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

Abstract

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 effect on neural crestdependent 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 U2-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. Sulik et a1This 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.

Behavioral deficits induced by bingelike exposure to alcohol in neonatal rats: Importance of developmental timing and number of episodes

“…Animal models have proved useful in evaluating outcomes of developmental exposure to alcohol (Driscoll, Streissguth, & Riley, 1990;Meyer, Kotch, & Riley, 1990a;1990b), and have illuminated the importance of blood alcohol profiles and patterns of exposure in determining neurobehavioral outcomes West et al, 1989). Experimental animal studies have identified relatively sharp temporal windows of vulnerability to alcohol-induced soft-tissue dysmorphology (Sulik, 1984;Sulik, Johnston, Daft, Russell, & Dehart, 1986). Animal models also provide the best means to investigate the role of developmental timing in determining the neurobehavioral outcomes (Clarren et al, 1990;.…”

Combinatorial transcriptional interaction within the cardiac neural crest: A pair of HANDs in heart formation

“…In chick embryos, neural fold/NC ablation (Creazzo et al, 1998), Hox antisense experiments , teratogenic retinoic acid exposure (Broekhuizen et al, 1998) and haemodynamic perturbations (Hogers et al, 1999) have all caused 4 th and 6 th arch abnormalities. Similarly in mouse, teratogenic exposure to haloacetic acids (Hunter et al, 1996), ethanol (Sulik et al, 1986), and retinoic acid (RA) gives rise to arch abnormalities. Related or analogous pathological defects of the mouse 4 th and 6 th aortic arches and outflow tract are also seen when a large number of genes have been transgenically altered.…”

Gestational exposure to ethanol suppresses msx2 expression in developing mouse embryos

“…This notion has been supported by animal studies. Single intraperitoneal injections of ethanol given to pregnant C57BL͞6J mice between E7 and E11 resulted in craniofacial abnormalities, including exencephaly and hypoplasia of the midfacial region and anomalies of the DiGeorge sequence (68)(69)(70). The onset of expression of msx2 in mouse embryos has been reported to occur as early as E9 and is still expressed as late as E17 (26).…”

“…The onset of expression of msx2 in mouse embryos has been reported to occur as early as E9 and is still expressed as late as E17 (26). Using closely spaced (4 hr) dual intraperitoneal injections of alcohol to mimic ''binge'' drinking, abnormalities with facial features similar to those noted in human FAS infants have been induced in fetal mice only when alcohol is present on or before E8 (31,(70)(71)(72)(73). By contrast, similar alcohol exposures at later stages of murine gestation could not induce murine craniofacial abnormalities.…”