Placental Docosahexaenoic Acid Research Articles

Maternal Docosahexaenoic Acid Supplementation Alters Maternal and Fetal Docosahexaenoic Acid Status and Placenta Phospholipids in Pregnancies Complicated by High Body Mass Index.

An optimal fetal supply of docosahexaenoic acid (DHA) is critical for normal brain development. The relationship between maternal DHA intake and DHA delivery to the fetus is complex and is dependent on placental handling of DHA. Little data exist on placental DHA levels in pregnancies supplemented with the recommended dose of 200 mg/d. Our objective was to determine how prenatal DHA at the recommended 200 mg/d impacts maternal, placental, and fetal DHA status in both normal-weight and high-BMI women compared to women taking no supplements. Maternal blood, placenta, and cord blood were collected from 30 healthy pregnant women (BMI 18.9-43.26 kg/m2) giving birth at term. Red blood cells (RBCs) and villous tissue were isolated, and lipids were extracted to determine DHA content by LC-MS/MS. Data were analyzed by supplement group (0 vs. 200 mg/d) and maternal BMI (normal weight or high BMI) using two-way ANOVA. We measured maternal choline levels in maternal and cord plasma samples. Supplementation with 200 mg/d DHA significantly increased (p < 0.05) maternal and cord RBC DHA content only in pregnancies complicated by high BMI. We did not find any impact of choline levels on maternal or cord RBC phospholipids. There were no significant differences in total placental DHA content by supplementation or maternal BMI (p > 0.05). Placental levels of phosphatidylinositol (PI) and phosphatidic acid containing DHA species were higher (p < 0.05) in high-BMI women without DHA supplementation compared to both normal-BMI and high-BMI women taking DHA supplements. Maternal DHA supplementation at recommended doses cord increased RBC DHA content only in pregnancies complicated by higher BMI. Surprisingly, we found that obesity was related to an increase in placental PI and phosphatidic acid species, which was ameliorated by DHA supplementation. Phosphatidic acid activates placental mTOR, which regulates amino acid transport and may explain previous findings of the impact of DHA on placental function. Current recommendations for DHA supplementation may not be achieving the goal of improving fetal DHA levels in normal-weight women.

Docosahexaenoic acid insufficiency impairs placental angiogenesis by repressing the methylene-bridge fatty acylation of AKT in preeclampsia

IntroductionPreeclampsia (PE), characterised by hypertension in pregnancy, is regarded as a placental metabolism-related syndrome affecting 5–8% of pregnancies worldwide. The insufficiency of polyunsaturated fatty acids (PUFAs), such as docosahexaenoic acid (DHA), is a causative factor of PE pathogenesis. However, its molecular aetiology is yet to be comprehensively elucidated. MethodsCRISPR/Cas9 was used to construct Fads2 knockout mice. Gas chromatography–mass spectrometry was used to detect placental fatty acid levels. Gene Expression Omnibus was used to analyze placental FADS2 mRNA levels. CCK-8 assay was used to assess cell growth capacity. Cell migration and invasion abilities were measured by transwell and wound healing assay. Tube forming assay was used to test angiogenesis ability. The co-immunoprecipitation assay was used to validate interactions between two proteins. AKT inhibitor MK-2206 and methylene-bridge fatty acylation inhibitor tryptophan were used to rescue experiments. ResultsCompared to those in women with normal pregnancies, the DHA levels in the placentas of patients with PE decreased with the downregulation of FADS2, the key desaturase in the synthesis of PUFAs. Pregnant Fads2+/− mice exhibited PE-like symptoms, including proteinuria and elevated systolic arterial blood pressure, due to defective placental angiogenesis. Mechanistically, FADS2 knockdown in trophoblasts decreased cellular DHA levels and repressed the methylene-bridge fatty-acylation of AKT, inhibiting AKT-VEGFA signalling, which is crucial for angiogenesis. DiscussionOur results suggest that placental DHA insufficiency downregulates placental angiogenesis via inhibiting fatty acylating AKT and AKT-VEGFA signalling, a novel insight into abnormal fatty acid metabolism in PE.

Placental F4-Neuroprostanes and F2-Isoprostanes are altered in gestational diabetes mellitus and maternal obesity

We investigated whether gestational diabetes mellitus (GDM) associated with maternal obesity modifies the placental profile of F4-Neuroprostanes and F2-Isoprostanes, metabolites of non-enzymatic oxidation of docosahexaenoic acid (DHA) and arachidonic acid (AA), respectively. Twenty-five placental samples were divided into lean (n=11), obesity (n=7) and overweight/obesity+GDM (n=7) groups. F4-Neuroprostanes and F2-Isoprostanes were higher in obesity compared to lean controls, but reduced to levels similar to lean women when obesity is further complicated with GDM. Lower content of F2-Isoprostanes suggests adaptive placental responses in GDM attenuating oxidative stress. However, low levels of placental F4-Neuroprostanes may indicate impaired DHA metabolism in GDM, affecting fetal development and offspring health. These results were not related to differences in placental content of DHA, AA and polyunsaturated fatty acids status nor to maternal diet or gestational weight gain. Placental DHA and AA metabolism differs in obesity and GDM, highlighting the importance of investigating the signalling roles of F4-Neuroprostanes and F2-Isoprostanes in the human term placenta.

Myo-inositol moderates maternal BMI and glycemia related variations in in-vitro placental 13C-DHA-metabolism, altering their relationships with birthweight

Transplacental docosahexaenoic-acid (DHA) supply for fetal development is regulated by placental DHA-lipid metabolism. Both maternal diabetes and obesity are linked to possible decreased fetal circulating DHA and increased placental DHA-lipids. Since myo-inositol is a promising intervention for gestational diabetes (GDM), we aimed to determine whether myo-inositol could rectify perturbations in placental DHA metabolism associated with maternal increasing glycemia and obesity and examine links with birthweight. Term placental villous explants from 17 women representing a range of BMIs and mid-gestational glycemia, were incubated with 13C-labeled-DHA for 48 h, in 0.3 µmol/L (control) or 60 µmol/L myo-inositol. Individual newly synthesized 13C-DHA-labeled lipid species were quantified by liquid-chromatography-mass-spectrometry. Compared with controls, incubation with myo-inositol decreased most 13C-DHA-lipids in placental explants from women with higher BMI or higher glycemia, but increased 13C-DHA-lipids with normal BMI or lower glycemia. Myo-inositol also increased 13C-DHA-labeled lipids in cases of lower birthweight centile, but induced decreases at higher centiles. Myo-inositol therefore lowered DHA-lipids in placenta with high basal placental DHA-lipid production (higher BMI and glycemia) but increased DHA-lipids where basal processing capacity is low. Myo-inositol thus moderates placental DHA metabolism towards a physiological mean which may in turn moderate birthweight.

Placental 13C-DHA metabolism and relationship with maternal BMI, glycemia and birthweight

BackgroundFetal docosahexaenoic acid (DHA) supply relies on preferential transplacental transfer, which is regulated by placental DHA lipid metabolism. Maternal hyperglycemia and obesity associate with higher birthweight and fetal DHA insufficiency but the role of placental DHA metabolism is unclear.MethodsExplants from 17 term placenta were incubated with 13C-labeled DHA for 48 h, at 5 or 10 mmol/L glucose treatment, and the production of 17 individual newly synthesized 13C-DHA labeled lipids quantified by liquid chromatography mass spectrometry.ResultsMaternal BMI positively associated with 13C-DHA-labeled diacylglycerols, triacylglycerols, lysophospholipids, phosphatidylcholine and phosphatidylethanolamine plasmalogens, while maternal fasting glycemia positively associated with five 13C-DHA triacylglycerols. In turn, 13C-DHA-labeled phospholipids and triacylglycerols positively associated with birthweight centile. In-vitro glucose treatment increased most 13C-DHA-lipids, but decreased 13C-DHA phosphatidylethanolamine plasmalogens. However, with increasing maternal BMI, the magnitude of the glucose treatment induced increase in 13C-DHA phosphatidylcholine and 13C-DHA lysophospholipids was curtailed, with further decline in 13C-DHA phosphatidylethanolamine plasmalogens. Conversely, with increasing birthweight centile glucose treatment induced increases in 13C-DHA triacylglycerols were exaggerated, while glucose treatment induced decreases in 13C-DHA phosphatidylethanolamine plasmalogens were diminished.ConclusionsMaternal BMI and glycemia increased the production of different placental DHA lipids implying impact on different metabolic pathways. Glucose-induced elevation in placental DHA metabolism is moderated with higher maternal BMI. In turn, findings of associations between many DHA lipids with birthweight suggest that BMI and glycemia promote fetal growth partly through changes in placental DHA metabolism.

1035 DHA transport in the placentas of obese, diabetic, and normal weight patients

Docosahexaenoic acid (DHA) is important for fetal neural development. Our objective was to evaluate DHA in maternal and fetal plasma and by placental region in patients with obesity, pregestational diabetes, and normal weight. We performed a pilot study to evaluate DHA transport in patients with pre-pregnancy BMI ≥ 30 kg/m2 (OB), those with Type 1 or Type 2 DM diagnosed prior to pregnancy or in the first trimester (DM), and patients with pre-pregnancy BMI 18.5-24.9 kg/m2 without comorbidities (NL). Placental specimens were collected, rinsed 3 times and flash frozen in liquid nitrogen. Placental specimens were later thawed and total lipids extracted. Gas chromatography mass spectroscopy (GC-MS) was performed on placental extracts and maternal and cord plasma collected at delivery. Percentile of DHA of total fatty acids (DHA) was calculated and compared across groups. Our primary outcome was fetal plasma DHA. Secondary outcomes included maternal DHA and correlations with maternal and fetal DHA by placental region. 3 OB, 3 DM, and 5 NL patients were included. Maternal demographics were similar across groups (Table 1). OB and DM had higher pre-pregnancy BMI (38.7 ± 0.6 kg/m2 and 32.8 ± 2.9 kg/m2, respectively) compared to NL (22.6 ± 2.0 kg/m2, p < 0.001). Fetal plasma DHA was comparable across groups (Table 2). Similarly maternal plasma DHA and placental DHA by regions were similar across groups (Table 2). Maternal plasma DHA was correlated with fetal plasma DHA (0.739, p=0.009). Both maternal and fetal plasma DHA were correlated with chorionic plate (CP) DHA (0.671, p=0.024 and 0.669, p=0.024, respectively) and central villi (CV) DHA (0.676, p=0.022 and 0.858, p=0.001, respectively). Neither maternal nor fetal plasma DHA was correlated with subchorionic villi (SV) DHA (0.281, p=0.402 and 0.405, p=0.217). Similarly, CP DHA was correlated with CV DHA (0.788, p=0.001), but not SV DHA (0.442, p=0.113). In our pilot study, DHA concentrations were not significantly different in OB, DM and NL patients in maternal and fetal plasma or by placental region.View Large Image Figure ViewerDownload Hi-res image Download (PPT)

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 Supplementation in Pregnancy Modulates Placental Cellular Signaling and Nutrient Transport Capacity in Obese Women.

Maternal obesity in pregnancy has profound impacts on maternal metabolism and promotes placental nutrient transport, which may contribute to fetal overgrowth in these pregnancies. The fatty acid docosahexaenoic acid (DHA) has bioactive properties that may improve outcomes in obese pregnant women by modulating placental function. To determine the effects of DHA supplementation in obese pregnant women on maternal metabolism and placental function. Pregnant women were supplemented with DHA or placebo. Maternal fasting blood was collected at 26 and 36 weeks' gestation, and placentas were collected at term. Academic health care institution. Thirty-eight pregnant women with pregravid body mass index ≥30 kg/m2. DHA (800 mg, algal oil) or placebo (corn/soy oil) daily from 26 weeks to term. DHA content of maternal erythrocyte and placental membranes, maternal fasting blood glucose, cytokines, metabolic hormones, and circulating lipids were determined. Insulin, mTOR, and inflammatory signaling were assessed in placental homogenates, and nutrient transport capacity was determined in isolated syncytiotrophoblast plasma membranes. DHA supplementation increased erythrocyte (P < 0.0001) and placental membrane DHA levels (P < 0.0001) but did not influence maternal inflammatory status, insulin sensitivity, or lipids. DHA supplementation decreased placental inflammation, amino acid transporter expression, and activity (P < 0.01) and increased placental protein expression of fatty acid transporting protein 4 (P < 0.05). Maternal DHA supplementation in pregnancy decreases placental inflammation and differentially modulates placental nutrient transport capacity and may mitigate adverse effects of maternal obesity on placental function.

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.

Docosahexaenoic acid supplementation during pregnancy as phospholipids did not improve the incorporation of this fatty acid into rat fetal brain compared with the triglyceride form

Prenatal docosahexaenoic acid (DHA) supply is important to ensure an adequate infant neurodevelopment. Several fat supplements with DHA under different chemical structures are available. There is an increased placental phospholipase activity at the end of pregnancy. The hypothesis of this study was to discern whether DHA consumption during pregnancy as phospholipids (PLs) could be more available for placental DHA uptake and fetal accretion than triglycerides (TGs) form. We aimed to evaluate maternofetal DHA status in pregnant rats fed with DHA as PL from egg yolk or TG from algae oil to determine which source might be most effective during pregnancy. Three experimental diets were tested: 2.5% DHA-TG (n = 10), 2.5% DHA-PL (n = 9), and 9% DHA-PL (n = 9). The total PL content of these diets was 2%, 12%, and 38%, respectively. We determined dietary fat absorption and quantified fatty acids by gas chromatography in maternal and fetal tissues. Dietary PL enhanced significantly dietary fat absorption. However, animals fed the highest PL-content diet (38% PL and 9% DHA-PL) stored most of the absorbed fat in maternal liver, promoting hepatic steatosis, which was not observed in the lower PL-content diets (12% and 2%). Despite higher fat absorption of PL-containing diets, maternal and fetal tissues (including fetal brain) did not show major differences in DHA content between the 2.5% DHA-PL and 2.5% DHA-TG–fed groups. We conclude that the chemical form of DHA consumed by the rat during gestation (PL or TG) does not differentially affect DHA accretion into fetal brain, and both lipid sources can be equally used for maternal DHA supplementation during pregnancy.

Maternal high fat diet deficient in vitamin B12 influences long chain polyunsaturated fatty acid composition in rats

Objective: In India, there is a rise in non-communicable diseases due to diets deficient in vitamin B12, low in docosahexaenoic acid (DHA) and increased consumption of westernized diet. The present study aims to examine the effect of maternal high fat diet (HFD) in absence of vitamin B12 on pregnancy outcome and tissue fatty acid composition in dams.Methods: Pregnant Wistar rats were assigned to following diets: Control (C), HFD, High fat diet supplemented with omega-3 fatty acids (HFDO), 4) High fat diet deficient in vitamin B12 (HFBD), High fat deficient in vitamin B12 supplemented with omega-3 fatty acids (HFBDO).Results: There was no effect on pregnancy outcome as a consequence of different dietary treatments. The levels of DHA in HFBD group were lower (p < 0.05 for both) in placenta as compared to both control and HFD groups, which were improved by omega-3 fatty acid supplementation.Conclusion: This data suggests that maternal HFD (using dairy fat) did not adversely affect pregnancy outcome. However, maternal HFBD reduced levels of placental DHA. This may have implications for reduced fetal brain growth and development.

Placental DHA and mRNA levels of PPARγ and LXRα and their relationship to birth weight

A very large number of fatty acids play wide range of physiological roles in cellular growth and function in placental as well as fetal growth. However, docosahexaenoic acid (DHA), in addition to its critical role in cellular membranes, is known to act as a ligand for several nuclear receptors and regulates the activity of transcription factor families like peroxisome proliferator-activated receptor, liver X receptor (LXR), retinoid X receptor (RXR), and sterol regulatory element binding protein (SREBP). These transcription factors and DHA are known to regulate the placental and fetal growth and development. The objective of the present study was to examine the fatty acids and transcription factors in the placenta of women delivering low birth weight (LBW) babies. The present study examines the fatty acid and mRNA levels of various transcription factors in the placentae of women delivering normal birth weight (NBW) (n=38) and women delivering LBW (n=36). Placental fatty acids were analyzed using gas chromatography. Placental mRNA levels of PPARα, PPARγ, SREBP-1c, LXRα, RXRα, and RXRγ were examined using quantitative real time PCR. Placental DHA levels and mRNA levels of placental PPARγ and LXRα were lower (P<.05 for all) in women delivering LBW babies. There was a positive association of placental PPARγ mRNA levels and placental DHA levels with baby weight (P<.05 for both). Our data suggest that lower placental DHA and transcription factors may have a vitalrole in the etiology of LBW babies.

High Fat Diet Administration during Specific Periods of Pregnancy Alters Maternal Fatty Acid Profiles in the Near-Term Rat.

Excessive fat intake is a global health concern as women of childbearing age increasingly ingest high fat diets (HFDs). We therefore determined the maternal fatty acid (FA) profiles in metabolic organs after HFD administration during specific periods of gestation. Rats were fed a HFD for the first (HF1), second (HF2), or third (HF3) week, or for all three weeks (HFG) of gestation. Total maternal plasma non-esterified fatty acid (NEFA) concentrations were monitored throughout pregnancy. At day 20 of gestation, maternal plasma, liver, adipose tissue, and placenta FA profiles were determined. In HF3 mothers, plasma myristic and stearic acid concentrations were elevated, whereas docosahexaenoic acid (DHA) was reduced in both HF3 and HFG mothers. In HF3 and HFG mothers, hepatic stearic and oleic acid proportions were elevated; conversely, DHA and linoleic acid (LA) proportions were reduced. In adipose tissue, myristic acid was elevated, whereas DHA and LA proportions were reduced in all mothers. Further, adipose tissue stearic acid proportions were elevated in HF2, HF3, and HFG mothers; with oleic acid increased in HF1 and HFG mothers. In HF3 and HFG mothers, placental neutral myristic acid proportions were elevated, whereas DHA was reduced. Further, placental phospholipid DHA proportions were reduced in HF3 and HFG mothers. Maintenance on a diet, high in saturated fat, but low in DHA and LA proportions, during late or throughout gestation, perpetuated reduced DHA across metabolic organs that adapt during pregnancy. Therefore a diet, with normal DHA proportions during gestation, may be important for balancing maternal FA status.

Effects of maternal n-3 fatty acid supplementation on placental cytokines, pro-resolving lipid mediators and their precursors.

The aim of this study was to determine whether supplementation with fish oil-derived n-3 polyunsaturated fatty acids (n-3 PUFA) during pregnancy modifies placental PUFA composition, the accumulation of specialised pro-resolving lipid mediators (SPMs, specifically resolvins (Rv), protectins (PD) and upstream precursors) and inflammatory gene expression. Placentas were collected from women (n=51) enrolled in a randomised, placebo controlled trial of n-3 PUFA supplementation from 20-week gestation. Lipids were extracted for fatty acid analysis and SPMs were quantitated by mass spectrometry. Gene expression was determined by qRT-PCR. Using multiple regression analysis, data were correlated for placental n-3 PUFA and SPM levels with PUFA levels in maternal and cord blood erythrocytes. Supplementation with n-3 PUFAs increased placental docosahexaenoic acid (DHA) levels, but not eicosapentaenoic acid (EPA) levels (P<0.05), and increased the levels of the SPM precursors 18-hydroxyeicosapentaenoic acid and 17-hydroxydocosahexaenoic acid (17-HDHA) by two- to threefold (P<0.0005). RvD1, 17R-RvD1, RvD2 and PD1 were detectable in all placentas, but concentrations were not significantly increased by n-3 PUFA supplementation. Placental DHA levels were positively associated with maternal and cord DHA levels (P<0.005), and with placental 17-HDHA concentrations (P<0.0001). Placental mRNA expression of PTGS2, IL1β, IL6 and IL10 was unaffected by n-3 PUFA supplementation, but TNFα expression was increased by 14-fold (P<0.05). We conclude that n-3 PUFA supplementation in pregnancy i) enhances placental accumulation of DHA and SPM precursors, ii) does not alter placental EPA levels, and iii) has no stimulatory effects on inflammatory gene expression. Further studies are required to ascertain the biological significance of SPMs in the placenta and the potential immunomodulatory effects of elevating placental SPM levels.

Reply to “Letter to the editor: ‘Fatty acids and placental transport: insight or in vitro artifact?’”

reply: In our recent paper (2) we reported on the effects of fatty acids on trophoblast cellular signaling and amino acid transport activity in vitro. As with any other cell culture experiments, we are aware that this is an artificial environment on multiple levels. No matter how well designed the experiment, cell cultures in and of themselves cannot completely reproduce in vivo physiological conditions. However, despite their inherent limitations, cell culture experiments do provide an important tool for studying cell physiology. In vivo, cells are exposed to a multitude of effectors at variable concentrations and we concur with Dr. Keelan (1) that it is important to study effectors in combination. However, a problem arises with respect to which effectors should be included. For example, when studying effects of fatty acids on trophoblast cell function, should all effectors known to affect mTOR signaling and amino acid transport be included in the cell culture media for the experiment to be considered valid? By analogy, in studies of insulin effects on cell function, do all known effectors impinging on the insulin signaling pathway (adiponectin, leptin, and cytokines, just to mention a few) have to be included for the experiment to be physiologically relevant? If so, Dr. Keelan's argument invalidates most of the published studies in cell physiology. We believe that a reductionist approach in which single effector molecules are studied remains valid and we disagree with the argument that fatty acids should only be studied in combination. We reported that, in the presence of oleic acid, the effects of docosahexaenoic acid (DHA) alone were no longer predominant. Dr. Keelan suggests that this finding should be interpreted that DHA responses were an in vitro artifact. However, such an interpretation fails to appreciate that DHA counteracted the observed effects of oleic acid alone. Clearly, both DHA and oleic acid have the capacity to influence trophoblast signaling and function, both in isolation and when combined. In our paper we demonstrate that DHA reduces the activity of the amino transporters System A and System L in cultured primary human trophoblast cells. In a separate study following pregnant women supplemented with DHA, we found that placental DHA levels measured at term inversely correlated with System A and System L amino acid transport capacity (3). Such data from clinical samples strongly support the assertion that the reported in vitro effects are physiologically relevant and not an experimental artifact. As already discussed in our paper, we believe that these results merit further exploration of the effects of fatty acids on trophoblast function, both singularly and in combination.

Maternal uterine secreted mediator, VEGF, enhances embryo development and implantation

Maternal uterine secreted mediator, VEGF, enhances embryo development and implantation

Matrix metalloproteinases-2, -3 and tissue inhibitors of metalloproteinases-1, -2 in placentas from preterm pregnancies and their association with one-carbon metabolites

Maternal nutrition is an important determinant of one-carbon metabolism and defects in the one-carbon metabolism may lead to poor obstetric outcomes. This study was designed to test the hypothesis that altered intake/metabolism of micronutrients (folic acid and vitamin B12) and docosahexaenoic acid (DHA) contributes to increased homocysteine and oxidative stress leading to altered levels of matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) in women delivering preterm. We have earlier reported increased vitamin B12, homocysteine, and oxidative stress along with reduced placental DHA in women delivering preterm. In this study, we further examine the placental levels of MMP2, MMP3, TIMP1, and TIMP2 in 75 women delivering at term and 73 women delivering preterm. Placental levels of MMPs and TIMPs were determined by ELISA. Placental MMP2 and MMP3 levels were higher (P<0.01) in women delivering preterm as compared with term. There was no difference in the placental TIMP1 and TIMP2 levels in women delivering preterm and at term. Further placental MMP2 and MMP3 levels were higher (P<0.01) in women with preterm labor as compared with those in labor at term, suggesting that MMPs may favor degradation of extracellular matrix in the placenta during preterm labor. Our study for the first time suggests a crucial role of micronutrients and MMPs in preterm birth. Future studies need to examine if epigenetic modifications through the one-carbon cycle contribute to increased levels of MMPs leading to preterm deliveries.

Association of brain-derived neurotrophic factor and tyrosine kinase B receptor in pregnancy

Abnormal brain development in a compromised prenatal and/or early postnatal environment is thought to be a risk factor for several neurobehavioural disorders. However, the mechanisms underlying these are not well understood. We have earlier reported reduced placental docosahexaenoic acid (DHA) levels in preterm deliveries. We have hypothesized that increased oxidative stress and reduced DHA levels may lead to changes in the circulating levels of maternal and cord brain-derived neurotrophic factor (BDNF) and its receptor tyrosine kinase B (TrkB) levels. A total number of 96 women delivering preterm and 95 women delivering at term were recruited. Plasma BDNF levels were measured in both mother and cord blood plasma using the BDNF Immuno Assay kit. Placental TrkB levels were analysed using sandwich enzyme-linked immunosorbent assay (ELISA). Maternal plasma BDNF levels and placental TrkB levels were higher (p<0.05) while cord plasma BDNF levels were lower (p<0.01) in women delivering preterm as compared to term. There was a negative association between levels of placental TrkB and DHA (p=0.034). A negative association between maternal plasma BDNF levels and placental weight (p=0.001) was observed while a positive association was seen between cord plasma BDNF levels and gestation (p=0.025). The reduction in cord BDNF levels may have implications for altered neurodevelopment in childhood and later life. Studies need to be undertaken to follow up children born preterm for risk of neurobehavioural disorders like attention deficit hyperactivity disorder (ADHD) to understand the effect of altered BDNF at birth on neurodevelopment.

Matrix Metalloproteinase-1 and -9 in Human Placenta during Spontaneous Vaginal Delivery and Caesarean Sectioning in Preterm Pregnancy

Preterm birth is a major public health problem in terms of loss of life, long-term and short term disabilities worldwide. The process of parturition (both term and preterm) involves intensive remodelling of the extracellular matrix (ECM) in the placenta and fetal membranes by matrix metalloproteinases (MMPs). Our previous studies show reduced docosahexaenoic acid (DHA) in women delivering preterm. Further omega 3 fatty acids are reported to regulate MMP levels. This study was undertaken to examine the placental levels of MMPs and their association with placental DHA levels in women delivering preterm. The levels of MMP-1 and MMP-9 in 74 women delivering preterm (52 by spontaneous vaginal delivery and 22 by caesarean sectioning) and 75 women delivering at term (59 by spontaneous vaginal delivery and 16 by caesarean sectioning) were determined by enzyme-linked immunosorbent assay (ELISA) and their association with placental DHA was studied. Placental MMP-1 levels were higher (p<0.05) in women delivering preterm (both by spontaneous vaginal delivery and caesarean sectioning) as compared to those delivering at term. In contrast, placental MMP-9 levels in preterm pregnancies was higher (p<0.05) in women with spontaneous vaginal delivery while lower (p<0.05) in women delivering by caesarean sectioning. Low placental DHA was associated with higher placental MMP-9 levels. Our study suggests a differential effect of mode of delivery on the levels of MMPs from placenta. Further this study suggests a negative association of DHA and the levels of MMP-9 in human placenta although the mechanisms need further study.

Reduced levels of placental long chain polyunsaturated fatty acids in preterm deliveries

Reports suggest that the placenta in preterm birth may provide clues to predicting the risk of individuals developing chronic diseases in later life. Placental delivery of long chain polyunsaturated fatty acids (LCPUFA) (constituents of the cell membrane and precursors of prostaglandins) is essential for the optimal development of the central nervous system of the fetus. The present study examines the levels of LCPUFA and their association with placental weight and birth outcome in 58 women delivering preterm and 44 women delivering at term. Docosahexaenoic acid (DHA) and arachidonic acid (ARA) levels were lower ( p<0.01) in women delivering preterm. There was a positive association of placental DHA with placental weight ( p=0.036) and nervonic acid with head circumference ( p=0.040) in the preterm group. Altered placental LCPUFA status exists in Indian mothers delivering preterm, which may influence the birth outcome.