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

被引：2

作者：

Liu, Fasheng ^{[1
]}

Hu, Hongmei ^{[1
,2
]}

Chen, Guilan ^{[1
]}

Lin, Yanqi ^{[1
]}

Li, Wei ^{[1
]}

Liu, Ziyi ^{[1
]}

Chen, Chao ^{[2
]}

Li, Xue ^{[2
]}

Sun, Sujie ^{[2
]}

Zhang, Li ^{[2
]}

Yang, Dou ^{[1
]}

Liu, Kangyu ^{[2
]}

Xiong, Guanghua ^{[1
]}

Liao, Xinjun ^{[1
]}

Lu, Huiqiang ^{[1
]}

Cao, Zigang ^{[1
,3
]}

Chen, Jianjun ^{[2
,4
]}

机构：

[1] Jinggangshan Univ, Affiliated Hosp, Coll Life Sci, Jiangxi Key Lab Dev Biol Organs,Jiangxi Engn Lab Z, Jian 343009, Jiangxi, Peoples R China

[2] Tongji Univ, Shanghai Peoples Hosp 4, Translat Res Inst Brain & Brain Like Intelligence, Shanghai Key Lab Anesthesiol & Brain Funct Modulat, Shanghai 200434, Peoples R China

[3] Jinggangshan Univ, Sch Life Sci, Jian 343009, Jiangxi, Peoples R China

[4] Tongji Univ, Sch Med, Birth Defects Grp, Room 505,Med Wing Bldg,1239 Siping Rd Yangpu Dist, Shanghai 200092, Peoples R China

来源：

FISH & SHELLFISH IMMUNOLOGY | 2023年 / 138卷

关键词：

Pexidartinib; Developmental toxicity; Immunotoxicity; Wnt signaling; GIANT-CELL TUMOR; INHIBITION; MICROENVIRONMENT; POLARIZATION; MACROPHAGES; BLOCKADE; MODEL;

D O I：

10.1016/j.fsi.2023.108849

中图分类号：

S9 [水产、渔业];

学科分类号：

0908 ;

摘要：

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 immunotox-icity in zebrafish were investigated. Zebrafish embryos at 6 h post fertilization (6 hpf) were exposed to 0, 0.5, 1.0, and 1.5 & mu;M 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 pex-idartinib 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.

引用

页数：9

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