Lenvatinib exposure induces hepatotoxicity in zebrafish via inhibiting Wnt signaling.

Abstract

Lenvatinib is a multi-kinase inhibitor for widely treating thyroid cancer. However, little studies have been done about it or its toxicity on embryonic development of vertebrate. In this study, we used zebrafish to assess the effect of lenvatinib on early embryonic development. Exposure of zebrafish embryos to 58, 117, 176 nM lenvatinib induced abnormal embryonic development, such as decreased heart rate, pericardial edema, delayed yolk absorption, and bladder atrophy. Lenvatinib exposure reduced liver area and down-regulated liver developmental related genes. The proliferation of hepatocytes and the expression of apoptosis-related genes were significantly reduced.by Lenvatinib. Furthermore, the imbalance of liver metabolism and abnormal liver tissue structure were observed in adult zebrafish after Lenvatinib exposure. Oxidative stress was up-regulated by lenvatinib and astaxanthin partially rescued hepatic developmental defects via downregulating oxidative stress. After lenvatinib exposure, Wnt signaling was down-regulated, and activation of Wnt signaling partially rescued hepatic developmental defects. Therefore, these results suggested that lenvatinib might induce zebrafish hepatotoxicity by down-regulating Wnt signaling related genes and inducing oxidative stress. This study provides a reference for the potential hepatotoxicity of lenvatinib during embryonic development and raises health concern about the potential harm of exposure to lenvatinib for foetuses.

• Authors: Ling Huang, Jieping Liu, Wanbo Li, Fasheng Liu, Mengqi Wan, Guilan Chen, Meile Su, Chen Guo, Fang Han, Guanghua Xiong, Xinjun Liao, Huiqiang Lu, Zigang Cao
• Journal: Toxicology (Toxicology) Vol. 462 Pg. 152951 (10 2021) ISSN: 1879-3185 [Electronic] Ireland
• PMID: 34534561 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2021 Elsevier B.V. All rights reserved.

Chemical References

• Phenylurea Compounds
• Protein Kinase Inhibitors
• Quinolines
• lenvatinib

Topics

• Animals
• Cell Proliferation (drug effects)
• Chemical and Drug Induced Liver Injury (etiology, physiopathology)
• Down-Regulation (drug effects)
• Embryo, Nonmammalian (drug effects)
• Embryonic Development (drug effects)
• Hepatocytes (drug effects, pathology)
• Oxidative Stress (drug effects)
• Phenylurea Compounds (administration & dosage, toxicity)
• Protein Kinase Inhibitors (administration & dosage, toxicity)
• Quinolines (administration & dosage, toxicity)
• Wnt Signaling Pathway (drug effects)
• Zebrafish (embryology)