Critical periods for alcohol teratogenesis in mice, with special reference to the gastrulation stage of embryogenesis

Studies directed towards determining a 'critical' developmental period for the induction of neural, ocular and craniofacial malformations typical of those in severe forms of the fetal alcohol syndrome (FAS) are described here. Sequential developmental analyses of C57Bl/6J mice whose mothers had been given alcohol either intraperitoneally or by gastric intubation on the seventh day of pregnancy (a time corresponding to three weeks after fertilization in humans) illustrate that early deficiencies in the anterior aspect of the embryonic disc of embryos at the gastrulation stage lead to defects characteristic of FAS. These include microcephaly, small nose, long upper lip with deficient philtral component, short palpebral fissures, microphthalmia and tortuous retinal vessels, as well as other eye defects involving primarily the anterior segment. Brain malformations are most marked in the derivatives of the ventromedial forebrain. Gastrulation is a period of intense mitotic activity (particularly in the developing mesoderm) in mammalian embryos. This, together with other studies showing that alcohol suppresses rates of cell division, suggests that alcohol-induced deficiencies in gastrulating mesodermal cells (cells responsible for inducing and maintaining neuroepithelial differentiation), as well as cellular deficiencies in the other germ layers in the anteromedial aspect of the embryonic disc, may play a significant role in the subsequent developmental abnormalities observed.