PUBLICATION
Pexidartinib hydrochloride exposure induces developmental toxicity and immunotoxicity in zebrafish embryos via activation of Wnt signaling
- Authors
- Liu, F., Hu, H., Chen, G., Lin, Y., Li, W., Liu, Z., Chen, C., Li, X., Sun, S., Zhang, L., Yang, D., Liu, K., Xiong, G., Liao, X., Lu, H., Cao, Z., Chen, J.
- ID
- ZDB-PUB-230604-32
- Date
- 2023
- Source
- Fish & shellfish immunology 138: 108849 (Journal)
- Registered Authors
- Lu, Huiqiang
- Keywords
- Developmental toxicity, Immunotoxicity, Pexidartinib, Wnt signaling
- MeSH Terms
-
- Aminopyridines/metabolism
- Aminopyridines/pharmacology
- Animals
- Embryo, Nonmammalian
- Inflammation/metabolism
- Wnt Signaling Pathway*
- Zebrafish*/genetics
- PubMed
- 37268155 Full text @ Fish Shellfish Immunol.
Citation
Liu, F., Hu, H., Chen, G., Lin, Y., Li, W., Liu, Z., Chen, C., Li, X., Sun, S., Zhang, L., Yang, D., Liu, K., Xiong, G., Liao, X., Lu, H., Cao, Z., Chen, J. (2023) Pexidartinib hydrochloride exposure induces developmental toxicity and immunotoxicity in zebrafish embryos via activation of Wnt signaling. Fish & shellfish immunology. 138:108849.
Abstract
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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping