Potential effects of bexarotene on neural development and function in zebrafish embryos

Bexarotene is a retinoid X receptor (RXR) agonist that plays a crucial role in cell growth and differentiation. It has shown potential in treating both early- and late-stage cutaneous T-cell lymphoma (CTCL). However, the impact of Bexarotene on the neurodevelopment of aquatic organisms, particularly aquatic vertebrates, remains poorly understood. This study aimed to investigate the effects of various concentrations of bexarotene (3 μg/L, 6 μg/L, and 9 μg/L) on the development of the zebrafish embryonic nervous system, using zebrafish as a model organism. The underlying molecular mechanisms were explored through a combination of pharmacological interventions, molecular biology, histopathology, and transcriptomics. Studies have shown that zebrafish embryos exposed to Bex show significant changes in development, including morphological abnormalities, head malformations, significantly shortened head length and width, reduced fluorescent area, cell apoptosis, shortened spinal motor neuron axon length, abnormal myelin development, decreased oligodendrocytes, cerebellar developmental damage, and abnormal behavior. Transcriptomics and qPCR results showed abnormal expression of neurodevelopmental genes (olig2, mbpa, atoh1a, gfap, ngn1, gap43, etc.). In addition, exposure to medium and high concentrations of bexarotene significantly increased acetylcholinesterase (AChE) activity. Bexarotene activates the Wnt signaling pathway, and treatment with the Wnt inhibitor IWR-1 can partially rescue the neurodevelopmental impairments in embryos. In summary, bexarotene offers new insights into the potential neurodevelopmental risks in zebrafish embryos, emphasizing the importance of preventing drug side effects and ensuring the safe and rational use of medications to protect the health of living organisms.