Nutritional Effects On Essential Fatty Acid Composition

营养对必需脂肪酸组成的影响

基本信息

批准号：
7732109
负责人：
Joseph Hibbeln
金额：
$ 84.66万
依托单位：
NATIONAL INSTITUTE ON ALCOHOL ABUSE AND ALCOHOLISM
依托单位国家：
美国
项目类别：
财政年份：
资助国家：
美国
起止时间：
至
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/7732109
关键词：
7 year old Adopted Adult Aging Alcohol abuse Alcohol consumption Alcohol-Related Neurodevelopmental Disorder Animal Feed Animals Anxiety Arachidonic Acids Be++ element Behavioral Beryllium Biological Assay Biological Availability Biological Process Bottle feeding Brain Carbon Clinical Research Collaborations Condition Cues Custom Daily Data Development Diet Diet Habits Dietary Alcohol Dietary Supplementation Dietary intake Disease model Docosahexaenoate Docosahexaenoic Acids Dose Erythrocytes Essential Fatty Acids Esters Fatty Acids Female Fetal Alcohol Syndrome Folate Food Selections Head Health Benefit Individual Infant Intake Isotopes Lead Life Light Measures Memory Mercury Metabolism Milk Modeling Mothers Motor Activity Mus National Health and Nutrition Examination Survey Nervous System Physiology Nervous system structure Neurophysiology - biologic function Neurotoxins Newborn Infant Noise Nutrient Nutritional Nutritional Study Omega-3 Fatty Acids Oral Organ Pathology Physiological Placenta Plasma Polyunsaturated Fatty Acids Pregnancy Procedures Process Rate Rattus Relative (related person)Research Research Personnel Reversal Learning Risk Robotics Sampling Short-Term Memory Smoker Smoking Supplementation System Task Performances Techniques Testing Time Tissues Trace metal Umbilical cord structure Universities Unsaturated Fatty Acids Upper arm Venous Visit Vitamins Week Work alcoholism/alcohol abuse alpha-Linolenic Acid binge drinking body system cohort day density drinking fatty acid metabolism feeding fetal follow-up functional loss in vivo interest latent nuclear antigen male maternal cigarette smoking memory retention men metabolomics neurodevelopment non-smoker prenatal prepulse inhibition prevent problem drinker programs pup research study transmethylation

项目摘要

Our past studies as well as those of others have indicated that alcohol abuse leads to a loss of docosahexaenoate (DHA), the major polyunsaturate in the nervous system. Nutritional inadequacies, particularly during early development, may also lead to such losses in this essential fatty acid. In following up this work, it is important to establish what losses in physiological functions are caused by the loss of DHA in various organ systems. In a collaboration with several investigators at Wayne State University, the relationships of alcohol intake during pregnancy is related to the mother's and newborn infant's essential fatty acid and vitamin status. Dietary intake of DHA throughout the study was estimated at 68 mg/day and might not support optimal fetal DHA accretion and subsequent neural development. The proportion of drinking days at the first prenatal visit is associated with decreased DHA in plasma and erythrocytes throughout the study and is the strongest at 24 weeks of gestation. In daily drinkers, high intakes of alcohol are associated with decreased DHA and arachidonic acid (AA) concentrations in plasma. The present findings indicate that maternal DHA deficiency is associated with high risk for fetal alcohol syndrome and may contribute to the mechanism(s) of alcohol-related neurodevelopmental disorders. Maternal folate was positively correlated with alcohol intake per drinking day, while infant venous plasma folate was negatively correlated with maternal smoking. It appears that concentrative transport of folate across the placenta occurs during pregnancy that smoking may negatively impact. Essential fatty acid metabolism was studied in male and female adults, both smokers and non-smokers, as a reference point for smoking alcoholics. Metabolism of D5-18:2n-6 and D5-18:3n-3 was studied in vivo after a single oral dose of the isotope mixture. Our results indicated that female smokers had a two-fold greater percent of the dose in their plasma, and a higher fractional rate for formation of D5-22:6n-3 from D5-22:5n-3 compared with non-smokers. Male smokers had elevated levels of total plasma n-3 fatty acids, more rapid turn over of 18:3n-3, a disappearance rate for D5-20:5n-3 that was both delayed and slower, and a greater percentage of D5-20:5n-3 that was directed towards D5-22:5n-3 formation relative to non-smokers. Smoking generally increased the bioavailability of plasma n-3 fatty acids, accelerated fractional synthetic rates, and increased the percent formation of some long chain n-3 polyunsaturated fatty acids. The relationship of dietary alcohol and essential fatty acid intakes were studied in 4168 adults taken from the cross-sectional National Health and Nutrition Examination Survey 2001-2002. Our results indicated that among men, decreased nutrient densities of saturated, monounsaturated, polyunsaturated, linoleic and alpha-linolenic acid were associated with alcohol consumption. Binge drinking men had significantly decreased intakes of saturated, monounsaturated, polyunsaturated and linoleic, alpha-linolenic, eicosapentaenoic and docosahexaenoic acids. Thus it appears that drinking alcohol lowers highly unsaturated fatty acids in tissues thru altered fatty acid metabolism but also thru altered food selection and dietary habits. Great progress was made in the successful rearing of pups from the second day of life using feeding bottles developed by Prof. J. Hoshiba. Rats and mice were raised on n-3 supplemeented or deficient milks to adulthood and tested in several behavioral tasks. There was no difference in motor activity or in the plus maze but escape latency and memory retention were poorer in the n-3 deficient rats. This technique now makes possible many experiments where control of individual fatty acids or other nutrients in the diet and thus in tissue composition is required. In the first such application, a major expperiment was performed where DPAn6 was compared to DHA feeding for the first 10 weeks of life. It was shown that the DPAn6-fed rats had the same deficit in spatial task performance as did the LA-fed group, i.e., that DPAn6 conferred none of the benefit that adding DHA did. Mice were also raised on similar diets by artificial rearing and a 50% loss of brain DHA was observed at adulthood in the n-3 deficient group. In the open field test, habituation was slower and decreases in the general level of activity were observed in the n-3 deficient group. Under usual conditions, no differences could be seen in the plus maze between these dietary fgroups. However, under stressful conditions, when a bright light and a loud noise were given during the testing, the n-3 deficient group spent less time in the open arms and made fewer entries and had fewer head dips, indicating a higher level of anxiety. The low DHA mice also performed less well in another spatial task, the reference memory version of the Barnes maze, but there were no differences observed in either the cued or the working memory versions. These experiments have established that the nervous sytem has a requirement for the 22-carbon n-3 highly unsaturated fatty acids for optimal function. In another major line of research, a two generational model of DHA deficiency in rats was used in order to characterize the loss in nervous system function. A deficit in spatial task peformance was observed in n-3 deficient rats using the Barnes circular maze along with a 58% loss of brain DHA. No differnces were observed in memory retention for this task but the n-3 adequate rats perfomed better in a reversal learning task. There was no difference in locomotor activity but slower habituation was observed in the open field apparatus. No differences between groups were observed in the plus maze. This two generational dietary model has been employed to produce mice on four different diets varying LNA and DHA so that four different levels of brain DHA are obtained. At adulthood, the animals were tested for prepulse inhibition (PPI), a measure of neuromotor gating. It was observed that four different levels of PPI was obtained in the four dietary groups with the most PPI being obtained in those with the highest DHA level, ie., those fed preformed DHA. A significantly lower PPI was observed in animals fed a high level of LNA but without preformed DHA even though it resulted in only about a 10% loss of brain DHA. This was the first experiment where it could be shown that there was a brain functional loss in animals fed LNA but without preformed DHA. A methodological development has been completed facilitating lipidomic and metabolomic approaches has been made with regard to high throughput fatty acid analysis. Labor intensive transmethylation procedures were simplified and then adopted to robotics. A robotic program and procedures, together with custom hardware have been developed and validated for plasma samples that can potentially produce 400 methyl ester samples per day. GCs have been converted to fast GC mode and analyses can now be completed within about 15 minutes. A program has been developed to process GC data for peak assignment and quantification. Large clinical studies are currently underway with this system. Umbilical cord samples from 2,500 subjects in the ALSPAC longitudinal cohort will be assayed. Additionally, 4,500 samples from 7 year olds will be assayed. In this cohort, trace metal analyses for methyl mercury and other elements is progressing. The benificial levels of essential fatty acids will be compared to the risks of these neurotoxicants.

我们过去的研究以及其他研究表明，酗酒导致神经系统中主要多不饱和的二十六烯酸酯（DHA）丧失。营养不足，特别是在早期发育期间，也可能导致这种必需脂肪酸的损失。在跟踪这项工作时，重要的是确定生理功能的损失是由各种器官系统中DHA丢失造成的。在与韦恩州立大学的几位研究人员的合作中，怀孕期间的酒精摄入关系与母亲和新生婴儿的必需脂肪酸和维生素状况有关。在整个研究中，DHA的饮食摄入量为68 mg/天，可能不支持最佳的胎儿DHA积聚和随后的神经发育。在整个研究过程中，血浆和红细胞的DHA降低与DHA的降低有关，在妊娠24周时是最强的DHA。在日常饮酒者中，高摄入量与血浆中的DHA和花生四烯酸（AA）浓度降低有关。目前的发现表明，母体DHA缺乏症与胎儿酒精综合征的高风险有关，并可能有助于与酒精相关的神经发育障碍的机制。母体叶酸与每天饮酒的酒精摄入呈正相关，而婴儿静脉血浆叶酸与孕妇吸烟呈负相关。看来叶酸在胎盘上的浓缩转运在怀孕期间发生，吸烟可能会对吸烟产生负面影响。在吸烟者和非吸烟者中，研究了必需的脂肪酸代谢，作为吸烟酗酒者的参考点。单一口服同位素混合物后，在体内研究了D5-18：2N-6和D5-18：3N-3的代谢。我们的结果表明，与非吸烟者相比，雌性吸烟者的血浆中剂量的百分之二高，而从D5-22：5N-3组成D5-22：6N-3的分数率更高。雄性吸烟者的总血浆N-3脂肪酸水平升高，更快地转移了18：3n-3，D5-20：5N-3的消失率既延迟又慢，而D5-20：5N-3的百分比更高，而D5-22：5N-3的比例是D5-22：5N-3的形成。吸烟通常增加了血浆N-3脂肪酸的生物利用度，加速的分数合成速率，并增加了一些长链N-3多不饱和脂肪酸的形成百分比。在2001 - 2002年的横截面国家健康和营养检查调查中，研究了4168名成年人，研究了饮食中酒精和必需脂肪酸摄入量的关系。我们的结果表明，在男性中，饱和，单不饱和，多不饱和，亚油酸和α-烯酚酸的营养密度降低与饮酒有关。暴饮暴食的男性的饱和，单不饱和，多不饱和和亚油果，α-中苯酚，二糖蛋白烯酸酯和二十二碳六烯酸的摄入量显着降低。因此，似乎饮酒会通过改变脂肪酸代谢的组织中的组织中高度不饱和的脂肪酸，但也通过改变食物选择和饮食习惯。使用J. Hoshiba教授开发的喂养瓶从生命的第二天开始成功饲养幼崽，取得了巨大进展。大鼠和小鼠在成年后的N-3补充或缺乏奶中饲养，并在几个行为任务中进行了测试。运动活动或加人迷宫没有差异，但是逃生潜伏期和记忆力保留率在N-3不足的大鼠中较差。现在，该技术使许多实验可以控制饮食中单个脂肪酸或其他营养素的控制，因此需要在组织组成中。在第一个这样的应用程序中，进行了一个主要的女性，其中将DPAN6与DHA喂食的前10周进行了比较。结果表明，DPAN6喂养的大鼠在空间任务性能方面的缺陷与la-fed群体相同，即DPAN6赋予了添加DHA所带来的任何好处。还通过人工饲养在类似的饮食上饲养小鼠，在N-3缺陷组的成年期间观察到50％的脑DHA损失。在开放式测试中，习惯较慢，在N-3缺陷组中观察到一般活性水平的降低。在通常的条件下，在这些饮食中的Froups之间的普及迷宫中看不到差异。但是，在压力条件下，当测试期间发出明亮的光线和大声的噪音时，N-3缺陷组在张开的手臂上花费了更少的时间，较少的参赛作品，头部倾斜较少，表明焦虑量更高。低DHA小鼠在另一个空间任务（Barnes Maze的参考记忆版本）中表现不佳，但是在提示或工作记忆版本中没有观察到的差异。这些实验已经确定，神经系统对22-碳N-3高度不饱和脂肪酸的需求需要最佳功能。在另一项主要研究中，使用了大鼠DHA缺乏症的两个世代模型，以表征神经系统功能的损失。使用Barnes圆形迷宫以及脑DHA损失58％，在N-3缺陷大鼠中观察到空间任务的缺陷。对于此任务的记忆保留率没有观察到不同的差异，但是N-3的足够大鼠在逆转学习任务中表现得更好。运动活性没有差异，但是在开放式设备中观察到较慢的习惯。在加号迷宫中没有观察到群体之间的差异。这两个世代的饮食模型已被用来在不同的LNA和DHA的四种不同饮食上产生小鼠，从而获得了四个不同水平的脑DHA。成年后，对动物进行了预硫抑制（PPI）的测试，这是神经运动门控的量度。据观察，在四个饮食组中获得了四个不同水平的PPI，其中PPI在DHA水平最高的人中获得的PPI最多，即喂养预先形成的DHA的PPI。在喂养高水平的LNA的动物中观察到PPI明显较低，但没有预先形成的DHA，即使它仅导致脑DHA损失约10％。这是第一个可以证明动物喂养LNA但没有预先形成的DHA的大脑功能丧失的实验。在高吞吐量脂肪酸分析方面，已经完成了一种方法论发展，促进了脂质组和代谢组方法。劳动密集型跨甲基化程序被简化，然后采用给机器人技术。已经开发了一个机器人程序和程序，以及定制硬件，并为血浆样品进行了验证，这些样品每天可能会产生400甲基样品。 GC已转换为快速GC模式，现在可以在大约15分钟内完成分析。已经开发了一个程序来处理GC数据以进行峰值分配和量化。该系统目前正在进行大型临床研究。将分析来自ALSPAC纵向队列中2500名受试者的脐带样品。此外，将分析来自7岁儿童的4,500个样本。在该队列中，轨迹金属分析的甲基汞和其他元素正在进行中。将基本脂肪酸的苯基水平与这些神经毒性的风险进行比较。

项目成果

期刊论文数量（51）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Validation of an equation predicting highly unsaturated fatty acid (HUFA) compositions of human blood fractions from dietary intakes of both HUFAs and their precursors.

验证从膳食摄入的 HUFA 及其前体中预测人类血液部分的高度不饱和脂肪酸 (HUFA) 组成的方程。

DOI：
10.1016/j.plefa.2017.03.005
发表时间：
2018
期刊：
Prostaglandins, leukotrienes, and essential fatty acids
影响因子：
0
作者：
Strandjord,SarahE;Lands,Bill;Hibbeln,JosephR
通讯作者：
Hibbeln,JosephR

Haploinsufficiency is not the key mechanism of pathogenesis in a heterozygous Elovl4 knockout mouse model of STGD3 disease.

单倍体不足并不是 STGD3 疾病杂合 Elovl4 敲除小鼠模型发病机制的关键机制。

DOI：
10.1167/iovs.05-1527
发表时间：
2006
期刊：
Investigative ophthalmology & visual science
影响因子：
4.4
作者：
Raz-Prag,Dorit;Ayyagari,Radha;Fariss,RobertN;Mandal,MdNawajesA;Vasireddy,Vidyullatha;Majchrzak,Sharon;Webber,AndreaL;Bush,RonaldA;SalemJr,Norman;Petrukhin,Konstantin;Sieving,PaulA
通讯作者：
Sieving,PaulA

Workshop on the Essentiality of and Recommended Dietary Intakes for Omega-6 and Omega-3 Fatty Acids.

关于 Omega-6 和 Omega-3 脂肪酸的重要性和建议膳食摄入量的研讨会。