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

营养素的协同作用和预防胎儿酒精谱系障碍 (FASD)：对大鼠模型大脑发育和功能的影响。

• 批准号: 10256641
• 负责人: Carol L Cheatham
• 金额: $ 18.47万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-10 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10256641
• 关键词: Adverse effects; Affect; Alcohols; Analysis of Variance; Animal Model; Animals; Appearance; Attenuated; Behavioral; Bilateral; Bioavailable; Biological Assay; Brain; Canada; Child; Choline; Client; Clinic; Cognitive; Consumption; Data; Development; Diagnosis; Diet; Dietary Intervention; Docosahexaenoic Acids; Ear; Eye; Face; Female; Fetal Alcohol Exposure; Fetal Alcohol Spectrum Disorder; Fetal alcohol effects; Fetus; Food; Goals; High Pressure Liquid Chromatography; Hippocampus (Brain); Human Milk; Infant Development; Intervention; Lecithin; Length; Liquid substance; Liver; Marketing; Measures; Medial; Modeling; National Institute of Diabetes and Digestive and Kidney Diseases; Neurologic Effect; Neurons; Nutrient; Obesity; Outcome; Phosphatidylserines; Phospholipids; Prefrontal Cortex; Pregnancy; Pregnant Women; Prevalence; Prevention; Proteins; Rattus; Reporting; Research; Research Design; Risk; Sampling; Scientist; Series; Short-Term Memory; Structure; Synapses; Synapsins; Testing; Therapeutic; Time; Training; Translating; Translations; United States; Uridine; Western Blotting; Woman; Work; alcohol abstinence; alcohol consumption during pregnancy; alcohol effect; alcohol exposure; attenuation; autism spectrum disorder; brain tissue; chicken egg; choline supplementation; cognitive ability; cognitive development; design; egg; executive function; experimental study; fetal; fetus at risk; flexibility; frontal lobe; improved; improved outcome; male; memory process; morris water maze; neurobehavioral; neuron development; novel strategies; nutrition; offspring; postnatal; postsynaptic; pre-clinical; preclinical study; pregnant; prenatal; prevent; programs; prophylactic; pup; spatial memory; success; synergism; unborn child

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.

7. 项目概要 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生率。无论是因为女性不知道自己怀孕了， 不了解风险、忽视风险或无法戒酒的妇女在怀孕期间确实饮酒，并且 因此，我们必须找到预防胎儿酒精谱系障碍（FASD）的方法。 最佳营养对于胎儿大脑的发育至关重要，而活跃饮酒者通常缺乏这种营养。 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。 临床转化显示出希望，但科学家报告的结果好坏参半或有限。重要的是，与每个 连续怀孕后，DHA 储备会耗尽，并且每次连续怀孕都会增加 FASD 的风险 增加。因此，母亲 DHA 缺乏可能与 FASD 有关。事实上，DHA 和胆碱协同作用 将 DHA 输送至大脑，支持大脑功能。这种协同活动进一步增强 添加尿苷。为了探索这种协同作用假设，我们将测试一种自然治疗性产前预防药物 含有 DHA、胆碱和尿苷，并且很容易在临床前转化为临床 - 鸡蛋 - 学习。我们的中心假设是鸡蛋中 DHA、胆碱和尿苷的协同活性将减轻 胎儿酒精暴露对发育中的海马体和额叶的影响。重要的是，这些 实验将是旨在建立机制的研究计划中的第一个 协同营养素可改善产前酒精暴露对胎儿大脑发育的影响。 在拟议的工作中，怀孕母鼠将在妊娠日 GD5 至 GD20 期间饲喂实验饲料 2（产前暴露：乙醇，配对喂养对照）X 5（饮食：鸡蛋、胆碱、DHA、尿苷，未补充） 设计。随后将观察幼崽的早期身体状况（耳朵展开、眼睛张开、皮毛出现） 以及一系列测试中的行为（例如，自我扶正、避免悬崖）发展。将进行分组比较 离散变量卡方分析成功之日。从 PD45 开始，随机子集（一名男性 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。数据将进行组间方差分析。脑组织将被检测 磷脂和尿苷含量以及突触蛋白将通过免疫印迹进行定量。我们预测 与不含鸡蛋的组相比，添加鸡蛋的组中乙醇的影响会减少。 该实验的结果将为无法戒烟的孕妇提供干预措施 怀孕期间饮酒及其胎儿有危险。如果我们的临床前工作显示出希望，我们 将把这项工作转化为诊所，与美国和加拿大的支持计划合作，为 他们的客户，从而改善未出生孩子的结果和随后的生活。