The effects of developmental ethanol exposure & postnatal choline supplementation on long-term choline metabolism

Prenatal alcohol exposure (PAE) can disrupt development, leading to alterations in physical, health, and behavioral outcomes, referred to as fetal alcohol spectrum disorders (FASD). Although alcohol likely impacts fetal development through many mechanisms, PAE could impact metabolism of choline, an essential nutrient that is important for brain development and function. Importantly, both preclinical and clinical studies show that choline supplementation can improve performance on hippocampal-dependent behavioral tasks, even when administered postnatally. However, the mechanisms by which choline mitigates prenatal alcohol-induced neurocognitive deficits are not well understood. Thus, the present study examined whether PAE leads to long-lasting changes in choline metabolism in the hippocampus and plasma of adolescent animals and if effects are modified by choline. From postnatal day (PD) 4-9, rat pups were given ethanol (EtOH; 5.25 g/kg/day) or sham intubations. From PD 10-30, subjects received s.c. choline chloride (100 mg/kg/day) or saline. Plasma and hippocampus were collected on PD 35 and choline metabolite levels were analyzed. Neither EtOH nor choline led to long-lasting changes in choline levels. However, EtOH-exposed females had reduced hippocampal betaine and plasma betaine:choline ratios. Plasma cystathionine was elevated in EtOH-exposed females treated with choline, suggesting choline activates anti-oxidative stress and anti-inflammation pathways among EtOH-exposed subjects. Choline alone increased homocysteine among females. In contrast, choline supplementation increased plasma SAM:SAH ratios in EtOH-exposed males, suggesting choline is modifying DNA methylation. Overall, these results provide insights to sex-specific mechanisms of action in which choline supplementation alters choline metabolic pathways in FASD.