Sulik K K, Johnston M C, Daft P A, Russell W E, Dehart D B
Department of Anatomy, School of Medicine, University of North Carolina, Chapel Hill 27514.
Am J Med Genet Suppl. 1986;2:97-112. doi: 10.1002/ajmg.1320250614.
Acute maternal ethanl (alcohol) administration induces different craniofacial anomalies in the offspring of experimental animals, depending on the gestational day of teratogen exposure. Previous studies in our laboratories have illustrated the sequence of developmental changes leading to the "typical" fetal alcohol syndrome (FAS) craniofacial phenotype which results from teratogen exposure during gastrulation. These facial features are accompanied by deficiencies in median forebrain derivatives. Ethanol teratogenesis at this time apparently results in a loss of midline territory of the embryonic disc with little effects on neural crest-dependent laterally derived structures including the visceral arches. Acute ethanol exposure in mice 1 1/2 days later, at a time when neural crest cells are populating the frontonasal prominence and the visceral arches, results in a craniofacial phenotype that is similar to that noted in the DiGeorge anomaly or sequence. Sequential scanning electron microscopic analysis in our laboratory of embryos exposed on day 8 1/2 have illustrated deficiencies in the developing facial prominences and the visceral arches. The developing forebrain and midbrain appear hypoplastic. We have also observed heart, great vessel, and thymus abnormalities in these fetuses. Histologic analyses indicate that a common pathogenetic basis for the above-mentioned (day 8 1/2-induced) fetal alcohol effects appears to be an interference with the integrity of the cranial (including occipital) neural crest. Other discrete cell populations may also be involved since we have observed abnormalities in other regions, including placodal and closing membrane tissues. This animal model provides evidence linking maternal ethanol abuse during the 3rd or 4th weeks of human gestation to the development in the conceptus of FAS or DiGeorge anomally craniofacial characteristics, respectively. As the DiGeorge anomaly has been noted in the offspring of alcoholic women, this animal model indicates that ethanol and/or its metabolites is, in these cases, the causative agent.
孕期母体急性摄入乙醇会在实验动物后代中诱发不同的颅面畸形，这取决于致畸剂暴露时的妊娠天数。我们实验室之前的研究已经阐明了导致“典型”胎儿酒精综合征（FAS）颅面表型的发育变化序列，该表型是由原肠胚形成期致畸剂暴露所致。这些面部特征伴有前脑中线衍生物的缺陷。此时乙醇致畸作用显然导致胚胎盘中线区域丧失，而对神经嵴依赖性的侧向衍生结构（包括内脏弓）影响较小。在1.5天后对小鼠进行急性乙醇暴露，此时神经嵴细胞正迁移至额鼻突和内脏弓，会导致一种颅面表型，类似于迪乔治异常或序列中所观察到的。我们实验室对在第8.5天暴露的胚胎进行的连续扫描电子显微镜分析表明，发育中的面部突起和内脏弓存在缺陷。发育中的前脑和中脑似乎发育不全。我们还在这些胎儿中观察到心脏、大血管和胸腺异常。组织学分析表明，上述（第8.5天诱导的）胎儿酒精效应的共同发病机制似乎是对颅（包括枕部）神经嵴完整性的干扰。其他离散的细胞群可能也参与其中，因为我们在其他区域观察到了异常，包括基板和闭合膜组织。这个动物模型提供了证据，将人类妊娠第3或第4周期间母体乙醇滥用分别与胎儿酒精综合征或迪乔治异常颅面特征的发育联系起来。由于在酗酒女性的后代中已发现迪乔治异常，这个动物模型表明，在这些情况下，乙醇和/或其代谢产物是致病因素。
