Injurious effects of acute ethanol exposure during late gestation on developing white matter in fetal sheep

Fetal exposure to maternal alcohol intake can be harmful to the developing brain but the effects of acute exposures are less well documented. Our objective was to determine the effects of acute alcohol exposure on developing white matter and to investigate the potential role of pro-inflammatory cytokines. Fifteen pregnant ewes underwent surgery at 110.0+/-1.0 days of the 147 day gestation for fetal catheterization. Ethanol (1g/kg maternal weight) was administered intravenously to 8 ewes for 1h on 3 consecutive days at 116.0+/-1.0 days of gestation (0.8 of full term); 7 pregnant control ewes received saline. Fetal brains were collected at necropsy 5 days after the initial ethanol exposure and processed for structural analysis. Maternal and fetal blood ethanol concentrations reached maximal values (0.11+/-0.01 g/dL) 1h after infusions commenced, declining to zero thereafter. Ethanol exposure did not cause fetal hypoxemia, acidemia, hypercapnia, hypoglycemia or hypotension. Subcortical white matter injury, defined as microglia/macrophage infiltration, axonal disruption, increased apoptosis, astrogliosis and altered glial cell morphology, was observed in 4 of the 8 ethanol-exposed fetuses. The injury occupied 6.6-18.3% of the cross-sectional area of cerebral white matter examined and was substantial in 2/8 and modest in 2/8 ethanol-exposed fetuses. Three remaining fetuses exhibited astrogliosis and elevated levels of apoptosis in cerebral white matter. There was a positive correlation between maternal and fetal blood ethanol concentrations and the extent of brain damage. There was no significant elevation in concentrations of the pro-inflammatory cytokines tumor necrosis factor-alpha, interleukin-1beta and interleukin-6 in fetal plasma. Developing white matter in the late gestation fetus is vulnerable to acute alcohol exposure, but mechanisms remain unclear.