Pexidartinib hydrochloride exposure induces developmental toxicity and immunotoxicity in zebrafish embryos via activation of Wnt signaling

• Published in: Fish & shellfish immunology Vol. 138; p. 108849
• Main Authors: Liu, Fasheng, Hu, Hongmei, Chen, Guilan, Lin, Yanqi, Li, Wei, Liu, Ziyi, Chen, Chao, Li, Xue, Sun, Sujie, Zhang, Li, Yang, Dou, Liu, Kangyu, Xiong, Guanghua, Liao, Xinjun, Lu, Huiqiang, Cao, Zigang, Chen, Jianjun
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01-07-2023
• Subjects: Developmental toxicity; Immunotoxicity; Pexidartinib; Wnt signaling; TGCT; Developmental toxicity; DMSO; Immunotoxicity; Pexidartinib; FLT-3; AO; LC50; Wnt signaling; KIT; CZRC; PDGFR; ITD; CSF-1R; hpf
• ISSN: 1050-4648; 1095-9947
• DOI: 10.1016/j.fsi.2023.108849

Pexidartinib, a macrophage colony-stimulating factor receptor (CSF-1R) inhibitor, is indicated for the treatment of tendon sheath giant cell tumor (TGCT). However, few studies on the toxicity mechanisms of pexidartinib for embryonic development. In this study, the effects of pexidartinib on embryonic development and immunotoxicity in zebrafish were investigated. Zebrafish embryos at 6 h post fertilization (6 hpf) were exposed to 0, 0.5, 1.0, and 1.5 μM concentrations of pexidartinib, respectively. The results showed that different concentrations of pexidartinib induced the shorter body, decreased heart rate, reduced number of immune cells and increase of apoptotic cells. In addition, we also detected the expression of Wnt signaling pathway and inflammation-related genes, and found that these genes expression were significantly upregulated after pexidartinib treatment. To test the effects of embryonic development and immunotoxicity due to hyperactivation of Wnt signaling after pexidartinib treatment, we used IWR-1, Wnt inhibitor, for rescue. Results show that IWR-1 could not only rescue developmental defects and immune cell number, but also downregulate the high expression of Wnt signaling pathway and inflammation-related caused by pexidartinib. Collectively, our results suggest that pexidartinib induces the developmental toxicity and immunotoxicity in zebrafish embryos through hyperactivation of Wnt signaling, providing a certain reference for the new mechanisms of pexidartinib function.
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•Pexidartinib hydrochloride induced development defects in zebrafish.•Pexidartinib hydrochloride could upregulate the expression levels of Wnt signaling and inflammation-related genes.•Pexidartinib exposure could reduce the number of immune cells and induce cell apoptosis.•Inhibition of Wnt signaling can rescue the development defects and immunotoxicity induced by Pexidartinib.