Perinatal biochemistry and physiology of long-chain polyunsaturated fatty acids

https://doi.org/10.1067/S0022-3476(03)00396-2Get rights and content

Abstract

Docosahexaenoic acid (DHA) and arachidonic acid (ARA) are important structural components of the central nervous system. These fatty acids are transferred across the placenta, are present in human milk, and are accumulated in the brain and retina during fetal and infant development. The high concentrations of DHA in the retina and of DHA and ARA in brain gray matter suggests that these fatty acids have important roles in retinal and neural function. Animal studies have shown that depletion of DHA from the retina and brain results in reduced visual function and learning deficits. The latter effects may be explained by changes in the membrane bilayer that alter membrane-associated receptors and signal transduction systems, ion channel activity, or direct effects on gene expression. DHA can be formed in the liver from alpha linolenic acid, but it is unclear if the rate of DHA synthesis in humans is sufficient to support optimal brain and retinal development. Although there is no evidence that the ability to form ARA from linoleic acid is limiting, supplementation with DHA reduces tissue ARA, possibly creating a conditional need for ARA in infants with a dietary intake of DHA. The amount of DHA in human milk varies widely and is positively correlated with visual and language development in breast-fed infants. Advances in understanding essential fatty acid requirements will benefit from intervention studies that use functionally relevant tests to probe the deficiency or adequacy of physiologically important pools of DHA and ARA in developing infants.

Section snippets

Polyunsaturated fatty acid metabolism

ARA and DHA are formed from LA and LNA, respectively, in the liver by a series of alternating desaturation (addition of a double bond) and elongation (addition of a 2-carbon unit) reactions.27., 28., 29. (Fig 1). Although LA and LNA are formed in plants, they cannot be formed in mammalian cells because of the absence of the Δ12 and 15 enzymes necessary to insert a double bond at the n (or ω) 6 or 3 position of a fatty acid carbon chain. LA and LNA are, therefore, considered essential dietary

Polyunsaturated fatty acid metabolism in development

Before birth, all of the n–6 and n–3 fatty acids accumulated by the fetus must originate from the maternal circulation through placental transfer, and after birth all must be derived from the milk or formula diet and later from complementary foods. The central question is the extent to which the developing fetus and infant is able to utilize LA and LNA or depends on exogenous ARA and DHA to meet the needs for optimal development. Delta 6 and Δ 5 desaturase activity has been shown in human fetal

Placental transfer of polyunsaturated fatty acids

Although it is clear that all of the n–6 and n–3 fatty acids accumulated in the fetus must ultimately be derived from the mother by placental transfer, the process involved in this transfer remains incompletely understood. The concentrations of DHA and ARA are 300- to 400-fold higher in fetal compared with maternal plasma phospholipids, whereas the their LA and LNA precursors are lower (Fig 2).89 Delta 6 and Δ5 desaturase are both present in placenta, and in ovine placenta Δ6 desaturase

Polyunsaturated fatty acids in human milk

It is well appreciated that fat is the most variable macronutrient in human milk and that the composition of the component fatty acids is also exceedingly variable.104 Human milk contains more than 150 different fatty acids, of which LA, LNA, ARA, DHA, and several other n–6 and n–3 fatty acids typically make up 15% to 20% of all the fatty acids present. Studies published in the last 5 years show that human milk from women who follow Western diets generally has 10% to 17% LA, 0.8% to 1.4% LNA,

Approaches to assessing requirement

The rate of nutrient accretion in fetal and infant tissues or the amounts provided by human milk can be used as a guide to estimating nutrient requirements of the preterm infants and term infants 0 to 6 months, respectively. The mean concentrations of DHA in human milk varies >10-fold, and concentrations of ARA vary >3-fold among different populations of women; the variability in milk DHA and ARA among individual women is even greater.104., 105., 106., 107., 108., 109., 110., 111., 112., 113.,

References (120)

  • S. Ferdinandusse et al.

    Identification of the peroxisomal β-oxidation enzymes involved in the biosynthesis of docosahexaenoic acid

    J Lipid Res

    (2001)
  • H. Sprecher et al.

    Reevaluation of the pathways for the biosynthesis of polyunsaturated fatty acids

    J Lipid Res

    (1995)
  • S.C. Cunnane et al.

    Carbon recycling into de novo lipogenesis is a major pathway in neonatal metabolism of linoleate and alpha-linolenate

    Prostaglandins Leukot Essent Fatty Acids

    (1999)
  • R.C. Sheaff Greiner et al.

    Linoleate, alpha-linolenate, and docosahexaenoate recycling into saturated and monounsaturated fatty acids is a major pathway in pregnant or lactating adults and fetal or infant rhesus monkeys

    J Lipid Res

    (1996)
  • J.P. DeLany et al.

    Differential oxidation of individual dietary fatty acids in humans

    Am J Clin Nutr

    (2000)
  • C. Galli et al.

    Effects of dietary fatty acids on the fatty acid composition of brain ethanolamine phosphaglyceride: reciprocal replacement of n-6 and n-3 polyunsaturated fatty acids

    Biochim Biophys Acta

    (1971)
  • N. Hrboticky et al.

    Effect of a linoleic acid rich vegetable oil “infant” formula on brain synaptosomal lipid accretion and enzyme thermotropic behaviour in the new-born piglet

    J Lipid Res

    (1989)
  • N. Hrboticky et al.

    Effect of vegetable oil formula rich in linoleic acid on tissue fatty acid accretion in brain, liver, plasma and erythrocytes of infant piglets

    Am J Clin Nutr

    (1990)
  • H. Frances et al.

    Influence of a dietary α-linolenic acid deficiency on learning in the Morris water maze and on the effects of morphine

    Eur J Pharmacol

    (1996)
  • S. Reisbick et al.

    Polydipsia in rhesus monkeys deficient in omega-3 fatty acids

    Physiol Behav

    (1990)
  • S. Reisbick et al.

    Home cage behavior of rhesus monkeys with long-term deficiency of omega-3 fatty acids

    Physiol Behav

    (1994)
  • K.S. Broughton et al.

    Total fat and (n-3:n-6) fat ratios influence eicosanoid production in mice

    J Nutr

    (2002)
  • S. Fischer et al.

    Polyunsaturated E3 and F3 alpha are excreted in human urine after ingestion of n-3 polyunsaturated fatty acids

    Biochim Biophys Acta

    (1988)
  • S.E. Carlson et al.

    Effect of long-chain n-3 fatty acid supplementation on visual acuity and growth of preterm infants with and without bronchopulmonary dysplasia

    Am J Clin Nutr

    (1996)
  • J.C. Putnam et al.

    The effect of variations in dietary fatty acids on the fatty acid composition of erythrocyte phosphatidylcholine and phosphatidylethanolamine in human infants

    Am J Clin Nutr

    (1982)
  • S.M. Innis et al.

    Plasma fatty acid response, metabolic effects, and safety of microalgal and fungal oils rich in arachidonic acid and docosahexaenoic acid in healthy adults

    Am J Clin Nutr

    (1996)
  • L.D. Arbuckle et al.

    Response of (n-3) and (n-6) fatty acids in brain, liver and plasma of piglets fed formula to increasing, but low, levels of fish supplementation

    J Nutr

    (1991)
  • G.R. Ward et al.

    Long-chain polyunsaturated fatty acid levels in formulae influence deposition of docosahexaenoic acid and arachidonic acid in brain and red blood cells of artificially reared neonatal rats

    J Nutr

    (1998)
  • L. Zimmer et al.

    Modification of dopamine neurotransmission in the nucleus accumbens of rats deficient in n-3 polyunsaturated fatty acids

    J Lipid Res

    (2000)
  • L. Zimmer et al.

    Chronic n-3 polyunsaturated fatty acid diet-deficiency acts on dopamine metabolism in the rat frontal cortex: a microdialysis study

    Neurosci Lett

    (1998)
  • A. Antal et al.

    Dopamine D2 receptor blockade alters the primary and cognitive components of visual evoked potentials in the monkey, Macaca fasciliaris

    Neurosci Lett

    (1997)
  • V.K. Bhargava et al.

    Role of 5-hydroxytryptamine in the modulation of acoustic brainstem (far-field) potentials

    Neuropharmacology

    (1977)
  • J.P. Poisson et al.

    Evidence that microsomes of human neonates desaturate essential fatty acids

    Biochim Biophys Acta

    (1993)
  • A. Rodriguez et al.

    Δ6- and Δ5-Desaturase activities in the human fetal liver: kinetic aspects

    J Lipid Res

    (1998)
  • M.A. Crawford et al.

    Essential fatty acid requirements in pregnancy and lactation with special reference to brain development

    Prog Lipid Res

    (1981)
  • S.L. Elias et al.

    Infant plasma trans, n-6, and n-3 fatty acids and conjugated linoleic acids are related to maternal plasma fatty acids, length of gestation, and birth weight and length

    Am J Clin Nutr

    (2001)
  • J. Farquharson et al.

    Infant cerebral cortex phospholipid fatty-acid composition and diet

    Lancet

    (1992)
  • M. Makrides et al.

    Fatty acid composition of brain, retina, and erythrocytes in breast- and formula-fed infants

    Am J Clin Nutr

    (1994)
  • H.P. Cho et al.

    Cloning, expression, and fatty acid regulation of the human delat-5 desaturase

    J Biol Chem

    (1999)
  • F.M. Campbell et al.

    Detection and cellular localization of plasma membrane-associated and cytoplasmic fatty acid-binding proteins in human placenta

    Placenta

    (1998)
  • A.K. Dutta-Roy

    Transport mechanisms for long-chain polyunsaturated fatty acids in the human placenta

    Am J Clin Nutr

    (2000)
  • P. Haggarty et al.

    Long-chain polyunsaturated fatty acid transport across the perfused human placenta

    Placenta

    (1997)
  • P.S. Sastry

    Lipids of nervous tissue: composition and metabolism

    Prog Lipid Res

    (1985)
  • R.M. Benolken et al.

    Membrane fatty acids associated with the electrical response in visual excitation

    Science

    (1973)
  • M. Neuringer et al.

    Biochemical and functional effects of prenatal and postnatal w-3 deficiency on retina and brain in rhesus monkeys

    Proc Natl Acad Sci U S A

    (1986)
  • T.G. Wheeler et al.

    Visual membranes: specificity of fatty acid precursors for the electrical response to illumination

    Science

    (1975)
  • S. de la Presa Owens et al.

    Docosahexaenoic and arachidonic acid reverse changes in dopaminergic and sertoninergic neurotransmitters in piglets frontal cortex caused by a linoleic and alpha linolenic acid deficient diet

    J Nutr

    (1999)
  • L. Zimmer et al.

    The dopamine mesocorticolimbic pathway is affected by deficiency in n-3 polyunsaturated fatty acids

    Am J Clin Nutr

    (2002)
  • B.J. Litman et al.

    The role of docosahexaenoic acid containing phospholipids in modulating G protein-coupled signaling pathways: visual transduction

    J Mol Neurosci

    (2001)
  • W.R. Leifert et al.

    Inhibition of cardiac sodium currents in adult rat myocytes by n-3 polyunsaturated fatty acids

    J Physiol

    (1999)
  • Cited by (391)

    • Moderate Freshwater Fish Intake, but Not n-3 Polyunsaturated Fatty Acids, Is Associated with a Reduced Risk of Small for Gestational Age in a Prospective Cohort of Chinese Pregnant Women

      2022, Journal of the Academy of Nutrition and Dietetics
      Citation Excerpt :

      In addition, because the study was conducted in a noncoastal area with a low intake of saltwater fish, the power of the study might be too small to examine the association between saltwater fish intake and SGA risk, and additional large-scale cohort studies of these species of fish are needed in the future. Previous studies have suggested that n-3 PUFAs may be a possible reason for the protective effect of fish on fetal growth,13,21,36 which is the structural and functional components of cell membranes and exerts important functions on fetal brain and retinal development.37 However, either total intake or dietary n-3 PUFAs was associated with reduced risk of SGA after controlling for potential covariates in this study.

    View all citing articles on Scopus
    View full text