TERATOGENIC EFFECTS OF RETINOIC ACID AND RELATED SUBSTANCES ON THE EARLY DEVELOPMENT OF THE ZEBRAFISH (BRACHYDANIO-RERIO) AS ASSESSED BY A NOVEL SCORING SYSTEM
TERATOGENIC EFFECTS OF RETINOIC ACID AND RELATED SUBSTANCES ON THE EARLY DEVELOPMENT OF THE ZEBRAFISH (BRACHYDANIO-RERIO) AS ASSESSED BY A NOVEL SCORING SYSTEM
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DOI：
10.1016/0887-2333(95)00012-w
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发表时间：
1995-06-01
影响因子：
3.2
通讯作者：
HERRMANN, K
中科院分区：
文献类型：
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作者：
HERRMANN, K
斑马鱼Brachydanio rerio的早期发展被证明适合作为一种测试系统，用于对怀疑对人类有害的药物进行预筛选。分析了全反式维甲酸和3，4-二氢-视黄醇(维生素A(2))、4-氧代维甲酸和几种顺式异构体等8种化学相关物质的致畸作用。斑马鱼的开发提供了几个作为测试系统的优势：全年可以收集大量的卵。因为胚胎是半透明的，所以可以在体内监测器官的发育。受精后第1天，眼睛、心脏和血液循环已可见，并同步发育至受精后第3天。维甲酸的效果可以很容易地评分，并且可以根据它们的有效性对物质进行排序和比较。此外，还提出了一种新的评分方法，该方法还允许比较这些物质对不同器官的致畸作用的相对强度，从而能够研究结构-活性关系。浓度为10(-9)-10(-6)M的全反式维甲酸会导致畸形，如水肿、脑畸形(无眼症、小头畸形和头畸形)、耳石和耳石重复，以及尾巴缩短和弯曲。相关物质表现出相似的作用，但它们的效果不同。就化学结构而言，其效力顺序为：酸；醛；醇；全反式大于或等于9-顺式；13-顺式；维甲酸=3，4-二氢；4-氧代。据报道，哺乳动物的效力也是如此。由于这种相似性，早期斑马鱼的发育似乎是一个合适的模型系统来预测药物对哺乳动物的致畸作用，特别是能够穿过胎盘屏障并到达哺乳动物子宫内胚胎的化学物质及其代谢物。
The early development of the zebrafish Brachydanio rerio is shown to be suitable as a test system for prescreening drugs suspected to be hazardous to humans. The teratogenic effects of all-trans-retinoic acid (tretinoin) and eight chemically related substances, such as 3,4-didehydro-retinol (vitamin A(2)), 4-oxo-retinoic acid and several cis isomers, are analysed. Zebrafish development offers several advantages as a test system: large amounts of eggs can be collected throughout the year. Because the embryo is translucent, organ development can be monitored in vivo. After 1 day, eyes, heart and blood circulation is visible already, and the development is synchronous up to day 3 after fertilization. The effects of the retinoids can be scored easily, and the substances can be ranked and be compared by their effectiveness. Further, a new scoring method is presented which also allows comparison of the relative strength of the teratogenic effects of the substances on the various organs enabling investigation of the structure-activity relationship. Concentrations of 10(-9)-10(-6)M all-trans-retinoic acid generate malformations such as oedema, brain deformities (anophthalmy, microcephaly and acephaly), duplication of the otic placodes and otoliths, and a shortened and bent tail. The related substances display similar effects but they differ in their effectiveness. With respect to the chemical structure, the order of potency is found to be: acid > aldehyde > alcohol; all-trans greater than or equal to 9-cis > 13-cis; tretinoin = 3,4-didehydro > 4-oxo. The same order of potency is reported for mammals. Because of this similarity early zebrafish development appears to be a proper model system for predicting teratogenic effects of drugs in mammals, especially of chemicals and their metabolites, which are able to cross the placental barrier and reach the mammalian embryo in utero.