A double-blind, randomized, controlled, parallel-group prospective trial was conducted to determine whether a dose-response existed for four different levels of docosahexaenoic acid (DHA) supplementation on the cognitive performance of infants. A total of 122 term infants were fed one of four different formulas varying in their DHA composition (0.00%, 0.32%, 0.64% and 0.96% of total fatty acids as DHA) from birth to 12 months. The three DHA-supplemented formulas also contained 0.64% of total fatty acids as arachidonic acid (ARA, 20:4n-6). Infants were tested at 4, 6, and 9 months of age on a visual habituation protocol that yielded both behavioral and psychophysiological indices of attention. Infants in all DHA+ARA-supplemented conditions had lower heart rates than those in the unsupplemented condition; there was no dose-response for this effect. The distribution of time that infants spent in different phases of attention (a cognitive index derived from the convergence of behavioral and cardiac responses) varied as a function of dosage. Infants supplemented at the two lower DHA doses spent proportionately more time engaged in active stimulus processing than infants fed the unsupplemented formula, while infants fed the highest dose were intermediate and did not differ from any other group.
The aim of this study was to examine infant feeding and the long-chain polyunsaturated fatty acid (LCPUFA) concentration of breast milk and formulas in relation to infant development. The prospective Pregnancy, Infection and Nutrition Study (n = 358) collected data on breastfeeding, breast milk samples and the formulas fed through 4 months post-partum. At 12 months of age, infants’ development was assessed (Mullen Scales of Early Learning). Linear regression was used to examine development in relation to breastfeeding, breast milk docosahexaenoic acid (DHA) and arachidonic acid (AA) concentration, and DHA and AA concentration from the combination of breast milk and formula. The median breast milk DHA concentration was 0.20% of total fatty acids [interquartile range (IQR) = 0.14, 0.34]; median AA concentration was 0.52% (IQR = 0.44, 0.63). Upon adjustment for preterm birth, sex, smoking, race and ethnicity and education, breastfeeding exclusivity was unrelated to development. Among infants exclusively breastfed, breast milk LCPUFA concentration was not associated with development (Mullen composite, DHA: adjusted β = −1.3, 95% confidence interval: −10.3, 7.7). Variables combining DHA and AA concentrations from breast milk and formula, weighted by their contribution to diet, were unassociated with development. We found no evidence of enhanced infant development related to the LCPUFA content of breast milk or formula consumed during the first four post-natal months.
arachidonic acid; breast milk; docosahexaenoic acid; infant feeding; polyunsaturated fatty acids; breastfeeding
Fatty acids in breast-milk such as docosahexaenoic acid and arachidonic acid, commonly known as DHA and ARA, contribute to the healthy development of children in various ways. However, the manufactured versions that are added to infant formula might not have the same health benefits as those in breast-milk. There is evidence that the manufactured additives might cause harm to infants’ health, and they might lead to unwarranted increases in the cost of infant formula.
The addition of such fatty acids to infant formula needs to be regulated. In the U.S., the Food and Drug Administration has primary responsibility for regulating the composition of infant formula. The central purpose of this study is to assess the FDA’s efforts with regard to the regulation of fatty acids in infant formula.
This study is based on critical analysis of policies and practices described in publicly available documents of the FDA, the manufacturers of fatty acids, and other relevant organizations. The broad framework for this work was set out by the author in his book on Regulating Infant Formula, published in 2011.
The FDA does not assess the safety or the health impacts of fatty acid additives to infant formula before they are marketed, and there is no systematic assessment after marketing is underway. Rather than making its own independent assessments, the FDA accepts the manufacturers’ claims regarding their products’ safety and effectiveness.
The FDA is not adequately regulating the use of fatty acid additives to infant formula. This results in exposure of infants to potential risks. Adverse reactions are already on record. Also, the additives have led to increasing costs of infant formula despite the lack of proven benefits to normal, full term infants. There is a need for more effective regulation of DHA and ARA additives to infant formula.
Infant formula; Fatty acids; Regulation; Docosahexaenoic acid; DHA
Docosahexaenoic acid (DHA) and arachidonic acid (ARA) are major components of the cerebral cortex and visual system, where they play a critical role in neural development. We quantitatively mapped fatty acids in 26 regions of the four-week-old breastfed baboon CNS, and studied the influence of dietary DHA and ARA supplementation and prematurity on CNS DHA and ARA concentrations.
Baboons were randomized into a breastfed (B) and four formula-fed groups: term, no DHA/ARA (T-); term, DHA/ARA supplemented (T+); preterm, no DHA/ARA (P-); preterm and DHA/ARA supplemented (P+). At four weeks adjusted age, brains were dissected and total fatty acids analyzed by gas chromatography and mass spectrometry.
DHA and ARA are rich in many more structures than previously reported. They are most concentrated in structures local to the brain stem and diencephalon, particularly the basal ganglia, limbic regions, thalamus and midbrain, and comparatively lower in white matter. Dietary supplementation increased DHA in all structures but had little influence on ARA concentrations. Supplementation restored DHA concentrations to levels of breastfed neonates in all regions except the cerebral cortex and cerebellum. Prematurity per se did not exert a strong influence on DHA or ARA concentrations.
1) DHA and ARA are found in high concentration throughout the primate CNS, particularly in gray matter such as basal ganglia; 2) DHA concentrations drop across most CNS structures in neonates consuming formulas with no DHA, but ARA levels are relatively immune to ARA in the diet; 3) supplementation of infant formula is effective at restoring DHA concentration in structures other than the cerebral cortex. These results will be useful as a guide to future investigations of CNS function in the absence of dietary DHA and ARA.
Arachidonic acid (ARA) and docosahexaenoic acid (DHA) are routinely added to infant formula to support growth and development. We evaluated the bioequivalence and safety of three ARA-rich oils for potential use in infant formula using the neonatal pig model. The primary outcome for bioequivalence was brain accretion of ARA and DHA. Days 3 to 22 of age, domestic pigs fed one of three formulas, each containing ARA at ~0.64% and DHA at ~0.34% total fatty acids (FA). Control diet ARA was provided by ARASCO® and all diets had DHA from DHASCO® (Martek Biosciences Corp., Columbia, MD). The experimental diets a1 and a2 provided ARA from Refined Arachidonic acid-rich Oil (RAO; Cargill, Inc., Wuhan, China) and SUNTGA40S (Nissui, Nippon Suisan Kaisha, Ltd., Tokyo, Japan), respectively. Formula intake and growth were similar across all diets, and ARA was bioequivalent across treatments in the brain, retina, heart, liver and day 21 RBC. DHA levels in the brain, retina and heart were unaffected by diet. Liver sections, clinical chemistry, and hematological parameters were normal. We conclude that RAO and SUNTGA40S, when added to formula to supply ~0.64% ARA are safe and nutritionally bioequivalent to ARASCO in domestic piglets.
Arachidonic acid; ARASCO; DHASCO; infant nutrition; pig
Docosahexaenoic acid (DHA, 22:6n-3) and arachidonic acid (ARA, 20:4n-6) are the major long chain polyunsaturated fatty acids (LCPUFA) of the central nervous system (CNS). These nutrients are present in most infant formulas at modest levels, intended to support visual and neural development. There are no investigations in primates of the biological consequences of dietary DHA at levels above those present in formulas but within normal breastmilk levels.
Methods and Findings
Twelve baboons were divided into three formula groups: Control, with no DHA-ARA; “L”, LCPUFA, with 0.33%DHA-0.67%ARA; “L3”, LCPUFA, with 1.00%DHA-0.67%ARA. All the samples are from the precentral gyrus of cerebral cortex brain regions. At 12 weeks of age, changes in gene expression were detected in 1,108 of 54,000 probe sets (2.05%), with most showing <2-fold change. Gene ontology analysis assigns them to diverse biological functions, notably lipid metabolism and transport, G-protein and signal transduction, development, visual perception, cytoskeleton, peptidases, stress response, transcription regulation, and 400 transcripts having no defined function. PLA2G6, a phospholipase recently associated with infantile neuroaxonal dystrophy, was downregulated in both LCPUFA groups. ELOVL5, a PUFA elongase, was the only LCPUFA biosynthetic enzyme that was differentially expressed. Mitochondrial fatty acid carrier, CPT2, was among several genes associated with mitochondrial fatty acid oxidation to be downregulated by high DHA, while the mitochondrial proton carrier, UCP2, was upregulated. TIMM8A, also known as deafness/dystonia peptide 1, was among several differentially expressed neural development genes. LUM and TIMP3, associated with corneal structure and age-related macular degeneration, respectively, were among visual perception genes influenced by LCPUFA. TIA1, a silencer of COX2 gene translation, is upregulated by high DHA. Ingenuity pathway analysis identified a highly significant nervous system network, with epidermal growth factor receptor (EGFR) as the outstanding interaction partner.
These data indicate that LCPUFA concentrations within the normal range of human breastmilk induce global changes in gene expression across a wide array of processes, in addition to changes in visual and neural function normally associated with formula LCPUFA.
Mitochondria can depolarize and trigger cell death through the opening of the mitochondrial permeability transition pore (MPTP). We recently showed that an increase in the long chain n3 polyunsaturated fatty acids (PUFA) docosahexaenoic acid (DHA; 22:6n3) and depletion of the n6 PUFA arachidonic acid (ARA; 20:4n6) in mitochondrial membranes is associated with a greater Ca2+ load required to induce MPTP opening. Here we manipulated mitochondrial phospholipid composition by supplementing the diet with DHA, ARA or combined DHA+ARA in rats for 10 weeks. There were no effects on cardiac function, or respiration of isolated mitochondria. Analysis of mitochondrial phospholipids showed DHA supplementation increased DHA and displaced ARA in mitochondrial membranes, while supplementation with ARA or DHA+ARA increased ARA and depleted linoleic acid (18:2n6). Phospholipid analysis revealed a similar pattern, particularly in cardiolipin. Tetralinoleoyl cardiolipin was depleted by 80% with ARA or DHA+ARA supplementation, with linoleic acid side chains replaced by ARA. Both the DHA and ARA groups had delayed Ca2+-induced MPTP opening, but the DHA+ARA group was similar to the control diet. In conclusion, alterations in mitochondria membrane phospholipid fatty acid composition caused by dietary DHA or ARA was associated with a greater cumulative Ca2+ load required to induced MPTP opening. Further, high levels of tetralinoleoyl cardiolipin were not essential for normal mitochondrial function if replaced with very-long chain n3 or n6 PUFAs.
AIM—To investigate whether low
docosahexaenoic acid (22:6ω3; DHA) status of malnourished, mostly
breast fed infants is a result of low ω3 fatty acid intake via breast milk.
METHODS—Fatty acid composition of
breast milk of eight Pakistani mothers, and of the erythrocytes of
their malnourished children was analysed.
RESULTS—The milk of the Pakistani
mothers contained low percentages of all ω3 and most ω6 fatty
acids, compared with milk of Dutch mothers. Breast milk DHA was
positively correlated with infant erythrocyte DHA and arachidonic acid
CONCLUSION—DHA status of these
malnourished children is strongly dependent on the ω3 fatty acid
intake from breast milk. Augmentation of the infants' ω3 long chain
polyunsaturated fatty acid status, or the ω3 and ω6 fatty acid
status in general, by supplementation is indicated in deprived
circumstances where access to fresh fish is difficult. However, in
terms of prevention, maternal supplementation of these long chain
polyunsaturated fatty acids, preferably from early pregnancy onwards,
may be a better option.
Human milk is the optimal nutrition for infants. When breastfeeding is not possible, supplementation of infant formula with long chain polyunsaturated fatty acids appears to promote neurodevelopmental outcome and visual function. Plant oils, that are the only source of fat in most of infant formulas, do not contain specific fatty acids that are present in human and cow milk and do not encounter milk fat triglyceride structure. Experimental data suggest that a mix of dairy lipids and plant oils can potentiate endogenous synthesis of n-3 long chain polyunsaturated fatty acids. This trial aims to determine the effect of an infant formula supplemented with a mixture of dairy lipids and plant oils on the erythrocyte membrane omega-3 fatty acid profile in full-term infants (primary outcome). Erythrocyte membrane long chain polyunsaturated fatty acids and fatty acids content, the plasma lipid profile and the insulin-growth factor 1 level, the gastrointestinal tolerance, the changes throughout the study in blood fatty acids content, in growth and body composition are evaluated as secondary outcomes.
In a double-blind controlled randomized trial, 75 healthy full-term infants are randomly allocated to receive for four months a formula supplemented with a mixture of dairy lipids and plant oils or a formula containing only plant oils or a formula containing plant oils supplemented with arachidonic acid and docosahexaenoic acid. Twenty-five breast-fed infants constitute the reference group. Erythrocyte membrane omega-3 fatty acid profile, long chain polyunsaturated fatty acids and the other fatty acids content, the plasma lipid profile and the insulin-growth factor 1 level are measured after four months of intervention. Gastrointestinal tolerance, the changes in blood fatty acids content, in growth and body composition, assessed by means of an air displacement plethysmography system, are also evaluated throughout the study.
The achievement of an appropriate long chain polyunsaturated fatty acids status represents an important goal in neonatal nutrition. Gaining further insight in the effects of the supplementation of a formula with dairy lipids and plant oils in healthy full-term infants could help to produce a formula whose fat content, composition and structure is more similar to human milk.
ClinicalTrials.gov Identifier NCT01611649
Full-term infants; Formula supplementation; Dairy lipids; Erythrocyte membrane omega-3 fatty acid profile
The influence of dietary long chain polyunsaturated fatty acid (LCP) supply, and especially of docosahexaenoic acid (DHA), on evoked potential maturation, was studied in 58 healthy preterm infants using flash visual evoked potentials (VEPs), flash electroretinography (ERG), and brainstem acoustic evoked potentials (BAEPs) at 52 weeks of postconceptional age. At the same time, the fatty acid composition of red blood cell membranes was examined. The infants were fed on breast milk (n = 12), a preterm formula supplemented with LCP (PF-LCP) (n = 21), or a traditional preterm formula (PF) (n = 25). In the breast milk and PF-LCP groups the morphology and latencies of the waves that reflect the visual projecting system were similar; in the PF group the morphology was quite different and the wave latencies were significantly longer. This could mean that the maturation pattern of VEPs in preterm infants who did not receive LCP was slower. Moreover, a higher level of erythrocyte LCP, especially DHA, was found in breast milk and PF-LCP groups compared with the PF group. ERG and BAEP recordings were the same in all three groups. These results suggest that a well balanced LCP supplement in preterm formulas can positively influence the maturation of visual evoked potentials in preterm infants when breast milk is not available.
Eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) are functionally the most important omega-3 polyunsaturated fatty acids (PUFAs). Oral supply of these fatty acids increases their levels in plasma and cell membranes, often at the expense of the omega-6 PUFAs arachidonic acid (ARA) and linoleic acid. This results in an altered pattern of lipid mediator production to one which is less pro-inflammatory. We investigated whether short term intravenous supply of omega-3 PUFAs could change the levels of EPA, DHA, ARA and linoleic acid in plasma and erythrocytes in patients with hepatic colorectal metastases.
Twenty patients were randomised to receive a 72 hour infusion of total parenteral nutrition with (treatment group) or without (control group) omega-3 PUFAs. EPA, DHA, ARA and linoleic acid were measured in plasma phosphatidylcholine (PC) and erythrocytes at several times points up to the end of infusion and 5 to 12 days (mean 9 days) after stopping the infusion.
The treatment group showed increases in plasma PC EPA and DHA and erythrocyte EPA and decreases in plasma PC and erythrocyte linoleic acid, with effects most evident late in the infusion period. Plasma PC and erythrocyte EPA and linoleic acid all returned to baseline levels after the 5–12 day washout. Plasma PC DHA remained elevated above baseline after washout.
Intravenous supply of omega-3 PUFAs results in a rapid increase of EPA and DHA in plasma PC and of EPA in erythrocytes. These findings suggest that infusion of omega-3 PUFAs could be used to induce a rapid effect especially in targeting inflammation.
http://www.clinicaltrials.gov identifier NCT00942292
Parenteral nutrition; Fish oil; Omega-3 fatty acids; Eicosapentaenoic acid; Docosahexaenoic acid; Arachidonic acid; Liver metastases
It takes more than 20 years before the human brain obtains its complex, adult configuration. Most dramatic developmental changes occur prenatally and early postnatally. During development, long-chain polyunsaturated fatty acids (LCPUFA) such as doxosahexaenoic acid (DHA) and arachidonic acid (AA) are accreted in the brain. Since breastfeeding is associated with a better developmental outcome than formula feeding, and human milk in contrast to traditional standard formula contains LCPUFA, the question arose whether LCPUFA supplementation of infant formula may promote the neurodevelopmental outcome. The current paper reviews the evidence available in full-term infants. It concludes that postnatal supplementation of formula with LCPUFA is associated with a beneficial effect on short-term neurodevelopmental outcome. However, no evidence is available that LCPUFA supplementation enhances neurodevelopmental outcome in full-term infants beyond the age of four months. Nevertheless, it should be realized that very limited information is available on the effect of LCPUFA supplementation on neurodevelopmental outcome at school age or later. It is conceivable that effects of LCPUFA supplementation first emerge or re-emerge at school age when more complex neural functions are expressed.
LCPUFA; docosahexaenoic acid; arachidonic acid; full-term; infant; neurodevelopment; cognition; breast feeding
The fatty acid compositions of the major cerebral cortex phospholipids, phosphatidylcholine, phosphatidylethanolamine, and phosphatidylserine were measured in 16 term and one preterm 'cot death' infants fed exclusively either breast milk or one of two formulas. Docosahexaenoic acid (DHA; C22:6n-3) content in cerebral cortex phosphatidylethanolamine and phosphatidylserine of breast fed infants was greater than in both formula groups with significances varying between p < 0.1 and p < 0.001. Compensation for this deficiency in DHA in the formula fed infants was largely achieved by increased incorporation of docosapentaenoic acid (C22:5n-6) in the cerebral cortex of term infants and Mead (C20:3n-9) and dihomo Mead acids (C22:3n-9) in the preterm infant. As the phospholipids most affected are known to perform an important role in membrane function and are possibly integral to neurotransmission it is recommended that breast milk substitute infant formulas should contain n-3 and n-6 series polyunsaturated fatty acids in proportions similar to those of human milk.
Breast milk fatty acid (FA) composition varies greatly among individual women, including in percentages of the long-chain polyunsaturated FAs (LCPUFA) 20:4n-6 (arachidonic acid, AA) and 22:6n-3 (docosahexaenoic acid, DHA), which are important for infant neurological development. It has been suggested that owing to wide variation in milk LCPUFA and low DHA in Western diets, standards of milk FA composition should be derived from populations consuming traditional diets. We collected breast milk samples from Tsimane women at varying lactational stages (6–82 weeks). The Tsimane are an indigenous, natural fertility, subsistence-level population living in Amazonia Bolivia. Tsimane samples were matched by lactational stage to samples from a US milk bank, and analysed concurrently for FA composition by gas-liquid chromatography. We compared milk FA composition between Tsimane (n = 35) and US (n = 35) mothers, focusing on differences in LCPUFA percentages that may be due to population-typical dietary patterns. Per total FAs, the percentages of AA, DHA, total n-3 and total n-6 LCPUFA were significantly higher among Tsimane mothers. Mean percentages of 18:2n-6 (linoleic acid) and trans FAs were significantly higher among US mothers. Tsimane mothers’ higher milk n-3 and n-6 LCPUFA percentages may be due to their regular consumption of wild game and freshwater fish, as well as comparatively lower intakes of processed foods and oils that may interfere with LCPUFA synthesis.
lactation; diet; docosahexaenoic acid; arachidonic acid; breast milk; infant and child nutrition
We reported that the compositions of arachidonic acid (ARA) in erythrocytes and plasma phospholipids (PL) in the elderly were lower than those in the young, though the ARA intake was nearly identical.
We further analyzed data in four study groups with different ages and sexes, and determined that the blood ARA levels were affected by the kinds of dietary fatty acids ingested.
One hundred and four healthy young and elderly volunteers were recruited. Dietary records together with photographic records from 28 consecutive days were reviewed and the fatty acid composition in plasma lipid fractions and erythrocyte PL was analyzed.
No correlations for ARA between dietary fatty acids and blood lipid fractions were observed. A significant negative correlation between eicosapentaenoic acid (EPA) + docosahexaenoic acid (DHA) intake and ARA composition in erythrocyte PL was observed. ARA composition in erythrocyte PL was significantly lower in elderly subjects than in young subjects, because EPA and DHA intake in elderly subjects was higher than in young subjects. However, after removing the effect of dietary EPA+DHA intake, the ARA composition in erythrocyte PL in elderly subjects was significantly lower than that in young subjects.
Changes in physical conditions with aging influenced the low ARA composition of erythrocyte in elderly subjects in addition to the effects of dietary EPA and DHA.
Docosahexaenoic acid (DHA) is a long-chain polyunsaturated fatty acid important for neonatal neurodevelopment and immune homeostasis. Preterm infants fed donor milk from a Midwestern source receive only 20% of the intrauterine accretion of DHA. We tested the hypothesis that DHA supplementation of donor mothers would provide preterm infants with DHA intake equivalent to fetal accretion.
Subjects and Methods
After Institutional Review Board approval and informed consent, human milk donors to the Mother's Milk Bank of Ohio were randomized to receive 1 g of DHA (Martek® [now DSM Nutritional Lipids, Columbia, MD]) or placebo soy oil. Dietary intake data were collected and analyzed by a registered dietitian. Fatty acids were measured by gas chromatography/flame ionization detection. Statistical analysis used linear mixed models.
Twenty-one mothers were randomly assigned to either the DHA group (n=10) or the placebo group (n=11). Donor age was a median of 31 years in both groups with a mean lactational stage of 19 weeks. Dietary intake of DHA at baseline in both groups was a median of 23 mg/day (range, 0–194 mg), significantly (p<0.0001) less than the minimum recommended intake of 200 mg/day. The DHA content of milk increased in the DHA-supplemented group (p<0.05).
The women enrolled in this study had low dietary DHA intake. Supplementation with preformed DHA at 1 g/day resulted in increased DHA concentrations in the donor milk with no adverse outcomes. Infants fed donor milk from supplemented women receive dietary DHA levels that closely mimic normal intrauterine accretion during the third trimester.
The erythrocyte membrane content of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), which constitutes the omega‐3 index (O3I), predicts cardiovascular disease mortality. The amount of EPA+DHA needed to achieve a target O3I is poorly defined, as are the determinants of the O3I response to a change in EPA+DHA intake. The objective of this study was to develop a predictive model of the O3I response to EPA+DHA supplementation in healthy adults, specifically identifying factors that determine the response.
Methods and Results
A randomized, placebo‐controlled, double‐blind, parallel‐group study was conducted in 115 healthy men and women. One of 5 doses (0, 300, 600, 900, 1800 mg) of EPA+DHA was given daily as placebo or fish oil supplements for ≈5 months. The O3I was measured at baseline and at the end of the study. There were no significant differences in the clinical characteristics between the groups at baseline. The O3I increased in a dose‐dependent manner (P<0.0001), with the dose of EPA+DHA alone accounting for 68% (quadratic, P<0.0001) of the variability in the O3I response. Dose adjusted per unit body weight (g/kg) accounted for 70% (linear, P<0.0001). Additional factors that improved prediction of treatment response were baseline O3I, age, sex, and physical activity. Collectively, these explained 78% of the response variability (P<0.0001).
Our findings validate the O3I as a biomarker of EPA+DHA consumption and identify additional factors, particularly body weight, that can be used to tailor EPA+DHA recommendations to achieve a target O3I.
blood cell; fatty acids; fish oil; metabolism; nutrition
This study determined the sensitivity of heart and brain arachidonic acid (ARA) and docosahexaenoic acid (DHA) to the dietary ARA level in a dose-response design with constant, high DHA in neonatal piglets. On day 3 of age, pigs were assigned to 1 of 6 dietary formulas varying in ARA/DHA as follows (% fatty acid, FA/FA): (A1) 0.1/1.0; (A2) 0.53/1.0; (A3-D3) 0.69/1.0; (A4) 1.1/1.0; (D2) 0.67/0.62; (D1) 0.66/0.33. At necropsy (day 28) higher levels of dietary ARA were associated with increased heart and liver ARA, while brain ARA remained unaffected. Dietary ARA had no effect on tissue DHA accretion. Heart was particularly sensitive, with pigs in the intermediate groups having different ARA (A2, 18.6 ± 0.7%; A3, 19.4 ± 1.0%) and a 0.17% increase in dietary ARA resulted in a 0.84% increase in heart ARA. Further investigations are warranted to determine the clinical significance of heart ARA status in developing neonates.
Piglet; Arachidonic acid; Infant nutrition; Docosahexaenoic acid
The nucleoside analogue arabinosylcytosine (araC) has been used for many years in the treatment of acute leukemia. Evidence in the literature suggests that araC may inhibit the growth of human colon carcinoma cell lines as well. Because araC action interferes with normal nucleoside metabolism, it is highly toxic to a number of normal cell types including bone marrow and intestinal mucosa cells. Here we investigate whether the omega-3 fatty acid docosahexaenoic acid (DHA) could selectively target araC toxicity toward colonic tumor cells while protecting the normal cells in vitro.
Cultures of normal rat colonic epithelial cells (4D/WT) and those transformed by v-src (D/v-src) were supplemented with graded concentrations of DHA or arachidonic acid (AA) alone or in combination with araC. AraC was only 1.6 fold more toxic to D/v-src than 4D/WT in cultures without added fatty acids. Supplementing with as little as 3 μM of either AA or DHA increased araC toxicity by more than 30-fold in the tumorigenic cells. The toxic effect of araC on the normal cells was also increased by the fatty acid supplementation. IC50 values were decreased 1.7 fold by DHA in the 4D/WT cells but a more than 7-fold decrease was observed during AA supplementation. As a result, the therapeutic index of araC (IC50 normal/IC50 tumor) was more than 3-fold higher in the DHA than the AA supplemented cells. The expression of protein kinase C isoform epsilon was decreased in AA alone supplemented D/v-src cultures but in combination with araC decreased only in DHA supplemented 4D/WT cells.
Low dose DHA supplementation may enhance araC chemotherapy in colon cancer while protecting normal tissues, possibly through control of PKC signalling pathways.
Docosahexaenoic acid (DHA) is a long-chain omega-3 polyunsaturated fatty acid (LCPUFA) that is critically important for the structure, development and function of the retina and central nervous system (CNS), ultimately contributing to improved cognition. It is known that the DHA content of breast milk is positively correlated with maternal DHA intake. Since there is a lack of information about the DHA status of pregnant and lactating women in rural Taiwan. The aims of the present study were to: 1) assess the DHA status of mothers and babies in urban setting, and 2) determine the content of DHA in the milk of nursing mothers.
All pregnant women who attended the Obstetrics and Gynecology Outpatient Clinic of Kinmen Hospital on Kinmen Island in Taiwan between May 1 and May 30, 2011 were invited by research nurses to enroll in the study. The maternal blood sample was obtained on the day of their delivery. Cord blood was collected by the obstetrician following delivery. Participants were asked to visit the doctor forty-two days after the delivery, at which time a nurse collected breast milk on the day mothers were visiting the doctor for post-natal well-baby check-up.
The DHA percentages of maternal and neonatal plasma phospholipids were 5.16% and 6.36%, respectively, which are higher than values reported for most populations elsewhere in the world. The DHA percentage for the breast milk of Kinmen mothers was also high (0.98%) relation to international norms. The DHA proportions in maternal and neonatal plasma phospholipids were positively correlated (r = 0.46, p = 0.01).
We show that the DHA status of mothers and newborns on Kinmen Island is satisfactory, thereby providing an evidence-based argument for promoting breastfeeding in Taiwan.
Breast milk; Lactation; Neonates; Fish intake; Kinmen; Docosahexaenoic acid; Pregnancy; Fatty acids
Polyunsaturated fatty acids are essential nutrients for humans. They are structural and functional components of cell membranes and pre-stages of the hormonally and immunologically active eicosanoids. Recent discoveries have shown that the long-chained omega-3 fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) also play an important role in the central nervous system. They are essential for normal brain functioning including attention and other neuropsychological skills.
Materials and methods
In our large observational study we monitored 810 children from 5 to 12 years of age referred for medical help and recommended for consuming polyunsaturated fatty acids (PUFA) in combination with zinc and magnesium by a physician over a period of at least 3 months. The food supplement ESPRICO® (further on referred to as the food supplement) is developed on the basis of current nutritional science and containing a combination of omega-3 and omega-6 fatty acids as well as magnesium and zinc. Study objective was to evaluate the nutritional effects of the PUFA-zinc-magnesium combination on symptoms of attention deficit, impulsivity, and hyperactivity as well as on emotional problems and sleep related parameters. Assessment was performed by internationally standardised evaluation scales, i.e. SNAP-IV and SDQ. Tolerance (adverse events) and acceptance (compliance) of the dietary therapy were documented.
After 12 weeks of consumption of a combination of omega-3 and omega-6 fatty acids as well as magnesium and zinc most subjects showed a considerable reduction in symptoms of attention deficit and hyperactivity/impulsivity assessed by SNAP-IV. Further, the assessment by SDQ revealed fewer emotional problems at the end of the study period compared to baseline and also sleeping disorders. Mainly problems to fall asleep, decreased during the 12 week nutritional therapy. Regarding safety, no serious adverse events occurred. A total of 16 adverse events with a possible causal relationship to the study medication were reported by 14 children (1.7%) and only 5.2% of the children discontinued the study due to acceptance problems. Continuation of consumption of the food supplement was recommended by the paediatricians for 61.1% of the children.
Our results suggest a beneficial effect of a combination of omega-3 and omega-6 fatty acids as well as magnesium and zinc consumption on attentional, behavioural, and emotional problems of children and adolescents. Thus, considering the behavioural benefit in combination with the low risk due to a good safety profile, the dietary supplementation with PUFA in combination with zinc and magnesium can be recommended.
Accepted 11 December
AIM—A follow up study of developmental quotient
(DQ) at 24 months of toddlers whose diets in early infancy differed in
fatty acid composition, and in whom an association between diet and DQ
was observed at 4months.
METHODS—81 toddlers were distributed among three
groups according to early type of diet: standard infant formula (SFo, n = 30); long chain polyunsaturated fatty acid (LC-PUFA) enriched formula
(LCPFo, n = 26); human milk (HM, n = 25). DQ at 24 months was
assessed by Brunet-Lézine's psychomotor developmental test. A
subgroup (n = 20; SFo 8; LCPFo 6; HM 6) was tested for erythrocyte
phosphatidylcholine and phosphatidylethanolamine.
RESULTS—No DQ differences were found by analysis
of variance. Neither DQ nor erythrocyte docosahexaenoic acid at 4 months were predictors of DQ scores at 24 months. Phosphatidylcholine
arachidonic and docosahexaenoic acid correlated positively, and
phosphatidylcholine linoleic acid and phosphatidylethanolamine
eicosapentaenoic acid negatively, with DQ. Multiple regression analysis
including these variables explained 52% of interindividual DQ
variance. A strong association was found between the erythrocyte
phosphatidylcholine arachidonic/linoleic acid ratio and DQ (r
= 0.75; p = 0.0001).
CONCLUSIONS—The diet/DQ association found at 4 months was not predictive of DQ scores at 24 months. Irrespective of
dietary or genetic factors, there appears to be a strong correlation
between the LC-PUFA composition of the red cell membrane and higher
Cholesterol and docosahexaenoic acid (DHA) are important nutrients for neural development of infants. However, little is known about the effect of cholesterol or DHA on concentrations of amino acids (AA) in neonatal tissues. This study was conducted with the piglet (an established model for studying human infant nutrition) to test the hypothesis that dietary supplementation with the lipids may modulate AA availability in tissues. Sixteen newborn pigs were nursed by sows for 24 h and then assigned to one of four treatment groups, representing supplementation with 0.0% (control), 0.2% cholesterol, 0.2% DHA, or cholesterol plus DHA to the basal milk-formula. All piglets were euthanized at 49 days of age. In brain, cholesterol supplementation reduced (P < 0.05) concentrations of glutamate, serine, glutamine, threonine, β-alanine, alanine, methionine, isoleucine, leucine, and γ-aminobutyrate but increased (P < 0.05) concentrations of glycine and lysine, whereas DHA supplementation similarly affected (P < 0.05) concentrations of the same AA (except for isoleucine and lysine) and taurine. In addition, concentrations of most AA in liver, muscle and plasma were substantially altered by dietary supplementation of cholesterol and DHA in a tissue-dependent manner. Further, DHA reduced concentrations of carnosine in skeletal muscle, as well as ammonia in both plasma and brain. The results reveal that cholesterol and DHA can regulate AA metabolism and availability in various tissues of piglets. These novel findings have important implications for designing the next generation of infant formula to optimize neonatal growth and development.
Cholesterol; Docosahexaenoic acid; Amino acids; Pigs
Conventional soybean lipid emulsions contain no docosahexaenoic acid (DHA) or arachidonic acid (AA). We investigated the relationship between blood DHA and AA status in 27 very-low-birth-weight (VLBW) infants with or without parenteral lipid emulsion.
Sixteen infants received parenteral lipid emulsion, and 11 infants were control group. The fatty acid composition of the erythrocyte membrane was analysed at birth and at 2 weeks of age.
No significant difference in AA levels was observed in the lipid emulsion group between the two time points, whereas the AA levels at 2 weeks were significantly lower than at birth in the control group. The DHA levels in both groups at 2 weeks were significantly lower than at birth, but no group differences were observed at both time points.
The use of parenteral soybean oil lipid emulsions in VLBW infants in the postnatal period may prevent the decline in the AA level but does not appear to influence the DHA level.
Arachidonic acid; Docosahexaenoic acid; Fat emulsions; Soybean oil; Very-low-birth-weight infants
To determine fatty acid levels in the US donor milk supply.
Donor human milk samples from Iowa (n=62), Texas (n=5), North Carolina (n=5), and California (n=5) were analyzed by gas chromatography. Levels in Iowa donor milk were compared before and after pasteurization using Student’s t-test. Docosahexaenoic acid (DHA) and arachidonic acid (ARA) levels were compared among all milk banks using ANOVA.
ARA (0.4 pre, 0.4 post, p=0.18) and DHA (0.073 pre, 0.073 post, p=0.84) were not affected by pasteurization. DHA varied between banks (p <0.0001), whereas ARA did not (p = 0.3). DHA levels from all banks were lower than published values for maternal milk and infant formula (p<0.0001).
Pasteurization of breastmilk does not affect DHA or ARA levels. However, DHA content in US donor milk varies with bank location and may not meet the recommended provision for preterm infants.
Long chain polyunsaturated fatty acids (LCPUFA); docosahexaenoic acid (DHA); arachidonic acid (ARA); donor human milk; neonatal nutrition