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Features of FASD cover a range of structural and functional defects including congenital heart defects (CHDs). Folic acid and choline, contributors of methyl groups to one\u2010carbon metabolism (OCM), prevent CHDs in humans. Using our avian model of FASD, we have previously reported that betaine, another methyl donor downstream of choline, prevents CHDs. The CHD preventions are substantial but incomplete. Ethanol causes oxidative stress as well as depleting methyl groups for OCM to support DNA methylation and other epigenetic alterations. To identify more compounds that can safely and effectively prevent CHDs and other effects of PAE, we tested glutathione (GSH), a compound that regulates OCM and is known as a \u201cmaster antioxidant.\u201d<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods\/Results<\/jats:title><jats:p>Quail embryos injected with a single dose of ethanol at gastrulation exhibited congenital defects including CHDs similar to those identified in FASD individuals. GSH injected simultaneously with ethanol not only prevented CHDs, but also improved survival and prevented other PAE\u2010induced defects. Assays of hearts at 8\u00a0days (HH stage 34) of quail development, when the heart normally has developed 4\u2010chambers, showed that this single dose of PAE reduced global DNA methylation. GSH supplementation concurrent with PAE normalized global DNA methylation levels. The same assays performed on quail hearts at 3\u00a0days (HH stage 19\u201020) of development, showed no difference in global DNA methylation between controls, ethanol\u2010treated, GSH alone, and GSH plus ethanol\u2010treated cohorts.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>GSH supplementation shows promise to inhibit effects of PAE by improving survival, reducing the incidence of morphological defects including CHDs, and preventing global hypomethylation of DNA in heart tissues.<\/jats:p><\/jats:sec>","DOI":"10.1111\/acer.14511","type":"journal-article","created":{"date-parts":[[2020,11,18]],"date-time":"2020-11-18T22:39:46Z","timestamp":1605739186000},"page":"69-78","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":18,"title":["Glutathione Protects the Developing Heart from Defects and Global DNA Hypomethylation Induced by Prenatal Alcohol Exposure"],"prefix":"10.1111","volume":"45","author":[{"given":"Safdar","family":"Jawaid","sequence":"first","affiliation":[{"name":"From the Division of Pediatric Cardiology (SJ, JPS, GHK, MMS, AC, CAG, MWJ, MW, SMF) Department of Pediatrics The Congenital Heart Collaborative Rainbow Babies and Children\u2019s Hospital Case Western Reserve University School of Medicine Cleveland Ohio USA"},{"name":"Department of Biomedical Engineering (SJ, MMS, AMR, MWJ) School of Engineering Case Western Reserve University Cleveland Ohio USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James P.","family":"Strainic","sequence":"additional","affiliation":[{"name":"From the Division of Pediatric Cardiology (SJ, JPS, GHK, MMS, AC, CAG, MWJ, MW, SMF) Department of Pediatrics The Congenital Heart Collaborative Rainbow Babies and Children\u2019s Hospital Case Western Reserve University School of Medicine Cleveland Ohio 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AC, CAG, MWJ, MW, SMF) Department of Pediatrics The Congenital Heart Collaborative Rainbow Babies and Children\u2019s Hospital Case Western Reserve University School of Medicine Cleveland Ohio USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Megan M.","family":"Sheehan","sequence":"additional","affiliation":[{"name":"From the Division of Pediatric Cardiology (SJ, JPS, GHK, MMS, AC, CAG, MWJ, MW, SMF) Department of Pediatrics The Congenital Heart Collaborative Rainbow Babies and Children\u2019s Hospital Case Western Reserve University School of Medicine Cleveland Ohio USA"},{"name":"Department of Biomedical Engineering (SJ, MMS, AMR, MWJ) School of Engineering Case Western Reserve University Cleveland Ohio USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amrin","family":"Chowdhury","sequence":"additional","affiliation":[{"name":"From the Division of Pediatric Cardiology (SJ, JPS, GHK, MMS, AC, CAG, MWJ, MW, SMF) Department of Pediatrics The Congenital Heart Collaborative Rainbow Babies and Children\u2019s Hospital Case Western Reserve University School of Medicine Cleveland Ohio USA"},{"name":"Brecksville\u2010Broadview Heights High School (AC) Broadview Heights Ohio USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Caitlyn A.","family":"Gillespie","sequence":"additional","affiliation":[{"name":"From the Division of Pediatric Cardiology (SJ, JPS, GHK, MMS, AC, CAG, MWJ, MW, SMF) Department of Pediatrics The Congenital Heart Collaborative Rainbow Babies and Children\u2019s Hospital Case Western Reserve University School of Medicine Cleveland Ohio USA"},{"name":"Fisk University (CAG) Nashville Tennessee USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew M.","family":"Rollins","sequence":"additional","affiliation":[{"name":"Department of Biomedical Engineering (SJ, MMS, AMR, MWJ) School of Engineering Case Western Reserve University Cleveland Ohio 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