Bexarotene regulates zebrafish embryonic development by activating Wnt signaling pathway

Area of Science:

• Developmental toxicology
• Pharmacology
• Zebrafish models

Background:

• Bexarotene (Bex) is an anti-tumor drug for cutaneous T-cell lymphoma (CTCL).
• Concerns exist regarding the safety and side effects of Bexarotene due to retinoid's biological activity.
• The precise effects of Bexarotene on organismal health, particularly during development, remain unclear.

Purpose of the Study:

• To evaluate the effects of Bexarotene on embryonic development using a zebrafish model.
• To investigate the underlying mechanisms of Bexarotene-induced developmental toxicity.
• To identify potential therapeutic interventions for Bexarotene's side effects.

Main Methods:

• Zebrafish embryos were exposed to varying concentrations of Bexarotene (3, 6, 9 μg/L) from 6 hours post-fertilization.
• Embryonic development, including hatching rate, morphological abnormalities (pericardial edema, yolk sac edema), and behavioral responses, was assessed at 96 hours post-fertilization.
• Transcriptome analysis and quantitative PCR (qPCR) were employed to examine gene expression related to heart and liver development and the Wnt signaling pathway.

Main Results:

• Bexarotene exposure led to significant heart and liver developmental defects in zebrafish embryos.
• Observed defects included reduced hatching rates, pericardial enlargement, heart rate irregularities, yolk sac edema, smaller liver size, and abnormal photo-optical motor responses.
• Gene expression analysis revealed upregulation of Wnt signaling pathway genes, and treatment with IWR-1 rescued these developmental defects.

Conclusions:

• Bexarotene induces embryonic developmental defects in zebrafish, primarily affecting heart and liver development.
• The mechanism involves the upregulation of the Wnt signaling pathway.
• Findings provide insights into Bexarotene's side effects and offer a basis for its safer clinical application.