Bexarotene regulates zebrafish embryonic development by activating Wnt signaling pathway

IF 5.2 2区医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL

Life sciences Pub Date : 2025-04-25 DOI:10.1016/j.lfs.2025.123664

Wenwen Zha , Ziang Wang , Weitao Hu , Chenkai Ge , Wenbin Yuan , Qinyuan Shen , Weirong Li , Wanqing Chen , Jingrong Tang , Zhonghao Xiao , Yunlong Meng , Lirong Huang , Zilin Zhong , Tao-Sheng Li , Jianjun Chen , Zigang Cao

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引用次数: 0

Abstract

Bexarotene (Bex) is a selective retinoid X receptor (RXR) agonist and is commonly used as an anti-tumor drug in the clinic to treat patients with cutaneous T-cell lymphoma (CTCL). With the widespread use of this drug, people are increasingly concerned about its side effects and safety of use. At present, the effects of bexarotene drugs on the health of organisms remain uncertain, but retinoid drugs are generally biologically active and may pose potential risks to them. Therefore, in this study, we used a zebrafish model to evaluate the effects of Bex on embryonic development. Six hours after fertilization, we exposed zebrafish embryos to 3 μg/L, 6 μg/L, and 9 μg/L bexarotene. At 96 hpf, compared with the control group, zebrafish embryos exposed to bexarotene showed obvious heart and liver development defects, including reduced hatching rate, pericardial enlargement, heart rate disorder, yolk sac edema, small liver area and abnormal photo-optical motor responses. Transcriptome and qPCR results showed abnormal expression of genes related to heart and liver development was induced by Bexarotene. Mechanistically, bexarotene induced a significant upregulation of the transcriptional expression levels of genes related to the Wnt signaling pathway, and IWR-1 was able to effectively rescue the heart and liver developmental defects of zebrafish caused by bexarotene. Therefore, our study showed that bexarotene may cause zebrafish embryonic developmental defects by upregulating the Wnt signaling pathway, revealing the side effects and associated novel mechanisms of bexarotene, and providing a theoretical basis for its safe and effective use in the treatment of clinically related diseases.

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贝沙罗汀通过激活Wnt信号通路调控斑马鱼胚胎发育

贝沙罗汀（Bex）是一种选择性类视黄醇X受体（RXR）激动剂，临床常用作抗肿瘤药物治疗皮肤t细胞淋巴瘤（CTCL）患者。随着该药物的广泛使用，人们越来越关注其副作用和使用安全性。目前，贝沙罗汀类药物对生物体健康的影响尚不确定，但类维甲酸类药物通常具有生物活性，可能对生物体构成潜在风险。因此，在本研究中，我们使用斑马鱼模型来评估Bex对胚胎发育的影响。受精后6小时，我们将斑马鱼胚胎暴露于3、6、9 μg/L的贝沙罗汀中。在96 hpf时，与对照组相比，贝沙罗汀暴露的斑马鱼胚胎出现明显的心脏和肝脏发育缺陷，包括孵化率降低、心包增大、心率紊乱、卵黄囊水肿、肝脏面积小、光运动反应异常。转录组和qPCR结果显示贝沙罗汀诱导心脏和肝脏发育相关基因的异常表达。在机制上，贝沙罗汀诱导Wnt信号通路相关基因的转录表达水平显著上调，IWR-1能够有效地挽救贝沙罗汀引起的斑马鱼心脏和肝脏发育缺陷。因此，我们的研究表明贝沙罗汀可能通过上调Wnt信号通路导致斑马鱼胚胎发育缺陷，揭示贝沙罗汀的毒副作用及相关新机制，为安全有效地使用贝沙罗汀治疗临床相关疾病提供理论依据。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Life sciences 医学-药学

CiteScore

12.20

自引率

1.60%

发文量

841

审稿时长

6 months

期刊介绍： Life Sciences is an international journal publishing articles that emphasize the molecular, cellular, and functional basis of therapy. The journal emphasizes the understanding of mechanism that is relevant to all aspects of human disease and translation to patients. All articles are rigorously reviewed. The Journal favors publication of full-length papers where modern scientific technologies are used to explain molecular, cellular and physiological mechanisms. Articles that merely report observations are rarely accepted. Recommendations from the Declaration of Helsinki or NIH guidelines for care and use of laboratory animals must be adhered to. Articles should be written at a level accessible to readers who are non-specialists in the topic of the article themselves, but who are interested in the research. The Journal welcomes reviews on topics of wide interest to investigators in the life sciences. We particularly encourage submission of brief, focused reviews containing high-quality artwork and require the use of mechanistic summary diagrams.