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.项目总结 尽管多产的营销活动解释了怀孕期间饮酒的危险， 美国胎儿酒精谱系障碍(FASD)的患病率为2%-5%，高于 自闭症谱系障碍的比率。不管是因为一个女人没有意识到怀孕， 对风险一无所知、对风险不屑一顾或无法戒酒的女性在怀孕期间确实饮酒，而且 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是必不可少的，而积极饮酒的人通常缺乏这种营养。 在动物模型中，一种名为胆碱的营养素已被证明可以改善胎儿酒精暴露的影响。 转化到临床上是有希望的，但科学家们报告的结果参差不齐或有限。重要的是，对于每个 连续怀孕，DHA储存会耗尽，每一次连续怀孕，FASD的风险 增加。因此，母体DHA缺乏可能与FASD有关。事实上，DHA和胆碱是共同作用的 将DHA输送到大脑，以支持大脑功能。这种协同活动进一步得到加强，因为 添加尿苷。为了探索这一协同假说，我们将测试一种天然的治疗性产前避孕药。 它含有DHA、胆碱和尿苷，很容易在临床前移植到临床--鸡蛋-- 学习。我们的中心假设是DHA、胆碱和尿苷在鸡蛋中的协同活性将缓解 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 实验将是一项研究计划的第一步，旨在建立 协同营养改善产前酒精暴露对胎儿大脑发育的影响。 在这项拟议的工作中，怀孕的水母将在妊娠第5天至第20天期间饲喂实验饲料。 在2(产前暴露：酒精，配对喂养对照)×5(饮食：鸡蛋，胆碱，DHA，尿苷，未添加)中 设计。随后的幼崽将被观察早期的身体状况(耳朵张开，眼睛张开，毛皮出现)。 以及在一系列测试中的行为(例如，自我扶正、悬崖回避)发展。将对组进行比较 在离散变量的卡方分析中取得成功的那一天。从PD45开始，随机子集(一名男性 每窝一只雌性)将在经典的Morris水迷宫空间和工作中接受培训和测试 记忆力测试。将对数据进行组间方差分析。将对脑组织进行检测 磷脂和尿苷含量以及突触蛋白将用免疫印迹进行定量。我们预测， 与不添加鸡蛋的组相比，添加鸡蛋的组的乙醇效应会降低。 这项实验的结果将为不能戒酒的孕妇提供干预措施。 在怀孕期间饮酒以及他们的高危胎儿。如果我们的临床前工作有希望，我们 将把这项工作翻译到诊所，与美国和加拿大的支持计划合作，为 因此，改善其未出生子女的结局和今后的生活。