Decades of public education regarding dire consequences of prenatal alcohol exposure (PAE) have not reduced alcohol consumption during pregnancy. PAE can result in fetal alcohol spectrum disorder (FASD). Recent reports have revealed high prevalence of FASD ( ≥1%), rivaling that of autism. Furthermore, roughly 40% of individuals with FASD have congenital heart defects (CHDs). PAE effects include damage to neural crest cells (NCCs), precursors of the autonomic nervous system and regulators of cardiogenesis. Common defects seen in FAE and in our avian FASD model include ventricular septal defects, atrial septal defects, absent major vessels, abnormal atrioventricular valves, and hypertrophic ventricles. Animal studies support that alcohol alters the one-carbon cycle and methylation and promotes oxidative stress. Analysis of human buccal samples reveal signature DNA methylation changes in FASD individuals that may become useful as biomarkers and elucidate mechanisms. Protecting NCCs by supplementation with methyl donors and anti-oxidants may reduce the effects of PAE. Our previous studies have shown that betaine, a methyl-donor, has efficacy in alleviating or preventing cardiac defects associated with CHDs in an avian model. However, as the embryos were only partially rescued, it is essential to test additional compounds. Glutathione is a methyl donor, reduces reactive oxygen species, and is readily available, making it an ideal choice. Quail embryos exposed to ethanol with and without glutathione were analyzed at on day 8. This is the first stage at which the quail heart has 4 chambers. Survival, gross body, eye, and heart abnormalities were assessed. Hearts were then optically cleared and imaged with optical coherence tomography for complete phenotyping. Our preliminary data shows an optimal dose of 1µM glutathione increased survival from 46% to 84% and decreased gross body or heart defects among survivors from 50% to 14% compared to ethanol injected controls. These survival and defect percentages are appreciably better than those seen with betaine (73% and 27% respectively). OCT heart imaging also demonstrates a decrease in heart defects commonly found in FASD. With this data, we suggest that glutathione is an excellent candidate for further analysis to determine if this easily accessible supplement alleviates the effects of PAE.
Glutathione supplementation decreases mortality and congenital heart disease in an avian model of fetal alcohol spectrum disorders
Stephanie Ford, Michael Jenkins, Michiko Watanabe, Ganga Karunamuni, Megan Sheehan; Glutathione supplementation decreases mortality and congenital heart disease in an avian model of fetal alcohol spectrum disorders. Pediatrics August 2019; 144 (2_MeetingAbstract): 293. 10.1542/peds.144.2MA3.293
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