遗传 ›› 2012, Vol. 34 ›› Issue (9): 1165-1173.doi: 10.3724/SP.J.1005.2012.01165

• 研究报告 • 上一篇    下一篇

三甲双酮对斑马鱼胚胎早期发育的影响

秦伟, 胡占英, 佟军威, 孟杰, 游雪甫, 张靖溥   

  1. 中国医学科学院北京协和医学院医药生物技术研究所药理室, 北京100050
  • 收稿日期:2012-04-05 修回日期:2012-07-13 出版日期:2012-09-20 发布日期:2012-09-25
  • 通讯作者: 张靖溥 E-mail:zjp5577@126.com
  • 基金资助:

    国家自然科学基金项目(编号:30772681), 国家科技重大专项新药创制项目(编号:2009ZX09301-003)和国家科技重大专项(编号:2008ZX09305-001)资助

Toxic effects of trimethadione on zebrafish early development

QIN Wei, HU Zhan-Ying, TONG Jun-Wei, MENG Jie, YOU Xue-Fu, ZHANG Jing-Pu   

  1. Laboratory of Pharmacology, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China
  • Received:2012-04-05 Revised:2012-07-13 Online:2012-09-20 Published:2012-09-25

摘要: 针对抗癫痫药物的临床神经性毒副作用及致畸性, 以三甲双酮为探针药建立了抗癫痫药毒性的斑马鱼胚胎模型。结果显示, 斑马鱼胚胎暴露于三甲双酮后出现浓度依赖性的畸形和死亡。畸形表型有生长迟缓, 脑区、眼和听囊变小, 半规管和耳石受损, 以及心血管系统异常。这些表型与临床病例和文献报道很相似。毛细胞染色显示听囊ML2神经丘毛细胞数明显减少。原位杂交检测发现脑标志基因zic1xb51、自噬基因atg5的表达图式发生了异常变化。RT-PCR检测显示听觉基因valhmx2 的表达水平也发生了异常变化。这些结果提示脑组织和控制身体平衡及听力的神经感受器是三甲双酮的主要毒性靶位。斑马鱼胚胎和幼体可以模拟三甲双酮对哺乳动物的致畸和神经毒性反应。

关键词: 三甲双酮, 药物毒性, 斑马鱼, 胚胎发育, 听囊, 基因表达

Abstract: To further understand the neural toxicity and teratogenicity of antiepileptic drugs in clinic, we established a zebrafish model for antiepileptic toxicity using trimethadione as a probe drug. The results indicated that embryonic malformation occurred under trimethadione treatment in a concentration-dependent manner. The defects included growth retardation, small head, eyes and acoustic capsule, deficient semicircular canals and otolith, and abnormal cardiovascular system. The number of hair cells in neuromast ML2 was obviously reduced in the treated larvae. Whole mount in situ hybridization indicated that the gene expression patterns of brain marker genes, such as zic1 and xb51, and autophagic gene atg5 was changed significantly. The result of RT-PCR showed that the expressions of hearing genes val and hmx2 were also changed in the trimethadione-treated embryos. All these findings suggest that brain tissue and the neural sensors for body balance and hearing are the main targets of trimethadione toxicity, and that zebrafish is able to mimic mammal responses to the teratogenicity and the neural toxicity of trimethadione in the embryonic and larva development.

Key words: Trimethadione, drug toxicity, zebrafish, embryonic development, acoustic vesicle, gene expression