Building the Brain: Maternal and Infant Needs 

Blood HUFA supplies brain DHA
298 reports of blood weight percentages (wt.%) of omega-3 HUFA were grouped in four ranges: high, moderate, low, very low. Regions with high blood levels (>8% EPA+DHA) included Japan and Scandinavia. Very low blood levels (≤4%) were observed in North America, Central and South America, Europe, the Middle East, Southeast Asia, and Africa. The very low range of blood EPA+DHA may increase risk for chronic disease.  Stark KD, Van Elswyk ME, Higgins MR, Weatherford CA, Salem N Jr.  Global survey of the omega-3 fatty acids, docosahexaenoic acid and eicosapentaenoic acid in the blood stream of healthy adults.  Prog Lipid Res. 2016 Jul;63:132-52. doi: 10.1016/j.plipres.2016.05.001.   

The n-3 HUFA, docosahexaenoic acid (DHA; 22:6n-3) and eicosapentaenoic acid (EPA; 20:5n-3) provide multiple health benefits for heart, brain and eyes. However, their intake is low in Western countries. Intakes can be increased by supplements, such as fish oil, algal oil, or krill oil. This four-week study showed similar plasma and RBC levels of EPA + DHA were achieved across fish oil and krill oil products when matched for dose, EPA, and DHA concentrations, indicating comparable oral bioavailability irrespective of formulation. Yurko-Mauro K, Kralovec J, Bailey-Hall E, Smeberg V, Stark JG, Salem N Jr. Similar eicosapentaenoic acid and docosahexaenoic acid plasma levels achieved with fish oil or krill oil in a randomized double-blind 4-week bioavailability study. Lipids Health Dis.2015 Sep 2;14:99. doi:10.1186/s12944-015-0109-z.

Elongation/desaturation of deuterated 2H5 linoleic acid (2H5-LA) to arachidonic acid (AA), and 2H5 alpha-linolenic acid (2H5-LNA) to form docosahexaenoic acid (DHA) was measured in19 preterm infants, 11 term, and 11 intrauterine growth-retarded (IUGR) infants. Higher time integrated concentrations of 2H5-AA and 2H5-DHA were observed in preterm infants relative to the other two groups. Growth retardation was associated with lower formation of AA and DHA. Uauy R; Mena P; Wegher B; Nieto S; Salem N. Long chain polyunsaturated fatty acid formation in neonates: Effect of gestational age and intrauterine growth. Pediatric Research 2000; 47: 127 135.

Periconceptional alcohol use was associated with a higher proportion of docosahexaenoic acid (22:6n-3) in cord blood (3.9% of total lipid in alcohol-exposed infants compared with 3.0% in control infants; P < 0.01). The higher 22:6n-3 fits a hypothesis that 22:6n-3 may be conserved selectively. Denkins YM; Woods J; Whitty JE; Hannigan JH; Martier SS; Sokol RJ; Salem N. Effects of gestational alcohol exposure on the fatty acid composition of umbilical cord serum in humans. Am. J. Clin. Nutr. 2000; 71: 300S-306S.

Alcohol consumption by Rhesus monkeys did not appear to affect the absorption of deuterium labeled 2H5-18:2n 6 or 2H5-18:3n-3 ethyl esters into the circulation. However, there was a greater enrichment of deuterium in the biosynthesized 20:4n-6 and 22:6n-3 in the monkeys exposed to alcohol compared to controls. Chronic alcohol exposure may stimulate the rate at which long chain polyunsaturated fatty acids are biosynthesized to compensate for increased lipid peroxidation. Pawlosky RJ; Salem N. Alcohol consumption in rhesus monkeys depletes tissues of polyunsaturated fatty acids and alters essential fatty acid metabolism. Alcoholism Clinical and Experimental Research 1999; 23: 311-317.

Fetal accretion of HUFA occurs during the last trimester of gestation, and premature infants are born with minimal HUFA reserves. Postnatally, human milk provides HUFA to the newborn. Maternal HUFA reserves depend upon diet and can be improved by supplementation of docosahexaenoic acid and arachidonic acid during pregnancy and lactation. Hamosh M; Salem N. Long chain polyunsaturated fatty acids. Biology of the Neonate 1998; 74: 106-120.

Gas chromatography/negative chemical ionization mass spectrometry was employed for high sensitivity detection of the following isotopes: 2H-labeled-linolenate, 13C-U-labeled-eicosapentaenoate, 13C-U-labeled linoleate, and 2H-labeled dihomo-gamma-linolenate that were given to rats either singly or together in a single oral dose. Rat blood was collected after dosing, and the isotopomers of the precursors and their main metabolites, including those containing both 13C and 2H, were detected simultaneously with good resolution and without interference from other isotopes. Lin Y, Salem N Jr. A technique for the in vivo study of multiple stable isotope-labeled essential fatty acids. Prostaglandins Leukot Essent Fatty Acids 2002 Aug-Sep;67(2-3):141-6.

The DHA in newborn infants must come from the mother. During the first year, an infant then gains additional DHA from food. Successive pregnancies may deplete maternal supplies and provide less DHA to later newborns. Woods J; Ward G; Salem N. Is docosahexaenoic acid necessary in infant formula? Evaluation of high linolenate diets in the neonatal rat. Pediatric Research 1996; 40: 687-694.

Brain HUFA levels and brain function
Using human APOE2, 3, and 4 isoform-specific transgenic mice, we found a lower brain uptake of docosahexaenoic acid (DHA) in APOE4 than in APOE2 mice that may limit the biodistribution of DHA in cerebral tissues. These data provide a mechanistic explanation for the lack of benefit of DHA in APOE4 carriers on cognitive function and the risk of Alzheimer’s disease. Vandal M, Alata W, Tremblay C, Rioux-Perreault C, Salem N Jr, Calon F, Plourde M. Reduction in DHA transport to the brain of mice expressing human APOE4 compared to APOE2.  J Neurochem. 2014 May;129(3):516-26. doi: 10.1111/jnc.12640.

Higher DHA intake correlated with lower relative risk of Alzheimer’s disease. A total of 485 healthy subjects, aged ≥55 were randomly assigned to 900 mg/d of DHA orally or matching placebo for 24 weeks. Supplementation improved learning and memory function. Yurko-Mauro K, McCarthy D, Rom D, Nelson EB, Ryan AS, Blackwell A, Salem N Jr, Stedman M; MIDAS Investigators.  Collaborators: Arguello F, Berwald B, Brody M, Edwards K, Galef F, Geohas J, Goldstein J, Griffin C, Kalafer M, Kirby L, Lefebvre G, McCarthy C, McElveen W, Moldauer L, Sheftell F, Stedman M, Thein S, Weiss T, Winston J. Beneficial effects of docosahexaenoic acid on cognition in age-related cognitive  decline.  Alzheimers Dement. 2010 Nov;6(6):456-64. doi: 10.1016/j.jalz.2010.01.013.

There was a 51% less brain DHA in mice with an n-3 fatty acid-deficient diet relative to those with a diet sufficient in n-3 fatty acids. Adequate and deficient mice did not differ in terms of locomotor activity in the open field test or in anxiety-related behavior in the elevated plus maze. Also, no difference in performance between all dietary groups in the cued and working memory version of the Barnes maze was observed. However, deficient mice showed impaired learning in the reference-memory version of the Barnes circular maze as they spent more time and made more errors in search of an escape tunnel. This indicated that motivational, motor and sensory factors did not contribute to the reference memory impairment.  Fedorova I, Hussein N, Di Martino C, Moriguchi T, Hoshiba J, Majchrzak S, Salem N Jr.  An n-3 fatty acid deficient diet affects mouse spatial learning in the Barnes circular maze.  Prostaglandins Leukot Essent Fatty Acids. 2007 Nov-Dec;77(5-6):269-77. Epub 2007  Nov 26.

We used a first-generational artificial rearing technique to demonstrate a deficit in spatial task performance in rats with low brain DHA due to a low n-3 fatty acid intake. The deficient rats exhibited a longer escape latency (p < 0.05) and poorer memory retention in the Morris water maze compared with n-3 fatty acid adequate and dam-reared rats. Adequate brain DHA levels are required for optimal spatial learning. Lim SY, Hoshiba J, Moriguchi T, Salem N Jr.  N-3 fatty acid deficiency induced by a modified artificial rearing method leads to poorer performance in spatial learning tasks.  Pediatr Res. 2005 Oct;58(4):741-8

To determine the reversibility of losses in brain function associated with the loss of brain DHA, rats were fed very low or adequate levels of n-3 fatty acids through three generations. The n-3 fatty acid deficient animals of the F3 generation were then given an n-3 adequate diet containing alpha-linolenic and docosahexaenoic acids (DHA) at birth, weaning (3 weeks) or young adulthood (7 weeks). Animals repleted since birth or at weaning were able to achieve nearly the same level of brain DHA and spatial task performance as animals maintained for three generations on an n-3 adequate diet. These findings indicate that some of the adverse effects of DHA deficiency during neurodevelopment may be reversible with an n-3 fatty acid supplemented diet. Moriguchi T, Salem N Jr.  Recovery of brain docosahexaenoate leads to recovery of spatial task performance. J Neurochem. 2003 Oct;87(2):297-309.

Despite a 76% lower brain DHA, n-3-deficient rats were able to acquire most simple 2-odor discrimination tasks, but were deficient in the acquisition of a 20-problem olfactory learning set. This deficit could not be attributed to changes in sensory capacity but, instead, appeared to represent a deficit in higher order learning. Catalan J, Moriguchi T, Slotnick B, Murthy M, Greiner RS, Salem N Jr. Cognitive deficits in docosahexaenoic acid-deficient rats. Behav Neurosci 2002 Dec;116(6):1022-31.

Lowering the LA to LNA ratio from 10:1 to 1:1 and 1:12 in artificially reared neonatal rat pups resulted in a significant higher percentage of brain DHA. The brain level of DHA in the group fed a 1:12 ratio was similar to that of a dam-reared reference group. The addition of long chain n-3 polyunsaturates such as DHA to infant formula may be necessary for adequate neural DHA accretion and optimal neural development.  Woods J, Ward G, Salem N Jr. Is docosahexaenoic acid necessary in infant formula? Evaluation of high linolenate diets in the neonatal rat. Pediatr Res. 1996 Nov;40(5):687-94.

Gas chromatography/negative chemical ionization/mass spectrometry using deuterium-labeled EFA showed that all elongases/desaturases necessary for the conversion of linolenic acid (18:3n-3) to docosahexaenoic acid (22:6n-3) are active in the first week after birth. The data clearly show that infants biosynthesize 22:6n-3, although amounts produced in vivo from dietary 18:3n-3 competing with 18:2n-6 may not be adequate for optimal neural development like that observed in breast-fed infants. Salem N; Wegher B; Mena P; Uauy R. Arachidonic and docosahexaenoic acids are biosynthesized from their 18 carbon precursors in human infants. Proc Nat Acad Sci 1996; 93: 49 54.

Time-course labeling experiments indicated that the intermediates, 20:5n-3 and 22:5n-3, may be converted to 22:6n-3 within the rodent brain. A rise of labeled 22:6n-3 in the brain at 24 h appeared to be due to uptake of this fatty acid from the blood. During rodent development, different regions within the brain may vary in their capacity to synthesize 22:6n-3, and this may be correlated with regional growth rates. Pawlosky RJ; Ward G; Salem N. Essential fatty acid uptake and metabolism in the developing rodent brain. Lipids 1996; 31: S103-S107

In an artificial rearing procedure, infant rats were removed from their mothers, gastrostomized, and fed synthetic formula, to produce rapid changes in CNS levels of DHA. At eight weeks of age, the n-3 deficient group had less than 50% of control total DHA content in brain, accompanied by more arachidonic acid (AA) (20:4n-6) and docosapentaenoic acid (22:5n-6). At both ten days of age and again at eight weeks, offspring of the n-3 deficient mothers exhibited less than 10% total DHA content. These differences are greater than those commonly reported after 2-3 generations of normal dietary deprivation in rodents. Ward G; Woods J; Reyzer M; Salem N. Artificial rearing of infant rats on milk formula deficient in n 3 essential fatty acids: A rapid method for the production of experimental n 3 deficiency. Lipids 1996; 31: 71-77.

F2 generation male rats consuming the n-3 deficient diet had only 18% of the DHA in rats consuming the n-3 adequate diet. The n-3 deficient animals made significantly more total errors in a 7-problem, 2-odor discrimination task and had longer escape latency in the Morris water maze task compared to the n-3 adequate group. Greiner RS; Moriguchi T; Hutton A; Slotnick BM; Salem N. Rats with low levels of brain docosahexaenoic acid show impaired performance in olfactory based and spatial learning tasks.  Lipids 1999; 34: S239-S243.

The a and b wave implicit times of electroretinograms of 8 wk old cats showed that animals raised in litters for which maternal diets lacked 20:4n-6 and 22:6n-3 had increased a and b wave implicit times compared with those of controls. Also, the rod outer segments and brains had lower amounts of 22:6n-3 and higher amounts of n-6 HUFA compared with control animals. Maintenance of 22:6n-3 status in the nervous system seems important for optimal retinal function. Only the diets containing 22:6n-3 supported a high accumulation of docosahexaenoic acid in these tissues. Pawlosky RJ; Denkins Y; Ward G; Salem N. Retinal and brain accretion of long chain polyunsaturated fatty acids in developing felines: The effects of corn oil based maternal diets. Am J Clin Nutr 1997; 65: 465-472.

Bone strength needs DHA (22:6n-3)
The present study determined whether provision of preformed dietary docosapentaenoic acid (DPAn-6) can replace DHA for normal long bone growth. Newborn pups were given artificial rat milk containing linoleic acid (LA) and supplemented with 1 % DHA (22:6n-3), 1 % DPAn-6 (22:5n-6), or 1 % DHA plus 0.4 % DPAn-6. The long bones (femur and tibia) in DPAn-6-treated rats contained higher DPAn-6 content and generally had the lowest bone mineral content and bone mineral density values.  Hence, DPAn-6 did not replace DHA for normal bone growth and maximal BMC in femur, indicating an indispensible role of DHA in bone health. Li Y, Seifert MF, Lim SY, Salem N Jr, Watkins BA. Bone mineral content is positively correlated to n-3 fatty acids in the femur of growing rats. Br J Nutr. 2010 Sep;104(5):674-85. doi: 10.1017/S0007114510001133

Measurement of bone mechanical properties (energy to peak load) of tibiae showed that (n-3) deficiency diminished structural integrity. Rats repleted with (n-3) fatty acids demonstrated accelerated bone modeling (cross-sectional geometry) and an improved second moment in tibiae compared with control (n-3)-adequate rats after 28 d of dietary treatment. This study showed that repletion with dietary (n-3) fatty acids restored the ratio of (n-6)/(n-3) PUFA in bone compartments and reversed compromised bone modeling in (n-3)-deficient rats. Reinwald S, Li Y, Moriguchi T, Salem N Jr, Watkins BA.   Repletion with (n-3) fatty acids reverses bone structural deficits in (n-3)-deficient rats. J Nutr. 2004 Feb;134(2):388-94.

Brain DHA  supports learning and memory
Docosahexaenoic acid (DHA; 22:6n-3), is much more abundant in brain and retina than elsewhere. This alerted scientists to possible special metabolic selections and functions for DHA. Dramatic results (2:31 min videoshow the need for DHA to develop effective learning and memory. Other studies have shown the benefit of DHA during recovery from brain damage.

 

revised October, 2017