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 information is collected from the mothers in order to ascertain whether alcohol affects food selection or has a more direct metabolic effect in mediating potential losses in blood stream essential fats. In participants not reporting alcohol intake during pregnancy, total DHA in the circulating plasma was similar at gestation and delivery, but was significantly lower at three months postpartum. The relative weight percentage of DHA and docosapentaenoic acid n-6 (DPAn6, 22:5n6) decreased postpartum while their respective metabolic precursors, eicosapentaenoic acid (EPA, 20:5n3) and arachidonic acid (AA, 20:4n6) increased. Similar results were found in erythrocytes. These observations may indicate increased DHA and DPAn6 synthesis from EPA and AA during pregnancy. 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 FASD drinking and may contribute to the mechanism(s) of alcohol-related neurodevelopmental disorders.? ? DHA and AA content in the arterial umbilical vessel wall was ~14% and ~10% higher in the Moderate (less than 4.5 oz/d) and Heavy (n = 32, greater than 4.5 oz/d) absolute alcohol per drinking day groups, respectively, than in Abstainers. Alcohol intake was positively correlated to both DHA and AA concentrations in the arterial vessel wall, but not in the venous wall. Maternal plasma DHA was positively correlated with both umbilical arteries and vein DHA, but there were no significant correlations for AA between maternal plasma and either umbilical vessel. Alcohol intake during pregnancy is associated with altered DHA and AA status in fetal tissues and may be a result of a direct influence of alcohol on fetal metabolism. Dietary folate and markers of alcohol consumption were positively associated, while exposure to smoke was negatively associated with plasma 5-methyl-tetrahydrofolic acid (5-MTHFA). More than half of the participants in this population failed to meet the recommended dietary allowance for dietary folate equivalents of 600 ?g per day during pregnancy and active/passive smoke exposure in this population may further compromise their folate status. Concentrations of 5-MTHFA in infant venous plasma were similar to infant arterial samples but were significantly different (~29% higher) than maternal plasma 5-MTHFA. 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.? ? 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. In another line of inquiry indicated a reduction in prepulse inhibition of the acoustic startle response in n-3 deficient mice. 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.? ? A developmental study of rat brain and retina indicated that there was not a reciprocal replacement of DHA with the n-6 polyunsaturate, DPAn6 during the brain growth period, as has been the dogma for adults. At 10 or 20 postnatal days there was a significant loss of 22-C HUFAs when safflower oil was fed with respect to safflower oil plus DHA. This was most pronounced in the cerebellum of the brain areas examined likely due to the fact that this area undergoes more rapid growth in the postnatal period. Non-reciprocal replacement of retinal DHA extended further into the young adult period.? ? A methodological development that should facilitate 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 procedure was 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 15 minutes. A program has been developed to process GC data for peak assignment and quantification. Large clinical studies will be undertaken in the coming year with this system.

National Institute of Health (NIH)
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Intramural Research (Z01)
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Alcohol Abuse and Alcoholism
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Golding, Jean; Northstone, Kate; Emmett, Pauline et al. (2012) Do ?-3 or other fatty acids influence the development of 'growing pains'? A prebirth cohort study. BMJ Open 2:
Hibbeln, Joseph R; Davis, John M (2009) Considerations regarding neuropsychiatric nutritional requirements for intakes of omega-3 highly unsaturated fatty acids. Prostaglandins Leukot Essent Fatty Acids 81:179-86
Brownawell, Amy M; Harris, William S; Hibbeln, Joseph R et al. (2009) Assessing the environment for regulatory change for eicosapentaenoic acid and docosahexaenoic acid nutrition labeling. Nutr Rev 67:391-7
Fedorova, Irina; Alvheim, Anita R; Hussein, Nahed et al. (2009) Deficit in prepulse inhibition in mice caused by dietary n-3 fatty acid deficiency. Behav Neurosci 123:1218-25
Pawlosky, Robert J; Hibbeln, Joseph R; Herion, David et al. (2009) Compartmental analysis of plasma and liver n-3 essential fatty acids in alcohol-dependent men during withdrawal. J Lipid Res 50:154-61
Masood, M Athar; Salem Jr, Norman (2008) High-throughput analysis of plasma fatty acid methyl esters employing robotic transesterification and fast gas chromatography. Lipids 43:171-80
Stark, Ken D; Lim, Sun-Young; Salem Jr, Norman (2007) Docosahexaenoic acid and n-6 docosapentaenoic acid supplementation alter rat skeletal muscle fatty acid composition. Lipids Health Dis 6:13
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Lin, Yu Hong; Salem Jr, Norman (2007) Whole body distribution of deuterated linoleic and alpha-linolenic acids and their metabolites in the rat. J Lipid Res 48:2709-24
Brown, Amira K; George, David T; Fujita, Masahiro et al. (2007) PET [11C]DASB imaging of serotonin transporters in patients with alcoholism. Alcohol Clin Exp Res 31:28-32

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