Abstract
Neural accretion of docosahexaenoic acid (DHA) is thought to play an important role in the neural development of human infants. The lack of DHA in infant formulas contributes to the lowered neural accretion of DHA observed in formula-fed infants relative to those breast-fed. We hypothesized that lowering the dietary linoleic acid (LA) to α-linolenic acid (LNA) ratio may lead to increases in the level of DHA in the developing brain and retina. Lowering the LA to LNA ratio from 10:1 to 1:1 and to 1:12 in the artificially reared (AR) neonatal rat pup resulted in a significant increase in the percentage of brain DHA between AR dietary groups. The brain level of DHA in the AR group fed a 1:12 ratio was similar to that of a dam-reared reference group. However, levels of DHA in the retina of all AR groups were significantly lower than that of the (chow fed) dam-reared group. It appears that LNA may serve as an adequate substrate for the accretion of DHA in the brain, but not the retina of the developing rat. In both the brain and the retina, levels of arachidonic acid in the AR pups fed the 1:1 ratio were similar to that of the dam-reared group. However, levels in the 1:12 group were significantly reduced. The addition of long chain n-3 polyunsaturates such as DHA to infant formula may therefore be necessary for adequate neural DHA accretion and optimal neural development.
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Abbreviations
- AR:
-
artificially reared
- LA:
-
linoleic acid, 18:2n-6
- AA:
-
arachidonic acid, 20:4n-6
- LNA:
-
α-linolenic acid, 18:3n-3
- DHA:
-
docosahexaenoic acid, 22:6n-3
- RMS:
-
rat milk substitute
- LC-PUFA:
-
long chain polyunsaturated fatty acid, 20-22 carbon chain length
References
Salem N Jr 1989 Omega-3 fatty acids: molecular and biochemical aspects. In: Spiller GA, Scala J (eds) New Protective Roles for Selected Nutrients. Alan R Liss, New York, pp 109–228.
Salem N Jr, Ward G 1993 Are ω3 fatty acids essential nutrients for mammals? In: Simopoulos AP (ed) Nutrition and Fitness in Health and Disease. S. Karger, Basel, Switzerland, pp 128–147.
Salem N Jr, Kim H-Y, Yergey JA 1986 Docosahexaenoic acid: membrane function and metabolism. In: Simopoulos AP, Kifer RR, Martin RE (eds) Health Effects of Polyunsaturated Fatty Acids in Seafoods. Academic Press, New York, pp 263–317.
Tinoco J, Babcock R, Hincenbergs I, Medwadowski B, Miljanich P, Williams MA 1979 Linolenic acid deficiency. Lipids 14: 166
Uauy R, Birch E, Birch D, Peirano P 1992 Visual and brain function measurements in studies of n-3 fatty acid requirements of infants. J Pediatr 120:S168–S180.
Innis SM 1991 Essential fatty acids in growth and development. Prog Lipid Res 30: 39–103.
Lamptey MS, Walker BL 1976 A possible essential role for dietary linolenic acid in the development of the young rat. J Nutr 106: 86–93.
Yamamoto N, Saitoh M, Moriuchi A, Nomura M, Okuyama H 1987 Effect of dietary α-linolenate/linoleate balance on brain lipid compositions and learning ability of rats. J Lipid Res 28: 144–151.
Wheeler TG, Benolken RM, Anderson RE 1975 Visual membranes: specificity of fatty acid precursors for the electrical response to illumination. Science 188: 1312–1314.
Neuringer M, Connor WE, Lin DS, Barstad L, Luck S 1986 Biochemical and functional effects of prenatal and postnatal ω3 fatty acid deficiency. Proc Natl Acad Sci USA 83: 4021–4025.
Uauy R, Birch DG, Birch E, Tyson JE, Hoffman DR 1990 Effect of dietary ω-3 fatty acids on retinal function of very-low-birth-weight neonates. Pediatr Res 28: 485–492.
Carlson SE, Rhodes PG, Ferguson M 1986 Docosahexaenoic acid status of preterm infants at birth and following feeding with human milk or formula. Am J Clin Nutr 44: 798–804.
Birch EE, Birch DG, Hoffman DR, Uauy R 1992 Dietary essential fatty acid supply and visual acuity development. Invest Ophthalmol Vis Sci 33: 3242–3253.
Carlson SE, Werkman SH, Peeples JM, Wilson WM 1994 Growth and development of premature infants in relation to ω-3 andω-6 fatty acid status. World Rev Nutr Diet 75: 63–69.
Rogers B 1978 Feeding in infancy and later ability and attainment: a longitudinal study. Dev Med Child Neurol 20: 421–426.
Taylor B, Wadsworth J 1984 Breast feeding and child development at five years. Dev Med Child Neurol 26: 73
Lucas A, Morley R, Cole TJ, Lister G, Leeson-Payne C 1992 Breast milk and subsequent intelligence quotient in children born preterm. Lancet 339: 261–264.
Makrides M, Neuman M, Simmer K, Pater J, Gibson R 1995 Are long-chain polyunsaturated fatty acids essential nutrients in infancy?. Lancet 345: 1463–1468.
Arbuckle LD, Innis SM 1992 Docosahexaenoic acid in developing brain and retina of piglets fed high or low α-linolenate formula with and without fish oil. Lipids 27: 89–93.
Clark KJ, Makrides M, Neumann MA, Gibson RA 1992 Determination of the optimal ratio of linoleic acid to α-linolenic acid in infant formulas. J Pediatr 120:S151–S158.
Crawford MA, Hassam AG, Stevens PA 1981 Essential fatty acid requirements in pregnancy and lactation with special reference to brain development. Prog Lipid Res 20: 31–40.
Dobbing J, Sands J 1979 Comparative aspects of the brain growth spurt. Early Hum Dev 3: 79–83.
Lake N 1994 Taurine and GABA in the rat retina during postnatal development. Vis Neurosci 11: 253–260.
Micali A, Parducci F, La Fauci MA, Urbani P, Santoro G, Puzzolo D 1989 Postnatal maturation of the retina in the albino rat. 1. The pigment epithelium. Arch Ital Anat Embriol 94: 405–424.
Diaz J, Moore E, Petracca F, Schacher J, Stamper C 1981 Artificial rearing of preweanling rats: the effectiveness of direct intragastric feeding. Physiol Behav 27: 1103–1105.
Diaz J, Moore E, Petracca F, Stamper C 1982 Artificial rearing of rat pups with a protein enriched formula. J Nutr 112: 841–847.
Diaz J, Moore E, Petracca F, Stamper C 1983 Somatic and central nervous system growth in artificially reared rat pups. Brain Res Bull 11: 643–647.
Tonkiss JL, Smart J, Massey RF 1987 Growth and development of rats artificially reared on rats' milk or rats' milk/milk-substitute combinations. Br J Nutr 57: 3–11.
Yeh Y-Y 1983 Small intestines of artificially reared rat pups: weight gain and changes in alkaline phosphatase, lactase and sucrase activities during development. J Nutr 113: 1489–1495.
Winters BL, Yeh S-M, Yeh Y-Y 1994 Linolenic acid provides a source of docosahexaenoic acid for artificially reared rat pups. J Nutr 124: 1654–1659.
Colombaioni L, Strettoi E 1993 Appearance of cGMP-phosphodiesterase immunoreactivity parallels the morphological differentiation of photoreceptor outer segments in the rat retina. Vis Neurosci 10: 395–402.
Harris WS, Zucker ML, Dujovne A 1988 ω-3 Fatty acids in hypertriglyceridemic patients: triglycerides vs methyl esters. Am J Clin Nutr 48: 992–997.
Hamazaki T, Urakaze M, Makuta M, Ozawa A, Soda Y, Tatsumi H, Yano S, Kumagai A 1987 Intake of eicosapentaenoic acid-containing lipids and fatty acid pattern of plasma lipids in the rat. Lipids 22: 994–998.
Knapka JJ 1983 Nutrition. In: Foster HL, Small JD, Fox JG (eds) The Mouse in Biomedical Research, Vol. III. Academic Press, New York, pp 51–67.
West D, Diaz J, Woods S 1982 Infant gastrostomy and chronic formula infusion as a technique to overfeed and accelerate weight gain of neonatal rats. J Nutr 112: 1339–1343.
Ward G, Reyzer M, Salem N Jr 1996 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 31: 71–77.
Hall W 1975 Weaning and growth of artificially reared rats. Science 190: 1313–1315.
Bligh EG, Dyer WJ 1959 A rapid method of total lipid extraction and purification. Can J Biochem Physiol 37: 911–917.
Morrison WR, Smith LM 1959 Preparation of fatty acid methyl esters and dimethylacetals from lipids with boron-fluoride-methanol. J Lipid Res 5: 600–608.
Moore E, Stamper C, Diaz J 1990 Artificial rearing of rat pups using rat milk. Dev Psychobiol 23: 169–178.
Smart JL, Stephens DN, Tonkiss J, Auestad NS, Edmond J 1984 Growth and development of rats artificially reared on different milk-substitutes. Br J Nutr 52: 227–237.
Sonnenberg N, Bergstrom JD, Ha YH, Edmond J 1982 Metabolism in the artificially reared rat pup: effect of an atypical rat milk substitute. J Nutr 112: 1506–1514.
Jensen RG, Lammi-Keefe CJ, Henderson RA, Bush VJ, Ferris AM 1992 Effect of dietary intake of n-6 and n-3 fatty acids on the fatty acid composition of human milk in North America. J Pediatr 120:S87–S92.
Koletzko B, Thiel I, Abiodun PO 1992 The fatty acid composition of human milk in Europe and Africa. J Pediatr 120:S62–S70.
Innis SM 1992 Human milk and formula fatty acids. J Pediatr 120:S56–S61.
Innis SM, Kuhnlein HV 1988 Long chain n-3 fatty acids in breast milk of Inuit women consuming traditional foods. Early Hum Dev 18: 185–189.
Harris WS, Connor WE, Lindsey BS 1984 Will dietaryω-3 fatty acids change the composition of human milk?. Am J Clin Nutr 40: 780–785.
Mills DE, Ward RP, Huang YS 1990 Fatty acid composition of milk from genetically normotensive and hypertensive rats. J Nutr 120: 431–435.
Sanders TAB, Mistry M, Naismith DJ 1984 The influence of a maternal diet rich in linoleic acid on brain and retinal docosahexaenoic acid in the rat. Br J Nutr 51: 57–66.
Yeh Y-Y, Gehman MF, Yeh S-M 1993 Maternal dietary fish oil enriches docosahexaenoate levels in brain subcellular fractions of offspring. J Neurosci Res 35: 218–226.
Sinclair AJ 1974 Fatty acid composition of liver lipids during development of rat. Lipids 9: 809–818.
Sinclair AJ 1975 Incorporation of radioactive polyunsaturated fatty acids into liver and brain of developing rat. Lipids 10: 175–184.
Mohrhauer H, Holman RT 1963 Alteration of the fatty acid composition of brain lipids by varying levels of dietary essential fatty acids. J Neurochem 10: 523–530.
Anderson GJ, Connor WE, Corliss JD 1990 Docosahexaenoic acid is the preferred dietary n-3 fatty acid for the development of the brain and retina. Pediatr Res 27: 89–97.
Willis AL 1981 Unanswered questions in EFA and PG research. Prog Lipid Res 20: 839–850.
Salem N Jr, Wegher B, Mena P, Uauy R 1996 Arachidonic and docosahexaenoic acids are biosynthesized from their 18-carbon precursors in human infants. Proc Natl Acad Sci USA 93: 49–54.
Jensen CL, Chen H, Fraley JK, Anderson RE, Heird WC 1996 Biochemical effects of dietary linoleic/α-linolenic acid ratio in term infants. Lipids 31: 107–113.
Report of the British Nutrition Foundation's Task Force 1992 Recommendations for intakes of unsaturated fatty acids. In: Unsaturated Fatty Acids Nutritional and Physiological Significance. Chapman & Hall, London, UK, pp 152–163.
ESPGAN Committee on Nutrition 1991 Comment on the content and composition of lipids in infant formulas. Acta Pediatr Scand 80: 887–896.
ISSFAL Board Statement 1995 Recommendations for the essential fatty acid requirement for infant formulas. J Am Coll Nutr 14: 213–214.
Carlson SE, Cooke RJ, Rhodes PG, Peeples JM, Werkman SH 1992 Effect of vegetable and marine oils in preterm infant formulas on blood arachidonic and docosahexaenoic acids. J Pediatr 1:S 159: 167
Carlson SE, Werkman SH, Peeples JM, Cooke RJ, Tolley EA 1993 Arachidonic acid status correlates with first year growth in preterm infants. Proc Natl Acad Sci USA 90: 1073–1077.
FAO/WHO 1994 Fats and Oils in Human Nutrition, Report of a Joint Expert Consultation, Chap. 7, Lipids in Early Development, Food and Nutrition Paper No. 57. FAO, Rome
Farquharson J, Forrester C, Patrick WA, Jamieson EC, Logan RW 1992 Infant cerebral cortex phospholipid fatty-acid composition and diet. Lancet 340: 810–813.
Makrides M, Neumann MA, Byard RW, Simmer K, Gibson RA 1994 Fatty acid composition of brain, retina, and erythrocytes in breast- and formula-fed infants. Am J Clin Nutr 60: 189–194.
Carlson SE, Cooke RJ, Rhodes PG, Peeples JM, Werkman SH, Tolley EA 1991 Long-term feeding of formulas high in linolenic acid and marine oil to very low birth weight infants: phospholipid fatty acids. Pediatr Res 30: 404–412.
Hoffman DR, Uauy R 1992 Essentiality of dietaryω-3 fatty acids for premature infants: plasma and red blood cell fatty acid composition. Lipids 27: 886–895.
Hrboticky N, MacKinnon MJ, Innis SM 1990 Effect of a vegetable oil formula rich in linoleic acid on tissue fatty acid accretion in the brain, liver, plasma, and erythrocytes of infant piglets. Am J Clin Nutr 51: 173–182.
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Supported in part by a Wyeth Neonatology Research Grant and the USUHS (to J.W.). The opinions or assertions contained herein are the private ones of the authors and are not to be construed as official or reflecting the views of the Department of Defense or the Uniformed Services University of Health Sciences.
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Woods, J., Ward, G. & Salem, N. Is Docosahexaenoic Acid Necessary in Infant Formula? Evaluation of High Linolenate Diets in the Neonatal Rat. Pediatr Res 40, 687–694 (1996). https://doi.org/10.1203/00006450-199611000-00007
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DOI: https://doi.org/10.1203/00006450-199611000-00007
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