Effects of maternal consumption of ethanol during pregnancy on the developing fetus and offspring: neurobehavioural outcomes, neuroendocrine function and cytochrome P450 2E1 enzyme activity.

Abstract

Maternal consumption of alcohol during pregnancy is associated with alterations in fetal development that negatively impact the offspring causing neurochemical and neurobehavioural dysfunction termed fetal alcohol spectrum disorders; the most severe outcome is fetal alcohol syndrome. Changes in maternal and fetal hypothalamic-pituitary-adrenal (HPA) axis activation, induction of cytochrome P450 2E1 (CYP2E1) enzyme activity and alterations in micronutrient status, including folate, following chronic ethanol exposure (CEE) are key contributors to the neuroendocrine and neurobehavioural effects observed in offspring. This study tested the following hypotheses: Maternal consumption of ethanol throughout pregnancy can: alter maternal and fetal HPA axis function and induce CYP2E1 enzyme activity in the third-trimester-equivalent; decrease folate status in the maternal-fetal unit, which can be mitigated by folic acid supplementation; and cause neurobehavioural deficits in offspring at low-moderate dose of maternal ethanol consumption. These hypotheses were tested in the guinea pig, a well established model of ethanol neurobehavioural teratogenicity. CEE had no effect on maternal HPA axis function at any gestational day (GD). Fetal cortisol was unaffected by CEE, but did increase with gestational age in both CEE and control. CEE increased maternal and GD 65 fetal liver CYP2E1 enzyme activity. Maternal supplementation with folic acid did not mitigate CEE fetal growth restriction, but did increase maternal red blood cell (RBC) folate at term. At term, maternal supplementation prevented the CEE-induced decrease in fetal liver folate, did not affect fetal RBC folate, and did not mitigate the nutritional-deficit-induced decrease in fetal hippocampal folate. Maternal consumption of 5% (v/v) ethanol decreased offspring birth weight, increased spontaneous locomotor activity, increased preference for ethanol, and delayed learning on day two of Morris water maze testing in young adult offspring. These data indicate that, in the guinea pig: there is a threshold blood ethanol concentration for HPA axis activation; CEE can induce CYP2E1 in the GD 65 fetus; folic acid supplementation is not protective in this model of CEE; and low-moderate CEE can cause neurobehavioural perturbations in offspring.