Department of Psychology, University of South Carolina, Columbia, SC 29208, USA.
Alcohol Clin Exp Res. 2012 Oct;36(10):1701-9. doi: 10.1111/j.1530-0277.2012.01784.x. Epub 2012 Apr 17.
Some of the most frequent deficits seen in children with fetal alcohol spectrum disorders (FASD) and in animal models of FASD are spatial memory impairments and impaired executive functioning, which are likely related to alcohol-induced alterations of the hippocampus and prefrontal cortex (PFC), respectively. Choline, a nutrient supplement, has been shown in a rat model to ameliorate some of alcohol's teratogenic effects, and this effect may be mediated through choline's effects on DNA methylation.
Alcohol was given by intragastric intubation to rat pups during the neonatal period (postnatal days 2 to 10) (ET group), which is equivalent to the third trimester in humans and a period of heightened vulnerability of the brain to alcohol exposure. Control groups included an intubated control group given the intubation procedure without alcohol (IC) and a nontreated control group (NC). Choline or saline was administered subcutaneously to each subject from postnatal days 2 to 20. On postnatal day 21, the brains of the subjects were removed and assayed for global DNA methylation patterning as measured by chemiluminescence using the cpGlobal assay in both the hippocampal region and PFC.
Alcohol exposure caused hypermethylation in the hippocampus and PFC, which was significantly reduced after choline supplementation. In contrast, control animals showed increases in DNA methylation in both regions after choline supplementation, suggesting that choline supplementation has different effects depending upon the initial state of the brain.
This study is the first to show changes in global DNA methylation of the hippocampal region and PFC after neonatal alcohol exposure. Choline supplementation impacts global DNA methylation in these 2 brain regions in alcohol-exposed and control animals in a differential manner. The current findings suggest that both alcohol and choline have substantial impact on the epigenome in the PFC and hippocampus, and future studies will be needed to describe which gene families are impacted in such a way that function of the nervous system is changed.
在胎儿酒精谱系障碍（FASD）儿童和 FASD 动物模型中，最常见的缺陷是空间记忆损伤和执行功能障碍，这可能分别与酒精对海马体和前额叶皮层（PFC）的影响有关。胆碱是一种营养补充剂，在大鼠模型中已被证明可以改善酒精的一些致畸作用，这种作用可能是通过胆碱对 DNA 甲基化的影响介导的。
在新生期（出生后第 2 至 10 天）通过胃内插管给大鼠幼仔灌酒（ET 组），这相当于人类的第三个三个月，也是大脑对酒精暴露高度敏感的时期。对照组包括接受插管但不给酒精的插管对照组（IC）和未治疗的对照组（NC）。从出生后第 2 天到第 20 天，每只动物都通过皮下注射给予胆碱或生理盐水。在出生后第 21 天，取出动物的大脑，并用 cpGlobal 测定法通过化学发光测定海马区和 PFC 中的整体 DNA 甲基化模式。
酒精暴露导致海马体和 PFC 中的过度甲基化，胆碱补充后显著减少。相比之下，在胆碱补充后，对照动物在这两个区域的 DNA 甲基化增加，这表明胆碱补充具有不同的效果，这取决于大脑的初始状态。
这项研究首次显示了新生期酒精暴露后海马体和 PFC 整体 DNA 甲基化的变化。胆碱补充以不同的方式影响暴露于酒精和未暴露于酒精的动物的这两个脑区的整体 DNA 甲基化。目前的研究结果表明，酒精和胆碱都对 PFC 和海马体的表观基因组有重大影响，未来的研究将需要描述哪些基因家族受到影响，从而改变神经系统的功能。
