Yu Jiakang, Gonzalez Salome, Martinez Leopoldo, Diez-Pardo Juan A, Tovar Juan A
Research Laboratory, Hospital Infantil Universitario La Paz, 28046 Madrid, Spain.
Pediatr Surg Int. 2003 Jul;19(5):355-8. doi: 10.1007/s00383-003-1010-9. Epub 2003 Jul 24.
Prenatal exposure of rat embryos to retinoic acid induces severe malformations involving various organs. The mechanisms of this embryopathy are known only in part. This study describes the malformations of the neural crest-derived organs in this model and shows that many of them fit into the pattern of disturbed neural crest organogenic control. Pregnant rats were exposed to either all-trans retinoic acid (125 mg/kg; n=17) or vehicle ( n=10) on E10. Fetuses were recovered on E21 and external and internal malformations were sought. The craniofacial area, the trachea, parathyroids, thymus, thyroid, heart, great vessels, and adrenals were examined. In contrast with normal controls, 100% of retinoic acid animals had craniofacial, 94% anorectal, 90% limb, and 55% neural tube defects. The thymus was absent or ectopic in 76%, the parathyroids were absent or single in 88%, and the thyroid was abnormal in 41%. There were neural crest-type (outflow tract and/or pharyngeal aortic arch defects) cardiovascular malformations in 90% and the adrenals were absent in 52%. Interestingly, 9 of 11 (88%) animals with neural tube defects had absent adrenal glands. This association was significant ( p<0.01) by Fisher exact test. Among the complex mechanisms of retinoic acid teratogenesis, severe disturbances of the neural crest pathway play a leading role. The simultaneous development of neural tube defects and adrenal agenesis suggests common pathogenic pathways.
大鼠胚胎在产前暴露于视黄酸会诱发涉及多个器官的严重畸形。这种胚胎病的机制仅部分为人所知。本研究描述了该模型中神经嵴衍生器官的畸形情况，并表明其中许多畸形符合神经嵴器官发生控制紊乱的模式。怀孕大鼠在胚胎第10天（E10）时，被给予全反式视黄酸（125毫克/千克；n = 17）或赋形剂（n = 10）。在胚胎第21天（E21）时取出胎儿，检查其外部和内部畸形情况。对头面部区域、气管、甲状旁腺、胸腺、甲状腺、心脏、大血管和肾上腺进行了检查。与正常对照组相比，100%的视黄酸处理动物出现头面部畸形，94%出现肛门直肠畸形，90%出现肢体畸形，55%出现神经管缺陷。76%的动物胸腺缺失或异位，88%的动物甲状旁腺缺失或为单个，41%的动物甲状腺异常。90%的动物出现神经嵴型（流出道和/或咽主动脉弓缺陷）心血管畸形，52%的动物肾上腺缺失。有趣的是，11只患有神经管缺陷的动物中有9只（88%）肾上腺缺失。通过Fisher精确检验，这种关联具有显著性（p < 0.01）。在视黄酸致畸的复杂机制中，神经嵴途径的严重紊乱起主导作用。神经管缺陷和肾上腺发育不全的同时出现提示存在共同的致病途径。
