| Principal Investigator: |
Norman Salem, Jr, PhD
(NN, NIAAA) |
| Lab staff: |
Nahed Mohamed H K Abdalla, PhD
(NN, NIAAA) John Douglas Doherty, PhD (NN, NIAAA) Irina M Fedorova, PhD (NN, NIAAA) Sun-young Lim, PhD (NN, NIAAA) James D Loewke, BS (NN, NIAAA) Sharon Majchrzak, BS (NN, NIAAA) Athar Masood, PhD (NN, NIAAA) Vietnam Nguyen (NN, NIAAA) Alla Polozova, PhD (NN, NIAAA) Samit Shah (NN, NIAAA) Ken D Stark, PhD (NN, NIAAA) Ali Syed (NN, NIAAA) |
| NIH Collaborators: |
Hee-Yong Kim, PhD
(MS, NIAAA) Burton J Litman, PhD (FS, NIAAA) Drake C Mitchell, PhD (FS, NIAAA) |
| Extramural Collaborators: |
Greg M Cole, PhD (Department of Neurology, UCLA) John Hannagan, PhD (Fetal Alcohol Research Center, Wayne State University) Junji Hoshiba, PhD (Animal Center for Medical Research, Okayama University Medical School) Toru Moriguchi, PhD (Wakunaga Pharmaceutical) Robert J Sokol, MD (Fetal Alcohol Research Center, Wayne State University) Bruce Watkins, PhD (Purdue University) |
| from October 01, 2004 to September 30, 2005 | |
| Human subject research: |
Human Tissues, Fluids, Cells, etc. Human Subjects |
| Total Staff Years: | 5.58 |
| Keywords: | neurosciences, fatty acids, nutritional disorders, prevention strategies, fetal alcohol exposure, docosahexaenoic acid, arachidonic acid, n-3 fatty acid deficiency, |
| Summary: | 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 (DPAn-6, 22:5n-6) decreased postpartum while their respective metabolic precursors, eicosapentaenoic acid (EPA, 20:5n-3) and arachidonic acid (AA, 20:4n-6) increased. Similar results were found in erythrocytes. These observations may indicate increased DHA and DPAn-6 synthesis from EPA and AA during pregnancy. Dietary intake of DHA throughout the study was estimated at 68 +/- 75 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 (< 4.5 oz/d) and Heavy (n = 32, * 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 µg 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. In another major line of research, a model of DHA deficiency was created in order to characterize the loss in nervous system function as well as to investigate the reversibility of function when DHA concentration is restored. A novel application to the field of essential fatty acid biology was made with the introduction of olfactory-based learning and memory-related tasks for brain function assessment and these findings were recently published. A study was carried out to determine whether lead was more neurotoxic when combined with low brain DHA status. The poorer acquisition of an olfactory discrimination in lead exposed rats appeared to be better when brain DHA levels were supported. Lead exposure during lactation also increased liver but not brain levels of AA and DHA. However, no DHA protection could be observed in lead exposed rats on spatial tasks or in olfactory-cued reversal learning. Analysis of the fatty acids in various tissues in the dmas and pups indicated that Pb exposure led to the loss of fatty acids, and non-essential fatty acids were preferentially lost. The often repeated clim in the literature that AA and DHA concnetrations are decreased by Pb exposure were demonstarted to be incorrect as they were only decreased on a percentage basis. A developmental study of rat brain and retina indicated that there was not a reciprocal replacement of DHA with the n-6 polyunsaturate, DPAn-6 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. Great progress was made in the successful rearing of pups from the second day of life using feeding bottles developed by Hoshiba. Animals were raised on n-3 supplemented or deficient rat milks to adulthood and tested for spatial task performance. 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 DPAn-6 was compared to DHA feeding for the first 10 weeks of life. The DPAn-6 feeding led to no difference in brain fatty acyl composition relative to an LA reference. In both of these cases though, the level of DHA had fallen appreciably in this first generation model. Associated with this loss in brain DHA was a loss in spatial task performance but no changes in electroretinographic parameters were observed. This experiment conclusively demonstrates that the nervous sytem has a requirement for the 22-carbon n-3 highly unsaturated fatty acids for optimal function. The AR model has now been extended to mice with some initial success. Significant progress has been made in the development of a high throughput method for measurement of fatty acid methyl esters. Fast GC for the analysis of fatty acid methyl esters has been estaqblished and splitless-fast GC injection techniques are being developed for microanalysis of plasma and CSF. A new procedure for the transmethylation of lipids has been developed specifically for adaptation to a robotic system for automation. The fast GC technique when combined with automation of fatty acid extraction and methylation as well as data management will allow for the determination of fatty acid compositions in large clinical trials and for population analysis. progress has been made in semi-automated peak identification and insertion into spreadsheets from the GC computer. |
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| Publications generated by this research: |
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