbo;Cao Zigang
由于越来越多的滥用药物被倾倒到废水中，越来越多的药物被检测到在水环境中，这可能会影响水生生物的生存。乐伐替尼是一种多靶点酪氨酸激酶抑制剂，临床上用于治疗分化型甲状腺癌、肾上皮细胞癌和肝癌。然而，关于乐伐替尼对胚胎发育影响的报道很少。在这项研究中，斑马鱼胚胎被用来评估乐伐替尼对心血管发育的影响。在受精后6小时（hpf）选择发育良好的斑马鱼胚胎，并暴露于0.05 mg/L、0.1 mg/L和0.2 mg/L乐伐替尼，直至72 hpf。经处理的胚胎表现出心脏水肿、心率降低、SV-BA距离延长、血管生成抑制和血液循环阻塞。乐伐替尼在心脏发育的整个阶段均引起心脏缺陷，并增加心肌细胞凋亡。处理胚胎中的氧化应激会积累，抑制氧化应激可以挽救乐伐替尼诱导的心脏缺陷。此外，我们发现乐伐替尼下调Notch信号传导，并且Notch信号传导的激活可以挽救心脏发育缺陷并下调乐伐替尼诱导的氧化应激水平。我们的研究结果表明，乐伐替尼可能通过诱导Notch介导的氧化应激产生而诱导心脏发育毒性，这引起了对水生生物暴露于乐伐替尼的危害的担忧。
Due to an increasing number of abused drugs dumped into the wastewater, more and more drugs are detected in the water environment, which may affect the survival of aquatic organisms. Lenvatinib is a multi‐targeted tyrosine kinase inhibitor, and is clinically used to treat differentiated thyroid cancer, renal epithelial cell carcinoma and liver cancer. However, there are few reports on the effects of lenvatinib in embryos development. In this study, zebrafish embryos were used to evaluate the effect of lenvatinib on cardiovascular development. Well‐developed zebrafish embryos were selected at 6 h post fertilization (hpf) and exposed to 0.05 mg/L, 0.1 mg/L and 0.2 mg/L lenvatinib up to 72 hpf. The processed embryos demonstrated cardiac edema, decreased heart rate, prolonged SV‐BA distance, inhibited angiogenesis, and blocked blood circulation. Lenvatinib caused cardiac defects in the whole stage of cardiac development and increased the apoptosis of cardiomyocyte. Oxidative stress in the processed embryos was accumulated and inhibiting oxidative stress could rescue cardiac defects induced by lenvatinib. Additionally, we found that lenvatinib downregulated Notch signaling, and the activation of Notch signaling could rescue cardiac developmental defects and downregulate oxidative stress level induced by lenvatinib. Our results suggested that lenvatinib might induce cardiac developmental toxicity through inducing Notch mediated‐oxidative stress generation, raising concerns about the harm of exposure to lenvatinib in aquatic organisms.