Supplementation with the Methyl Donor Betaine Prevents Congenital Defects Induced by Prenatal Alcohol Exposure

Background Despite decades of public education about dire consequences of prenatal alcohol exposure, drinking alcohol during pregnancy remains prevalent. As high as 40% of live-born infants exposed to alcohol during gestation and diagnosed with Fetal Alcohol Syndrome have congenital heart defects that can be life-threatening. In animal models, the methyl donor betaine, found in foods such as wheat bran, quinoa, beets and spinach, ameliorated neurobehavioral deficits associated with prenatal alcohol exposure (PAE) but effects on heart development are unknown. Methods Previously we modeled a binge drinking episode during the first trimester in avian embryos. Here we investigated whether betaine could prevent adverse effects of alcohol on heart development. Embryos exposed to ethanol with and without an optimal dose of betaine (5 μM) were analyzed at late developmental stages. Cardiac morphology parameters were rapidly analyzed and quantified using optical coherence tomography. DNA methylation at early stages was detected by immunofluorescent staining for 5-methylcytosine in sections of embryos treated with ethanol or co-treated with betaine. Results Compared to ethanol-exposed embryos, betaine-supplemented embryos had higher late-stage survival rates and fewer gross head and body defects than seen after alcohol exposure alone. Betaine also reduced the incidence of late-stage cardiac defects such as absent vessels, abnormal atrio-ventricular (AV) valves, and hypertrophic ventricles. Furthermore, betaine co-treatment brought measurements of great vessel diameters, interventricular septum (IVS) thickness, and AV leaflet volumes in betaine-supplemented embryos close to control values. Early-stage 5-methycytosine staining revealed that DNA methylation levels were reduced by ethanol exposure and normalized by co-administration with betaine. Conclusions This is the first study demonstrating efficacy of the methyl donor betaine in alleviating cardiac defects associated with PAE. These findings highlight the therapeutic potential of low-concentration betaine doses in mitigating PAE induced birth defects and has implications for prenatal nutrition policies, especially for women who may not be responsive to folate supplementation. This article is protected by copyright. All rights reserved.