Transfer Of Docosahexaenoic Acid Research Articles

Creation of a novel zebrafish model with low DHA status to study the role of maternal nutrition during neurodevelopment.

Docosahexaenoic acid (DHA), a dietary omega-3 fatty acid, is a major building block of brain cell membranes. Offspring rely on maternal DHA transfer to meet their neurodevelopmental needs, but DHA sources are lacking in the American diet. Low DHA status is linked to altered immune responses, white matter defects, impaired vision, and an increased risk of psychiatric disorders during development. However, the underlying cellular mechanisms involved are largely unknown, and advancements in the field have been limited by the existing tools and animal models. Zebrafish are an excellent model for studying neurodevelopmental mechanisms. Embryos undergo rapid external development and are optically transparent, enabling direct observation of individual cells and dynamic cell-cell interactions in a way that is not possible in rodents. Here, we create a novel DHA-deficient zebrafish model by 1) disrupting elovl2, a key gene in the DHA biosynthesis pathway, via CRISPR-Cas9 genome editing, and 2) feeding mothers a DHA-deficient diet. We show that low DHA status during development is associated with a small eye morphological phenotype and demonstrate that even the morphologically normal siblings exhibit dysregulated gene pathways related to vision and stress response. Future work using our zebrafish model could reveal the cellular and molecular mechanisms by which low DHA status leads to neurodevelopmental abnormalities and provide insight into maternal nutritional strategies that optimize infant brain health.

Dynamics of Docosahexaenoic Acid Utilization by Mouse Peritoneal Macrophages.

In this work, the incorporation of docosahexaenoic acid (DHA) in mouse resident peritoneal macrophages and its redistribution within the various phospholipid classes were investigated. Choline glycerophospholipids (PC) behaved as the major initial acceptors of DHA. Prolonged incubation with the fatty acid resulted in the transfer of DHA from PC to ethanolamine glycerophospholipids (PE), reflecting phospholipid remodeling. This process resulted in the cells containing similar amounts of DHA in PC and PE in the resting state. Mass spectrometry-based lipidomic analyses of phospholipid molecular species indicated a marked abundance of DHA in ether phospholipids. Stimulation of the macrophages with yeast-derived zymosan resulted in significant decreases in the levels of all DHA-containing PC and PI species; however, no PE or PS molecular species were found to decrease. In contrast, the levels of an unusual DHA-containing species, namely PI(20:4/22:6), which was barely present in resting cells, were found to markedly increase under zymosan stimulation. The levels of this phospholipid also significantly increased when the calcium-ionophore A23187 or platelet-activating factor were used instead of zymosan to stimulate the macrophages. The study of the route involved in the synthesis of PI(20:4/22:6) suggested that this species is produced through deacylation/reacylation reactions. These results define the increases in PI(20:4/22:6) as a novel lipid metabolic marker of mouse macrophage activation, and provide novel information to understand the regulation of phospholipid fatty acid turnover in activated macrophages.

Complexity of understanding the role of dietary and erythrocyte docosahexaenoic acid (DHA) on the cognitive performance of school-age children

ABSTRACTBackgroundEarly childhood is a period of rapid brain development, with increases in synapses rich in the omega-3 (ω-3) fatty acid, DHA (22:6ω-3) continuing well beyond infancy. Despite the importance of DHA to neural phospholipids, the requirement of dietary DHA for neurodevelopment remains unclear.ObjectivesThe aim was to assess the dietary DHA and DHA status of young children, and determine the association with cognitive performance.MethodsThis was a cross-sectional study of healthy children (5–6 y), some of whom were enrolled in a follow-up of a clinical trial (NCT00620672). Dietary intake data (n = 285) were assessed with a food-frequency questionnaire (FFQ) and three 24-h recalls. Family characteristics were collected by questionnaire, and anthropometric data measured. Venous blood was collected, cognitive performance assessed using several age-appropriate tools including the Kaufman Assessment Battery for Children. The relation between dietary DHA, RBC DHA, and child neurodevelopment test scores was determined using Pearson's correlation or Spearman's rho, and quintiles of test scores compared by Mann–Whitney U test.ResultsChild DHA intakes were highly variable, with a stronger association between RBC DHA and DHA intake assessed by FFQ (rho = 0.383, P < 0.001) compared with one or three 24-h recalls. Observed ethnic differences in DHA intake status as well as neurodevelopmental test scores led to analysis of the association between DHA intake and status with neurodevelopment test scores for White children only (n = 190). Child RBC DHA status was associated with neurodevelopment test scores, including language (rho = 0.211, P = 0.009) and short-term memory (rho = 0.187, P = 0.019), but only short-term memory was associated with dietary DHA (rho = 0.221, P = 0.003).ConclusionsChild RBC DHA but not dietary DHA was associated with multiple tests of cognitive performance. In addition, DHA intake was only moderately associated with RBC DHA, raising complex questions on the relation between diet, DHA transfer to membrane lipids, and neural function.

Acute injection of a DHA triglyceride emulsion after hypoxic-ischemic brain injury in mice increases both DHA and EPA levels in blood and brain✰

We recently reported that acute injection of docosahexaenoic acid (DHA) triglyceride emulsions (tri-DHA) conferred neuroprotection after hypoxic-ischemic (HI) injury in a neonatal mouse stroke model. We showed that exogenous DHA increased concentrations of DHA in brain mitochondria as well as DHA-derived specialized pro-resolving mediator (SPM) levels in the brain. The objective of the present study was to investigate the distribution of emulsion particles and changes in plasma lipid profiles after tri-DHA injection in naïve mice and in animals subjected to HI injury. We also examined whether tri-DHA injection would change DHA- and eicosapentaenoic acid (EPA)-derived SPM levels in the brain. To address this, neonatal (10-day-old) naïve and HI mice were injected with radiolabeled tri-DHA emulsion (0.375 g tri-DHA/kg bw), and blood clearance and tissue distribution were analyzed. Among all the organs assayed, the lowest uptake of emulsion particles was in the brain (<0.4% recovered dose) in both naïve and HI mice, while the liver had the highest uptake. Tri-DHA administration increased DHA concentrations in plasma lysophosphatidylcholine and non-esterified fatty acids. Additionally, treatment with tri-DHA after HI injury significantly elevated the levels of DHA-derived SPMs and monohydroxy-containing DHA-derived products in the brain. Further, tri-DHA administration increased resolvin E2 (RvE2, 5S,18R-dihydroxy-eicosa-6E,8Z,11Z,14Z,16E-pentaenoic acid) and monohydroxy-containing EPA-derived products in the brain. These results suggest that the transfer of DHA through plasma lipid pools plays an important role in DHA brain transport in neonatal mice subjected to HI injury. Furthermore, increases in EPA and EPA-derived SPMs following tri-DHA injection demonstrate interlinked metabolism of these two fatty acids. Hence, changes in both EPA and DHA profile patterns need to be considered when studying the protective effects of DHA after HI brain injury. Our results highlight the need for further investigation to differentiate the effects of DHA from EPA on neuroprotective pathways following HI damage. Such information could contribute to the development of specific DHA-EPA formulations to improve clinical endpoints and modulate potential biomarkers in ischemic brain injury.

Effects of dietary microalgae (Schizochytrium spp.) supplement on milk performance, blood parameters, and milk fatty acid composition in dairy cows

The objective of this study was to examine the effects of dietary inclusion of microalgae (Schizochytrium spp.) on milk yield, milk composition, and docosahexaenoic acid (DHA) transfer efficiency in dairy cows. Thirty-six lactating Chinese-Holstein dairy cows were randomly allocated to three treatment groups (n = 12; 0, 170, and 255 g microalgae supplement per day) in a 60-day experimental period. No significant treatment effect was observed on DMI and milk performance. Similarly, there was no significant microalgae supplement effect on blood haematological and biochemical parameters, except for platelets (P &amp;lt; 0.01) and thrombocytosis (P &amp;lt; 0.01), suggesting that the inclusion of microalgae in dairy cow diets would not affect production performance and animal health. Compared to the control group, adding 170 and 255 g microalgae to diets significantly increased the proportion of linoleic acid, DHA, n-3 and n-3/n-6 ratio in the blood (P &amp;lt; 0.05). Consequently, DHA concentration and n-3/n-6 ratio were increased in milk, indicating that the milk fatty acid composition could be affected by nutritional manipulation. The overall DHA transfer efficiency was 10.1% and 11.3% for 170 and 255 g microalgae supplement, suggesting that the addition of microalgae to dairy cow diets is a feasible strategy to produce DHA enriched milk in practice.

Elevated Glucose and Insulin Levels Decrease DHA Transfer across Human Trophoblasts via SIRT1-Dependent Mechanism.

Gestational diabetes mellitus (GDM) results in reduced docosahexaenoic acid (DHA) transfer to the fetus, likely due to placental dysfunction. Sirtuin-1 (SIRT1) is a nutrient sensor and regulator of lipid metabolism. This study investigated whether the high glucose and insulin condition of GDM regulates DHA transfer and expression of fatty acid transporters and if this effect is related to SIRT1 expression and function. Syncytialized primary human trophoblasts were treated with and without glucose (25 mmol/L) and insulin (10−7 mol/L) for 72 h to mimic the insulin-resistance conditions of GDM pregnancies. In control conditions, DHA transfer across trophoblasts increased in a time- and dose-dependent manner. Exposure to GDM conditions significantly decreased DHA transfer, but increased triglyceride accumulation and fatty acid transporter expression (CD36, FABP3, and FABP4). GDM conditions significantly suppressed SIRT1 mRNA and protein expression. The SIRT1 inhibitor decreased DHA transfer across control trophoblasts, and recombinant SIRT1 and SIRT1 activators restored the decreased DHA transport induced by GDM conditions. The results demonstrate a novel role of SIRT1 in the regulation of DHA transfer across trophoblasts. The suppressed SIRT1 expression and the resultant decrease in placental DHA transfer caused by high glucose and insulin levels suggest new insights of molecular mechanisms linking GDM to fetal DHA deficiency.

Docosahexaenoic Acid Included in Layer Feed as an Unextracted Aurantiochytrium limacinum Biomass Is Efficiently Transferred to Eggs When Provided in Mash or Pellet Form

SUMMARY Pelleting is commonly used in the production of poultry feed as it can reduce waste, kill pathogenic bacteria, and improve productivity. However, high temperatures used during production can negatively impact some feed ingredients. Omega-3 long-chain polyunsaturated fatty acid (n-3 LC-PUFA)-rich ingredients are often added to poultry feed to increase the n-3 LC-PUFA concentration of meat and eggs, adding value due to the health benefits associated with n-3 LC-PUFA consumption. Fish oils have traditionally been used for this purpose, but the n-3 LC-PUFA they contain are susceptible to oxidation, which can result in rancidity in enriched poultry products. Alternatively, protists that are primary producers of n-3 LC-PUFA are used. When provided in an unextracted form, these organisms could potentially protect the n-3 LC-PUFA they contain from oxidation. Aurantiochytrium limacinum is a marine protist, rich in docosahexaenoic acid (DHA), an n-3 LC-PUFA associated with various health benefits. We supplemented layer feed with A. limacinum and investigated the effect of pelleting on the recovery of DHA from feed and the efficiency of DHA transfer from feed to eggs. Pelleting did not decrease the concentration of DHA in feed. Also, no differences were observed between the groups fed mash or pelleted feeds in terms of the level of DHA enrichment of eggs. These results indicate that DHA, in the form of an A. limacinum biomass, is resistant to pelleting conditions and can be used as an ingredient in pelleted poultry diets to increase the DHA concentration of poultry products.

Lipids at the plant–animal interface: a stable isotope labelling method to evaluate the assimilation of essential fatty acids in the marine copepod Calanus finmarchicus

AbstractLinking production, transfer and subsequent bioavailability of nutritionally significant matter from phytoplankton to higher trophic levels is a fundamental aspect in understanding marine food webs. The plant–animal interface is of interest because of the highly variable transfer between producers and consumers, and the myriad of factors that influence it. Essential fatty acids (EFAs) are dietary nutrients that are necessary for normal function in all consumers, yet it remains unclear how efficiently they are transferred through marine food webs. We introduced a 13C-labelled carbon source to the cryptophyte Rhodomonas salina to quantify primary production of two omega-3 long-chain polyunsaturated fatty acids (PUFAs), eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). We investigated transfer and assimilation efficiencies of these EFAs from phytoplankton to the calanoid copepod Calanus finmarchicus in an 8-day feeding experiment. We found low production of both EFAs in R. salina. Assimilation efficiencies of both EFAs ranged from 5 to 15% throughout the experiment, remaining slightly higher on average for DHA. This was mirrored in more efficient trophic transfer of DHA (up to 28%, compared to 13% for EPA). These results add to previously scarce experiments empirically quantifying the assimilation and transfer efficiency of EFAs in a basic marine planktonic food chain.

Relationships between docosahexaenoic acid compositions of maternal and umbilical cord erythrocytes in pregnant Japanese women

Previous reports have shown that the transfer of docosahexaenoic acid (DHA) from mother to fetus during pregnancy is important for development of the child's nervous and visual functions. The amount of DHA passing through the placenta varies depending on the relative DHA compositions of the erythrocytes in the maternal blood and the umbilical cord. Prior research has reported that if the DHA composition of the maternal erythrocytes is over 5.6 g%, DHA in the erythrocytes of the child undergoes bioattenuation, whereas it undergoes biomagnification if the maternal erythrocyte composition is lower than 5.6 g%. The relationship between DHA levels in maternal erythrocytes during pregnancy and in umbilical cord erythrocytes at delivery was assessed in Japanese pregnant women. This study was performed as an adjunct study of the Japan Environment and Children's Study. DHA compositions of maternal erythrocytes at 24–30 weeks of pregnancy and of umbilical cord erythrocytes at delivery were determined in 1368 mother-infant pairs. Median DHA values were 7.41% in the maternal erythrocytes and 6.84% in the umbilical cord erythrocytes, indicating significantly lower levels in the umbilical cord. When DHA composition in maternal erythrocytes was lower than 6.6%, DHA was theoretically higher in umbilical cord erythrocytes than in maternal erythrocytes. Conversely, when DHA composition in maternal erythrocytes was higher than 6.6%, DHA in umbilical cord erythrocytes was theoretically lower than in maternal erythrocytes. We therefore consider that there is a turning point of around 6% in the DHA composition of maternal and umbilical cord blood that is exchanged between mother and fetus: if the composition in the maternal blood is higher, then bioattenuation in DHA transfer from the maternal circulation to the umbilical cord occurs, while if it is lower, then biomagnification occurs. This corroborates the findings of previous research.

Tolerance of Broilers to Dietary Supplementation with High Levels of the DHA-Rich Microalga, Aurantiochytrium Limacinum: Effects on Health and Productivity.

Simple SummaryDocosahexaenoic acid (DHA) is an omega-3 fatty acid that is considered an essential part of the human diet. Increasing the amount of DHA in commonly consumed foodstuffs can benefit people predisposed to heart problems, depression, and even some forms of cancer. One of the best sources of DHA is oily fish, but the majority of people do not eat fish regularly. By formulating diets for livestock or poultry to include ingredients rich in omega-3 fatty acids, we can increase the omega-3 content of their respective meat and tissues. In this study we fed broilers diets supplemented with increasing amounts of a DHA-rich microalgae to investigate whether it was safe for the birds, in terms of their health and productivity and effective in terms of DHA transfer from feed to meat. The results of the present study showed that feeding the microalgae to chickens had no negative effects on their health in terms of their level of survival or growth. Moreover, we found that supplementing the microalgae resulted in a large increase in the DHA content of meat. This study demonstrated that feeding algae is a safe and effective way to improve the nutritional value of chicken meat.It is well established that the docosahexaenoic acid (DHA) content of commonly consumed meats, such as chicken, can be increased through dietary supplementation with DHA-rich ingredients. The purpose of this study was to investigate the tolerance of broilers to dietary supplementation with the unextracted biomass of a DHA-rich microalgae Aurantiochytrium limacinum, so as to ensure its safety, since it is accumulated in broiler meat. Healthy day-old male Ross 308 chicks (n = 1120) were evenly distributed to 32 pens (35 chicks per pen), with pens randomly allocated to one of four dietary treatments, each having eight replicates. The dietary groups included one untreated control and three treatments corresponding to three inclusion levels (0.5, 2.5, and 5.0%) of All-G-Rich®, with the birds receiving the experimental diets ad libitum during the study (day 0–42). Bird survival, blood parameters, productivity, and breast and thigh DHA content were determined after 42 days of feeding. Supplementation at up to 10 times the intended use level had no negative effects on the mortality, blood parameters or productivity of the birds, while significant increases in the meat DHA content were observed. These results indicate that supplementation with Aurantiochytrium limacinum is a safe and effective way to increase broiler tissue DHA content.

Do autochthonous resources enhance trophic transfer of allochthonous organic matter to aquatic consumers, or vice versa?

AbstractAutochthonous and allochthonous resources are known to differ in nutritional quality and trophic support for aquatic food webs, but it is less clear how these high‐ and low‐quality resources interact to affect trophic transfer and consumer production. We conducted 30‐d feeding trials to investigate the resource assimilation, somatic growth, and fatty‐acid (FA) composition of the widespread benthic generalist isopod Asellus aquaticus, in response to different ratios of low‐quality allochthonous (leaf litter) to high‐quality autochthonous diets (algae). Wet mass growth of Asellus was lowest when fed 100% leaf litter or algae (0.53 ± 0.46 and 0.55 ± 0.57 mg·g−1·d−1, respectively; mean ± SE) and highest (4.95 ± 0.51 mg·g−1·d−1) with a diet of 90:10 leaf litter:algae ratio. Asellus tended to grow slower with increasing dietary algal proportions (10–100%), yet stable isotopes and Bayesian mixing models revealed consistently high algal assimilation (≥94%) by Asellus. Therefore, among the mixed‐diet treatments, Asellus biomass production using algal resources was optimized when terrestrial organic matter (OM) dominated over algae. Eicosapentaenoic acid (EPA):total FA, EPA:omega‐3 FA, and arachidonic acid:total FA declined, but docosahexaenoic acid (DHA):omega‐3 FA increased, with increasing growth of Asellus. Tissue EPA concentrations of Asellus were similar among treatments, so reductions in EPA:omega‐3 and EPA:total FA were due to increases in DHA concentration. Overall, our results suggest synergistic effects between autochthonous and allochthonous resources on Asellus growth and that allochthonous OM particularly facilitates the trophic transfer of autochthonous resources. Asellus preferentially retains DHA at low algal availability. This may improve its neural tissue development and so its success in accessing algae. The growth and FA responses of the widespread Asellus can enhance resource and DHA transfer to visual predators that have greater DHA demands, particularly when brownification of boreal freshwaters likely intensifies upon global climate change.

Docosahexaenoic acid (DHA) accretion in the placenta but not the fetus is matched by plasma unesterified DHA uptake rates in pregnant Long Evans rats

Maternal delivery of docosahexaenoic acid (DHA, 22:6n-3) to the developing fetus via the placenta is required for fetal neurodevelopment, and is the only mechanism by which DHA can be accreted in the fetus. The aim of the current study was to utilize a balance model of DHA accretion combined with kinetic measures of serum unesterified DHA uptake to better understand the mechanism by which maternal DHA is delivered to the fetus via the placenta. Female rats maintained on a 2% α-linolenic acid diet free of DHA for 56 days were mated, and for balance analysis, sacrificed at 18 days of pregnancy, and fetus, placenta and maternal carcass fatty acid concentration were determined. For tissue DHA uptake, pregnant dams (14–18 days) were infused for 5 min with radiolabeled 14C-DHA and kinetic modeling was used to determine fetal and placental serum unesterified DHA uptake rates. DHA accretion rates in the fetus were determined to be 38 ± 2 nmol/d/g, 859 ± 100 nmol/d/litter and 74 ± 3 nmol/d/pup, which are all higher (P < 0.05) than the fetal serum unesterified DHA uptake rates of 16 ± 6 nmol/d/g, 239 ± 145 nmol/d/litter and 14 ± 8 nmol/d/pup. No differences (p > 0.05) in placental DHA accretion rates versus serum unesterified DHA uptake rates were observed as values varied only 6–35% between studies. No differences in placental accretion and uptake rates suggests that serum unesterified DHA is a significant pool for the maternal-placental transfer of DHA, and lower fetal DHA uptake compared to accretion supports remodeling of placental DHA for delivery to the fetus.

Reduced DHA transfer in diabetic pregnancies: mechanistic basis and long-term neurodevelopmental implications.

Infants born to diabetic mothers have a higher frequency of impaired neurodevelopment. The omega-3 or n-3 fatty acid docosahexaenoic acid (DHA) is an important structural component of neural tissue and is critical for fetal brain development. Maternal DHA supplementation during pregnancy is linked to better infant neurodevelopment; however, maternal-fetal transfer of DHA is reduced in women with diabetes. Evidence of mechanisms explaining altered maternal-fetal DHA transfer in this population is limited. This review explores existing evidence underpinning reduced maternal-fetal DHA transfer in maternal fuel metabolism in this population. Further research is necessary to evaluate the role of peroxisome proliferator-activated receptors in modulating placental fatty acid binding and maternal-fetal DHA transfer. Considerations for clinical practice include a diet high in DHA and/or provision of supplemental DHA to obstetric diabetic patients within minimum guidelines.

Efficacy of docosahexaenoic acid-enriched formula to enhance maternal and fetal blood docosahexaenoic acid levels: Randomized double-blinded placebo-controlled trial of pregnant women with gestational diabetes mellitus

Gestational diabetes mellitus (GDM) compromises the level of docosahexaenoic acid (DHA) in phospholipids of maternal and fetal red blood cells and fetal plasma. This is of some concern because of the importance of DHA for fetal neuro-visual development. We have investigated whether this abnormality could be rectified by supplementation with DHA-enriched formula. Women with GDM (n=138) recruited from Newham University Hospital, London received two capsules of DHA-enriched formula (active-group) or high oleic acid sunflower seed oil (placebo-group) from diagnosis until delivery. Maternal (baseline and delivery) and fetal (cord blood) red blood cell and plasma phospholipid fatty acid composition, and neonatal anthropometry were assessed. One hundred and fourteen women (58 active, 56 placebo) completed the trial. The active-group compared with the placebo-group had significantly enhanced level of DHA in plasma phosphatidylcholine (4.5% vs 3.8%, P=0.011), red blood cell phosphatidylcholine (2.7% vs 2.2%, P=0.022) and phosphatidylethoanolamine (9.5% vs 7.6%, P=0.002). There was no difference in cord plasma and red blood cell phospholipid DHA between the two groups. The neonates of the two groups of women had comparable anthropometric measurements at birth. Daily supplementation of 600mg DHA enhances maternal but not fetal DHA status in pregnancy complicated by GDM. The inefficacy of the supplement to improve fetal status suggests that the transfer of DHA across the placenta maybe impaired in women with the condition. Regardless of the mechanisms responsible for the impairment of the transfer, the finding has implications for the management of neonates of women with GDM because they are born with a reduced level of DHA and the condition is thought to be associated with a risk of neuro-developmental deficits. We suggest that babies of women with GDM, particularly those not suckling, similar to the babies born prematurely require formula milk fortified with a higher level of DHA.

Children’s docosahexaenoic acid (DHA), but not maternal DHA in pregnancy, is associated with psychometric tests scores at 5‐6 years of age (124.2)

Docosahexaenoic acid (DHA) is an important component of neural lipids, affecting neural function throughout life. However, the dietary, genetic and other variables that impact DHA transfer to the brain, and the potential for early deficiency to have lasting effects remains unclear. We addressed the effect of DHA in gestation and children’s intake and blood lipid DHA on cognition at 5.75 years of age. Pregnant women, n=271 were enrolled at 16 weeks gestation and randomized to 400 mg DHA/day or placebo until infant delivery; 95 children returned for follow up, and were assessed with 153 additional children. Diet was assessed using 3 day records and frequency questionnaires, and venous blood was collected. Cognitive tests included the Peabody Picture Vocabulary Test (PPVT) and Kaufman Assessment Battery for Children (KABC). The median (IQR) DHA intake was 49.4 (23.8‐102) mg/day. The red blood cell mean ± SD DHA was 5.14 ± 1.50 percent total fatty acids. No evidence of persisting effects of DHA in pregnancy on child development were found. Children’s own DHA status, but not DHA intake, was associated with better PPVT and KABC Sequential, Learning, Simultaneous, and Mental Performance scores (P &lt;0.05). Child blood lipid 22:5n‐6 and the 22:5n‐6/DHA ratio were associated with poorer PPVT and KABC performance. DHA intake explained only 15% of variability in RBC DHA, raising complex questions on the relationship between diet, DHA transfer to membrane lipids, and neural function.

Maternal n‐3 docosahexaenoic acid in gestation is associated with better early language development in term gestation infants.

Docosahexaenoic acid (DHA) is an n‐3 fatty acid present in high amounts in structural lipids of the brain and retina where it plays key roles in neurogenesis and neurite outgrowth, and the visual transduction pathway. Inadequate dietary n‐3 fatty acids during development may have short and long‐term implications for brain development, but whether n‐3 fatty acid deficiency occurs among pregnant women sufficient to limit DHA transfer for optimum fetal brain development is unclear. We used a longitudinal intervention with 400mg/d DHA or placebo from 16 wk gestation until delivery, n=220, and assessed language development at 9 mths of age. DHA supplementation increased the maternal mean erythrocyte phosphatidylethanolamine DHA by 30% at 36 wk gestation. The ability to detect contrasting consonants not present in the native language(s) is present in young infants but lost with development, usually about 9 mth age. We assessed language development using infant‐controlled habituation procedures, as the ability to discriminate phonetic difference in a voiced English and Hindi contrast. More infants of mothers in the DHA supplement than placebo group were unable to distinguish the contrast, consistent with better language development in the supplement group. DHA status in pregnancy is to be important for early infant neural development, yet in some women poor DHA status may be limit infant development. Supported by CIHR.

Long-chain Polyunsaturated Fatty Acid Transport across Human Placental Choriocarcinoma (BeWo) Cells

Long-chain polyunsaturated fatty acids (LCPUFAs) such as docosahexaenoic acid (DHA) and arachidonic acid (AA) are essential for proper development of fetal brain and retina. These LCPUFAs are selectively enriched in the fetal circulation compared with the maternal circulation. In the current study we investigated the transfer of LCPUFAs and a non-essential fatty acid (oleic acid, OA) in a transwell monolayer system of placental choriocarcinoma (BeWo) cells. We show that incubation with OA results in increased triglyceride accumulation and lipid droplet formation compared with that of DHA. The relative amount of transfer of DHA across the cell monolayer was ∼4-fold greater compared with that of OA when these fatty acids were added individually at 100 μM. This reflects the different fates of these two fatty acids in their metabolism and subsequent transport across the placental trophoblasts to the fetus. When using a mixture of fatty acids mimicking the composition of plasma non-esterified fatty acids during the last trimester of pregnancy, the transfer of OA and the LCPUFAs (DHA and AA) into the basolateral reservoir was not significantly different, whereas the transfer of palmitic acid (PA) was ∼3.5-fold higher than OA transfer. However, since the concentration of OA compared to LCPUFAs was 10-fold higher in the donor chamber, the relative transport of the LCPUFAs was higher compared with that of OA. In addition, we show that inhibiting esterification of fatty acids into acyl-CoA can modulate, in part, the degree of transport through the cells. In conclusion, the transwell model system closely mimics the mechanisms of differential fatty acid transport as observed in vivo. LCPUFAs were transported through the cells more efficiently than shorter fatty acids such as OA.

Maternal Di-(2-ethylhexyl)-phthalate Exposure Influences Essential Fatty Acid Homeostasis in Rat Placenta

Maintaining essential fatty acid (EFA) homeostasis during pregnancy is critical for fetal development. As the organ that controls the maternal-to-fetal supply of nutrients, the placenta plays a significant role in guiding EFA transfer to the fetus. Many EFA homeostasis proteins are regulated by peroxisome proliferator-activated receptors (PPARs). The metabolites of di-(2-ethylhexyl)-phthalate (DEHP), a ubiquitous environmental contaminant, might influence EFA homeostasis via trans-activation of PPARs with subsequent downstream effects on EFA transporters and enzymes. To investigate DEHP's effect on placental/fetal EFA homeostasis, female Sprague–Dawley rats were orally gavaged with either vehicle or DEHP at 750 or 1500 mg/kg/day from gestational day (GD) 0 to GD 19. Changes in the expression of several EFA homeostasis regulating proteins were determined in the junctional (JXN) and labyrinthine (LAB) zones of the placenta, including PPAR isoforms (α, β and γ), fatty acid translocase (FAT/CD36), fatty acid transport protein 1 (FATP1), plasma membrane fatty acid binding protein (FABPpm), heart cytoplasmic fatty acid binding protein (HFABP), cytochrome P450 (CYP) 4A1, and cyclooxygenase (COX)-1 and -2. Additionally, effects of DEHP maternal exposure on the placental transfer and fetal distribution of representative EFAs, arachidonic acid (AA) and docosahexaenoic acid (DHA), and the placental production of prostaglandins (PGs) were investigated. Expression of PPARα, PPARγ, FAT/CD36, FATP1, HFABP and CYP4A1 was up-regulated in JXN and/or LAB while COX-2 was down-regulated in JXN. PPARβ, FABPpm, and COX-1 demonstrated variable expression. Reduced directional maternal-to-fetal placental transfer and altered fetal distribution of AA and DHA were observed in concordance with a decreased total placental PG production. These results correlate with previous in vitro data, suggesting that DEHP could influence placental EFA homeostasis with potential downstream effects in the developing fetus.

Docosahexaenoic Acid (DHA) Supplementation Benefits Pregnancy Complicated with Gestational Diabetes Mellitus (GDM)

GDM, characterized by an alteration of glucose regulation which is first detected during pregnancy, is associated with elevated blood glucose, insulin resistance, pro‐inflammatory agents, and increased nitric oxide (NO) synthesis. Our purpose was to assess supplementation of mothers with GDM with 600 mg/day DHA (randomized to receive DHA or placebo, corn oil) (week 24 of pregnancy‐delivery, GDM mothers, n=31). Blood samples were collected at weeks 24 and 36 in pregnancy. At delivery, blood from the mother and umbilical cord were collected to assess transfer of DHA from mother to fetus and placental tissue for NO synthesis. DHA supplementation significantly increased maternal red blood cell (RBC) DHA concentration but not fetal RBC DHA. Supplementation reduced fasting glucose in GDM compared to controls and insulin resistance tended to decrease substantially more in supplemented mothers than controls. Inflammatory markers were not different between the groups, likely explained on the basis of small sample size. Placental endothelial cells from controls had increased L‐arginine utilization and elevated NO synthesis compared to the DHA supplementation group. We hypothesize that DHA decreased expression of L‐arginine transport protein and/or diminished activity of endothelial NO synthase. In conclusion, DHA supplementation of women with GDM demonstrated favorable effects regarding glucose metabolism and the NO synthetic pathway compared to controls, underscoring the importance of this n‐3 long chain fatty acid in pregnancy complicated by diabetes. (Fondo Nacional de Innovacion en Salud de Chile and Nestle)

Perinatal long chain polyunsaturated fatty acid supply Are there long term consequences?

Long-chain polyunsaturated fatty acids (LC-PUFA), especially docosahexaenoic acid (DHA), are essential components of biological membranes or act as precursors for eicosanoid formation, in case of the 20 carbon atom fatty acids, arachidonic acid (AA), dihomo-c-linolenic acid and eicosapentaenoic acid. During pregnancy LC-PUFA are enriched in the fetal circulation relative to maternal plasma. The corresponding placental processes have not been fully elucidated so far, but there are good indications that the LC-PUFA enrichment during the materno-fetal transfer is mediated by differences in the incorporation into lipid classes within the placenta between fatty acids and that specific fatty acid binding and transfer proteins are of major importance. In vitro a plasma membrane fatty acid binding protein could be identified, which preferentially binds DHA and AA compared to linoleic and oleic acids; in addition the m-RNA expression of fatty acid transfer protein 4 (FATP-4) in placental tissue was found to correlate significantly with the DHA percentage in cord blood phospholipids. After birth the percentage of LC-PUFA in infantile blood rapidly declines to levels depending on the dietary LC-PUFA supply, although preterm and full-term babies can convert linoleic and _-linolenic acids into AA and DHA, respectively. Breast milk provides preformed LC-PUFA, and breastfed infants have higher LC-PUFA levels in plasma and tissue than infants fed formulas without LC-PUFA. The high percentage of DHA in brain and other nervous tissue and the fact that the perinatal period is a period of fast brain growth suggests the importance of placental DHA transfer and dietary DHA content for optimal infantile development. Most but not all randomized, double blind, controlled clinical trials in preterm and in healthy full term infants demonstrated benefits of formulas supplemented with DHA and AA for the neurological development compared to formulas without LC-PUFA. Furthermore, according to the concept of “metabolic programming” during the perinatal period a dietary factor, such as the availability of LC-PUFA, might have long term consequences. From the available data it has to be assumed that LC-PUFA are conditionally essential substrates during early life and a further investigation of the biological mechanisms related to their availability for the infant and of potential life long effects on cognitive function and potentially also risk factors for cardiovascular diseases and allergy are certainly warranted.