Department of Pediatrics, Congenital Heart Collaborative, UH Rainbow Babies and Children's Hospital, School of Medicine, Case Western Reserve University, Cleveland, Ohio.
Department of Biomedical Engineering, Case Western Reserve University, Cleveland, Ohio.
Alcohol Clin Exp Res. 2017 Nov;41(11):1917-1927. doi: 10.1111/acer.13495. Epub 2017 Oct 11.
Despite decades of public education about dire consequences of prenatal alcohol exposure (PAE), 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 PAE, but effects on heart development are unknown.
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 (EtOH) 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 EtOH or cotreated with betaine.
Compared to EtOH-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 atrioventricular (AV) valves, and hypertrophic ventricles. Furthermore, betaine cotreatment brought measurements of great vessel diameters, interventricular septum 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 EtOH exposure and normalized by co-administration with betaine.
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 have implications for prenatal nutrition policies, especially for women who may not be responsive to folate supplementation.
尽管几十年来公众一直接受关于产前酒精暴露（PAE）严重后果的教育，但怀孕期间饮酒仍很普遍。高达 40%的在妊娠期间暴露于酒精并被诊断出患有胎儿酒精谱系障碍的活产婴儿患有可能危及生命的先天性心脏病。在动物模型中，甜菜碱作为一种甲基供体，存在于麦麸、藜麦、甜菜和菠菜等食物中，可改善与 PAE 相关的神经行为缺陷，但对心脏发育的影响尚不清楚。
我们之前在禽类胚胎中模拟了妊娠早期的一次 binge drinking 事件。在这里，我们研究了甜菜碱是否可以预防酒精对心脏发育的不良影响。用乙醇（EtOH）和含有最佳剂量甜菜碱（5μM）的 EtOH 暴露胚胎，并在晚期发育阶段进行分析。使用光学相干断层扫描快速分析和量化心脏形态参数。用免疫荧光染色检测胚胎中 5-甲基胞嘧啶的方法检测早期的 DNA 甲基化，这些胚胎用 EtOH 处理或与甜菜碱共同处理。
与 EtOH 暴露的胚胎相比，补充甜菜碱的胚胎晚期存活率更高，与单独暴露于酒精相比，头部和身体的严重畸形缺陷更少。甜菜碱还降低了晚期心脏缺陷的发生率，如血管缺失、房室瓣异常和心室肥厚。此外，甜菜碱共同处理使补充甜菜碱的胚胎的大血管直径、室间隔厚度和房室瓣叶容积的测量值接近对照值。早期的 5-甲基胞嘧啶染色显示，DNA 甲基化水平因 EtOH 暴露而降低，并通过与甜菜碱共同给药而恢复正常。
这是第一项证明甲基供体甜菜碱在缓解与 PAE 相关的心脏缺陷方面有效性的研究。这些发现强调了低浓度甜菜碱剂量在减轻 PAE 引起的出生缺陷方面的治疗潜力，对产前营养政策具有重要意义，特别是对可能对叶酸补充不敏感的妇女。
