Brain malformations in prenatal mice following acute maternal ethanol administration

Acute maternal ethanol administration (two i.p. injections of 2.9 g ethanol/kg maternal body wt) to C57B1/6J mice during gastrulation stages of embryogenesis (gestational day 7) induces a spectrum of brain and facial malformations characteristic of those seen in the human Fetal Alcohol Syndrome. Scanning electron microscopic and light microscopic analyses of the brains of embryos of gestational days 11-14 demonstrate ventro-medial forebrain deficiencies of varying degrees of severity in affected specimens. Even at the mild end of the spectrum, reductions in the size of the septal nuclei and the shape of the third ventricle are observed. As the severity of the effect increases, the septal nuclei disappear altogether, resulting in midline fusion of the corpora striata (basal ganglia). In such cases, the third ventricle is totally absent anteriorly (preoptic area) and significantly narrowed at more posterior levels, adjacent to the ventromedial nuclei. In addition, the hippocampal primordium is absent at levels which include the corpora striata, and septation of the cerebral cortex is incomplete. More posteriorly, at the level of the posterior commissure, the hippocampal primordium is present, but greatly reduced in size, and the entire brain is distinctly narrower in width. Still further posteriorly, at levels of the metencephalon which include the tectum and cerebellar plate, the cerebral aqueduct is significantly expanded, fusion of midline (raphe) structures is incomplete and the cerebellar plate does not extend as far medially as it does normally. Interestingly, these abnormalities are analogous to those observed in the holoprosencephaly series of malformations. The results of the present study support our hypothesis that severe forms of the Fetal Alcohol Syndrome mimic certain aspects of the holoprosencephaly spectrum, and indicate that special attention should be paid to possible deficiencies in the septal nuclei and basal ganglia of children born to women who abuse alcohol. The fact that gross brain malformations can be induced in this animal model at a time corresponding to the third week of human gestation (a time when most women remain unaware of pregnancy) is of significance in terms of the possible prevention of alcohol-induced birth defects and mental deficiency in man.