Synergy of nutrients and the prevention of Fetal Alcohol Spectrum Disorders (FASD): effects on brain development and function in a rat model.

7.项目摘要 尽管大量的营销活动解释了怀孕期间饮酒的危险， 在美国，胎儿酒精谱系障碍（FASD）的患病率为2- 5%，高于 自闭症谱系障碍的发病率无论是因为一个女人不知道怀孕， 妇女在怀孕期间确实饮酒，但她们不知道或忽视这种风险，或无法戒酒， 因此，我们必须找到一种方法来预防FASD。 最佳的营养对于发育中的胎儿大脑至关重要，并且通常缺乏活跃的饮酒者。 一种营养素，胆碱，已被证明可以改善动物模型中胎儿酒精暴露的影响。 转化到临床显示出希望，但科学家报告混合或有限的结果。重要的是，每 连续怀孕，DHA储存变得耗尽，并且随着每次连续怀孕，FASD的风险 增大因此，母亲DHA缺乏可能与FASD有关。事实上，DHA和胆碱一起工作， 将DHA输送到大脑，支持大脑功能。这种协同活性通过以下进一步增强： 添加尿苷。为了探索这种协同作用的假设，我们将测试一种天然的治疗性产前预防药物， 含有DHA，胆碱和尿苷，很容易转化为临床-鸡蛋-在临床前 study.我们的中心假设是，鸡蛋中DHA、胆碱和尿苷的协同作用将减轻 胎儿酒精暴露对海马和额叶发育的影响。重要的是这些 实验将是一项旨在建立机制的研究计划中的第一项， 协同营养素改善产前酒精暴露对胎儿脑发育的影响。 在拟定工作中，妊娠母鼠将从妊娠第5天至第20天饲喂实验饲料 在2（产前暴露：乙醇，成对喂养对照）× 5（饮食：鸡蛋，胆碱，DHA，尿苷，未补充）中 设计将观察后续幼仔的早期体格检查（耳朵张开、眼睛睁开、被毛外观） 和行为（例如，自扶正，悬崖回避）的发展，在一系列的测试。比较各组 在离散变量的卡方分析中取得成功的那一天。从PD 45开始，随机子集（1只雄性 每窝一只雌性）将在经典的莫里斯水迷宫空间和工作中接受训练和测试。 记忆测试将对数据进行组间方差分析。将对脑组织进行分析， 磷脂和尿苷含量以及突触蛋白将用免疫印迹定量。我们预测 与非蛋组相比，在蛋补充组中乙醇的作用将降低。 这项实验的结果将为无法禁欲的孕妇提供干预措施 在怀孕期间和胎儿处于危险中时饮酒。如果我们的临床前工作显示出希望， 将把这项工作转化为诊所，与美国和加拿大的支持项目合作，为 这是一个很好的方法，可以帮助他们的客户，从而改善他们未出生的孩子的结果和随后的生活。

7. PROJECT SUMMARY Despite prolific marketing campaigns explaining the dangers of consuming alcohol during pregnancy, the prevalence of Fetal Alcohol Spectrum Disorders (FASD) in the United States is 2-5%, which is higher than the rate of Autism Spectrum Disorders. Whether it is because a woman was unaware of the pregnancy, ignorant of the risk, dismissing of the risk, or unable to abstain, women do drink during pregnancy, and therefore, it is imperative that we find a way to prevent FASD. Optimal nutrition is essential for the developing fetal brain and is generally lacking in active drinkers. One nutrient, choline, has been shown to ameliorate the effects of fetal alcohol exposure in animal models. Translation to the clinic shows promise, but scientists report mixed or limited results. Importantly, with each successive pregnancy, DHA stores become depleted, and with each successive pregnancy, the risk of FASD increases. Thus, maternal DHA deficiency may be implicated in FASD. Indeed, DHA and choline work together to deliver DHA to the brain where it supports brain function. This synergistic activity is further enhanced by the addition of uridine. To explore this synergy hypothesis, we will test a natural therapeutic prenatal prophylactic that contains DHA, choline, and uridine and is easily translatable to the clinic - the chicken egg - in a preclinical study. Our central hypothesis is that the synergistic activity of DHA, choline, and uridine in egg will mitigate the effects of fetal alcohol exposure on the developing hippocampus and frontal lobes. Importantly, these experiments will be the first in a program of research designed to establish the mechanisms through which synergistic nutrients ameliorate the effect of prenatal alcohol exposure on fetal brain development. In the proposed work, pregnant dams will be fed experimental diets from gestational day GD5 to GD20 in a 2 (Prenatal Exposure: Ethanol, Pair-fed Control) X 5 (Diet: Egg, Choline, DHA, Uridine, Unsupplemented) design. Subsequent pups will be observed for early physical (ear unfurling, eye opening, appearance of fur) and behavioral (e.g., self-righting, cliff avoidance) development in a series of tests. Groups will be compared on day of success in a Chi-square analysis for discrete variables. Starting on PD45, random subsets (one male and one female per litter) will be trained and tested on a classic Morris Water Maze spatial and working memory tests. Data will be subjected to analyses of variance between groups. Brain tissue will be assayed for phospholipid and uridine content and synaptic proteins will be quantified with immunoblots. We predict that the ethanol effects will be reduced in the egg-supplemented groups compared to the non-egg groups. The results of this experiment will inform interventions for pregnant women who are unable to abstain from consuming alcohol during pregnancy and their at-risk fetuses. If our preclinical work shows promise, we will translate the work to the clinic, working with support programs in the US and Canada to provide the food to their clients and thereby, improve the outcomes and the subsequent lives of their unborn children.