Abnormal heart and great vessel development following acute ethanol exposure in mice.

Two maternal intraperitoneal doses of ethanol (2.9 g/kg) administered on gestational day (GD) 8, 12 hours (8 d, 12 h) and 8 d, 16 h result in abnormal heart and great vessel development in C57B1/6J mice. Heparinized hearts from GD 9 to 18 conceptuses were dissected to expose the forming or already completed ventricular septum and great vessels and then routinely processed for scanning electron microscopy. As early as GD 9 (12 hours post-treatment), size deficiency and abnormal external contour of the cardiac tube were notable. By GD 12, deficiencies in the size of the conal and atrioventricular (A-V) endocardial cushions, as well as abnormal positioning of the A-V canal, were demonstrable. On GD 13, when the ventricular septum should be complete, a range of deficiencies in the conal tissue was observed. Deficiencies observed were a lack of closure of the ventricular septum in the region of the membranous septum, and lack of septation of the conal portion of the developing heart. These deficiencies persist and have been documented through GD 18. Other abnormalities noted on GD 18 include double-outlet right ventricle, as well as distal defects of the great vessels including interrupted aortic arch, right aortic arch, and a vascular ring. While these defects are comparable to those seen in the fetal alcohol syndrome, they also overlap considerably with cardiac defects that are characteristic of those in the DiGeorge Syndrome as well as in the CHARGE Association. Recent work by others as well as the fact that acute ethanol exposure in this animal model corresponds to a time of neural crest cell migration has led to the speculation that this cell population is involved in the cardiovascular pathogenesis described.

Fetal alcohol syndrome and DiGeorge anomaly: critical ethanol exposure periods for craniofacial malformations as illustrated in an animal model.

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.