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Previously, using a mouse model of FASD, we showed that prenatal alcohol exposure (PAE) directly impairs blood\u2013brain barrier (BBB) development by inducing excessive angiogenesis, altering TJ protein and glucose transporter expression, and modifying the endothelial secretome in the neonatal cerebral cortex. Here, we investigated whether ethanol\u2010induced effects on endothelial cells involve epigenetic reprogramming, specifically through alterations in DNA methylation profiles. Using human brain microcapillary endothelial cells (HBMECs) treated with ethanol, we observed reduced 5\u2010methylcytosine (5mC) labeling intensity and DNA methyltransferase (DNMT) activity, accompanied by changes in the levels of DNMT1, DNMT3a, DNMT3b, methyl\u2010CpG binding protein 2 (MeCP2), and vascular endothelial zinc finger 1 (VEZF1). These effects were associated with altered methylation levels at the promoters of BBB\u2010related genes, including\n                    <jats:italic>GLUT1<\/jats:italic>\n                    and\n                    <jats:italic>CLDN5<\/jats:italic>\n                    . Notably, ethanol\u2010induced hypomethylation persisted over a prolonged period, even after ethanol withdrawal in HBMEC cultures. Treatment with S\u2010adenosylmethionine (SAM) prevented ethanol\u2010induced hypomethylation in\u00a0vitro. In\u00a0vivo, PAE resulted in increased cortical vascular permeability along with persistent vascularization deficits. Together, our findings suggest that ethanol induces long\u2010lasting changes in endothelial cells that may compromise cerebral vasculature formation and function, with modulation of DNA methylation representing a potential molecular mechanism underlying these effects.\n                  <\/jats:p>\n                  <jats:p>\n                    <jats:boxed-text content-type=\"graphic\" position=\"anchor\">\n                      <jats:graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" mimetype=\"image\/png\" position=\"anchor\" specific-use=\"enlarged-web-image\" xlink:href=\"graphic\/jnc70375-gra-0001-m.png\">\n                        <jats:alt-text>image<\/jats:alt-text>\n                      <\/jats:graphic>\n                    <\/jats:boxed-text>\n                  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