Role of neurotrophins in pregnancy and offspring brain development.

Neurotrophins are a family of functionally and structurally related proteins which play a key role in the survival, development, and function of neurons in both the central and peripheral nervous systems. Brain-derived neurotrophic factor (BDNF), nerve growth factor (NGF), neurotrophin-3 (NT-3), and neurotrophin-4 (NT-4) are the family members of neurotrophins. Neurotrophins play a crucial role in influencing the development of the brain and learning and memory processes. Studies demonstrate that they also play crucial role in influencing reproductive and immune systems. Neurotrophins have been shown to influence various processes in the mother, placenta, and fetus during pregnancy. Development and maturation of feto-placental unit and the fetal growth trajectories are influenced by neurotrophins. In addition to neurotrophins, neuropeptides like neuropeptide Y also play a crucial role during various processes of pregnancy and during fetal brain development. Neurotrophins have also been shown to have a cross talk with various angiogenic factors and influence placental development. Alterations in the levels of neurotrophins and neuropeptides lead to placental pathologies resulting in various pregnancy complications like preeclampsia, intrauterine growth restriction and preterm births. Studies in animals have reported low levels of maternal micronutrients like folic acid, vitamin B12 and omega-3 fatty acids influence brain neurotrophins resulting in impaired cognitive functioning in the offspring. Maternal nutrition is also known to affect the expression of neuropeptides. It is essential to understand the role of various neurotrophins across various stages of pregnancy and its relationship with neurodevelopmental outcomes in children. This will lead to early prediction of poor neurodevelopmental outcomes. The present review describes evidence describing the role of neurotrophins in determining pregnancy outcome and altered neurodevelopment in the offspring. The possible mechanism through which maternal nutrition influences neurotrophins and neuropeptides to regulate offspring brain development and function is also discussed.

Omega-3 fatty acids differentially influences embryotoxicity in subtypes of preeclampsia.

Background: Early (EOP) and late onset (LOP) preeclampsia are two subtypes of preeclampsia. This study examines the effect of maternal omega-3 fatty acids and vitamin E supplementation in a rat model of preeclampsia.Method: Pregnant Wistar rats were assigned to control; EOP; LOP; EOP+omega-3 fatty acid supplementation+vitamin E and LOP+omega-3 fatty acid supplementation+vitamin E. L-Nitroarginine methylester was used to induce preeclampsia. Blood Pressure (BP) was recorded during pregnancy and dams were dissected at d14 and d20 of gestation.Results: Animals from EOP and LOP groups demonstrated higher systolic and diastolic BP, lower weight gain, lower conceptuses size, lower conceptuses weight and fetal weight as compared to control. EOP and LOP groups showed higher percentage of fetal resorptions and embryotoxicity (deformities and hematomas).Conclusion: Supplementation reduced the diastolic BP, percentage of resorptions and embryotoxicity only in the LOP group, suggesting a need for differential supplementation regime for the two subtypes of preeclampsia.

Effect of maternal omega-3 fatty acids and vitamin E supplementation on placental apoptotic markers in rat model of early and late onset preeclampsia.

AIM: Disturbed placentation results in pregnancy complications like preeclampsia. Placental development is influenced by apoptosis during trophoblast differentiation and proliferation. Increased oxidative stress upregulates placental apoptosis. We have earlier reported increased oxidative stress, lower omega-3 fatty acids and vitamin E levels in women with preeclampsia. Current study examines effect of maternal omega-3 fatty acids and vitamin E supplementation on apoptotic markers across gestation in a rat model of preeclampsia. MAIN METHODS: Pregnant Wistar rats were randomly assigned to control; early onset preeclampsia (EOP); late onset preeclampsia (LOP); early onset preeclampsia + omega-3 fatty acid + vitamin E supplementation (EOP + O + E) and late onset preeclampsia + omega-3 fatty acid + vitamin E supplementation (LOP + O + E) groups. Animals (Control, EOP, EOP + O + E) were sacrificed at d14 and d20 of gestation while animals (LOP, LOP + O + E) were sacrificed at d20 to collect blood and placentae. Protein and mRNA levels of apoptotic markers were analyzed by ELISA and RT-PCR respectively. KEY FINDINGS: Protein levels of proapoptotic markers like Bcl-2 associated X-protein (BAX) (p < 0.05), caspase-8 and 3 (p < 0.01 for both) and malondialdehyde (p < 0.01) were higher only in the EOP group as compared to control. However, the antiapoptotic marker, B cell lymphoma 2 (Bcl-2) protein levels were lower in both the subtypes of preeclampsia (p < 0.01 for both). SIGNIFICANCE: Our findings suggest that supplementation was beneficial in reducing the caspase-8 and 3 in early onset preeclampsia but did not normalize BAX and Bcl-2 levels. This has implications for reducing placental apoptosis in preeclampsia.

Maternal omega-3 fatty acids and vitamin E improve placental angiogenesis in late-onset but not early-onset preeclampsia.

Abnormal placental vasculature is associated with preeclampsia. Preeclampsia is of two types, i.e., early- and late-onset preeclampsia (LOP), both having different etiologies. We have earlier demonstrated low levels of omega-3 fatty acids and vitamin E in women with preeclampsia. The current study examines the effect of maternal omega-3 fatty acids and vitamin E supplementation on angiogenic factors in a rat model of preeclampsia. Pregnant rats were divided into a total of five groups control, early-onset preeclampsia (EOP); LOP; EOP supplemented with omega-3 fatty acid and vitamin E and LOP supplemented with omega-3 fatty acid and vitamin E. Preeclampsia was induced by administering L-nitroarginine methylester (L-NAME) at the dose of 50 mg/kg body weight/day. The vascular endothelial growth factor gene expression and protein levels were lower (p < 0.01 for both) in animals from both EOP as well as LOP groups (p < 0.01). In the EOP group, the protein levels of VEGF receptor-1 were also lower (p < 0.01). Supplementation of omega-3 fatty acids and vitamin E to LOP improved the levels of VEGF and VEGF receptor-1 only in the LOP but not in the EOP group. In the EOP group, the gene expression of hypoxia inducible factor 1 alpha (HIF-1α) in the placenta was higher (p < 0.05) and supplementation normalized these levels. Our findings indicate that maternal supplementation of omega-3 fatty acids and vitamin E has differential effect on preeclampsia subtypes.

Maternal dairy fat diet does not influence neurotrophin levels and cognitive performance in the rat offspring at adult age.

Cognitive development may be influenced by maternal nutrition especially fats. Indian population is vegetarian and main source of fat is dairy. This study investigates the effect of dairy fat consumption during pregnancy in an animal model on fatty acids, brain neurotrophins (brain derived neurotrophic factor: BDNF; and nerve growth factor: NGF) and cognitive performance in adult offspring. Pregnant Wistar rats were assigned to control (Control C) and four treatment groups: High fat diet (HFD); High fat diet supplemented with omega-3 fatty acids (HFDO); High fat diet deficient in vitamin B12 (HFBD); High fat deficient in vitamin B12 supplemented with omega-3 fatty acids (HFBDO). Half the dams were dissected on d20 of gestation, and the brains of their pups were collected. The remaining dams delivered on d22 of gestation and were assigned to a control diet. The cognitive performance of these adult offspring was assessed at 6 mo of age. Brain fatty acids were comparable to control in the pups at birth and offspring at 6 mo of age. The protein levels of BDNF in the pup brain at birth were lower in both the HFD (p < 0.01) and HFBD (p < 0.05) groups as compared to control. The mRNA levels of TrK B were lower (p < 0.05) in the pup brain at birth in the HFD as compared to control group. In the offspring at 6 mo of age the protein levels of BDNF and NGF in all the treatment groups were similar to that of control. However, the mRNA levels of only BDNF (p < 0.01 for both) were higher in the HFBD group as compared to both control and HFD groups. The cognitive performance of the adult offspring from various dietary groups was similar to control. In conclusion, consumption of a maternal high dairy fat diet although lowered the levels of brain BDNF in the pup at birth it does not affect the cognitive health of the adult offspring.

Increased intake of vitamin B12, folate, and omega-3 fatty acids to improve cognitive performance in offspring born to rats with induced hypertension during pregnancy.

Vitamin B12, folic acid, and docosahexaenoic acid levels are reported to be altered in women with preeclampsia. This study examined the effect of the above nutrients on brain neurotrophins and on the cognitive performance in adult offspring in a pregnancy-induced hypertension rat model. Pregnant dams were assigned to control, PIH-induced, and PIH-induced supplemented with vitamin B12, folate, omega-3 fatty acids, and the combined supplementation of vitamin B12, folate, and omega-3 fatty acids groups. In the PIH group, brain-derived neurotrophic factor levels (BDNF) were lower in the offspring at birth, while the adult offspring showed lower levels of docosahexaenoic acid (DHA) in the hippocampus and BDNF (p < 0.05 for both) in the cortex as compared to in the control group. They also demonstrated higher (p < 0.05) escape latency in the Morris water maze test and performed a greater (p < 0.01 for all) number of errors in the Radial eight-arm maze test. A combined supplementation of vitamin B12, folic acid, and omega-3 fatty acids improved the levels of LCPUFA, neurotrophins, and cognition. A maternal diet consisting of high levels of folate, vitamin B12, and DHA reduced the risk for cognitive disorders in the adult offspring in an animal model of pregnancy-induced hypertension.

Maternal Micronutrients, Omega-3 Fatty Acids and Gene Expression of Angiogenic and Inflammatory Markers in Pregnancy Induced Hypertension Rats.

BACKGROUND AND AIMS: Preeclampsia is a disorder of pregnancy and is associated with inflammation and altered angiogenesis. The present study examines the effect of micronutrient and omega-3 fatty acid supplementation (individual, as well as combined) on genes involved in inflammation and angiogenesis, as well as global DNA methylation levels in a pregnancy induced hypertension (PIH) rat model. METHODS: Pregnant Wistar rats were randomly assigned to six dietary groups: control, PIH (Pregnancy induced hypertension) Induced; PIH Induced with micronutrient supplements with vitamin B12 (PIHB), folate (PIHF), omega-3 fatty acid (PIHO), and combined supplementation (PIHC) (micronutrients and omega-3 fatty acids). Half the dams were dissected on 20 d of gestation to collect placental tissue, and half were allowed to deliver normally on 22 d of gestation and were assigned to a postnatal control diet. The offspring were dissected at 3 month of age. RESULTS: PIH induction increased the mRNA levels of the pro inflammatory cytokine IL-6 (p <0.01), while lowering the placental anti inflammatory cytokine IL-10 (p <0.05) at d20 of gestation. It also increased the expression of TNF-α (p <0.05) in the liver of 3 month old offspring. The combined supplementation of folic acid, vitamin B12 and omega-3 fatty acids improved placental IL-10 levels and decreased TNF-α levels in offspring livers. CONCLUSION: Our data indicate that a combined supplementation of vitamin B12, folic acid and omega-3 fatty acid was useful for the better management of preeclampsia in an animal model.

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.

Vitamin B12 Deficiency Across Three Generations Adversely Influences Long-chain Polyunsaturated Fatty Acid Status and Cardiometabolic Markers in Rats.

BACKGROUND AND AIMS: Vitamin B12 and omega-3 fatty acid deficiency is prevalent in the vegetarian population and is associated with adverse pregnancy outcomes and cardiometabolic risk. The present study investigates the long-term effects of vitamin B12 deficiency/supplementation in the presence of omega-3 fatty acids on cardiometabolic profile and long-chain polyunsaturated fatty acid levels (LCPUFA) in the F3 generation offspring. METHODS: Three generations of rats were fed the following diets: control; vitamin B12 deficient; vitamin B12 supplemented; vitamin B12 deficient + omega-3 fatty acid supplemented; vitamin B12 + omega-3 fatty acid supplemented. Animals were sacrificed at 3 months of age. RESULTS: Vitamin B12 deficiency lowered (p <0.01 for both) plasma eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), liver DHA (p <0.05), plasma/liver omega-3 fatty acids (p <0.05 for both), increased triglycerides (p <0.05) and systolic BP (p <0.01) and lowered cholesterol levels (p <0.05) as compared to control. Vitamin B12 deficiency in the presence of omega-3 fatty acids improved plasma/liver EPA, DHA and omega-3 fatty acid profile and maintained cholesterol, triglyceride and BP levels. Vitamin B12 supplementation lowered liver DHA (p <0.05) and cholesterol (p <0.01), whereas BP was similar to control. Combined supplementation of vitamin B12 and omega-3 fatty acids improved omega-3 fatty acid profile, lowered cholesterol/triglyceride levels and maintained the BP similar to that of control. CONCLUSION: Vitamin B12 deficiency across three generations adversely affects LCPUFA and cardiometabolic profile in the adult offspring. This study provides clues for a combined supplementation of vitamin B12 and omega-3 fatty acids to reduce the risk for noncommunicable diseases.

A combined supplementation of vitamin B12 and n-3 polyunsaturated fatty acids across two generations improves nerve growth factor and vascular endothelial growth factor levels in the rat hippocampus.

Vitamin B12 and n-3 polyunsaturated fatty acid (n-3 PUFA) are known to influence cognition. This study aims to examine if these nutrients affect the protein levels and gene expression of nerve growth factor (NGF) and vascular endothelial growth factor (VEGF) in the cortex and hippocampus in the second-generation offspring at 3 mo of age. Wistar rats were fed the following diets for two generations: Control (CON), vitamin B12 deficient (VBD), vitamin B12 deficient supplemented with n-3 PUFA (VBDO), vitamin B12 supplemented (VBS), vitamin B12 supplemented with n-3 PUFA (VBSO). The VEGF and NGF gene expression and protein levels in the hippocampus were lower (P⩽0.01) in the VBD group as compared to the CON group while the VBDO group restored the VEGF and NGF gene expression (P⩽0.01). The VBS group showed similar levels of NGF and VEGF to that of the CON group. However, the VBSO group demonstrated higher (P⩽0.05) NGF gene expression and protein levels in the hippocampus and higher cortex NGF protein levels as compared to the CON group. In addition, VEGF (in hippocampus) and NGF (in cortex and hippocampus) protein levels were also higher (P⩽0.05) in the VBSO group as compared to the VBS group. Our results indicate that the combined supplementation of vitamin B12 and n-3 PUFA improves NGF and maintains VEGF levels in the brain which may improve neurovascular function.

Effect of vitamin B12 and omega-3 fatty acid supplementation on brain neurotrophins and cognition in rats: A multigeneration study.

Vitamin B12 and omega-3 fatty acids are important nutrients required for neuronal functioning. We have demonstrated the beneficial effects of vitamin B12 and omega-3 fatty acid supplementation on brain neurotrophins and cognition in the first and second generation offspring. However, there is a need to examine if the effects are sustained in the third generation offspring. This study reports the effects of vitamin B12 and omega-3 fatty acid supplementation across three consecutive generations on brain neurotrophins like brain derived neurotrophic factor (BDNF); nerve growth factor (NGF) and cognitive performance in the third generation male offspring. Three successive generations of Wistar rats were assigned the following groups throughout pregnancy, lactation and adulthood: i) Control, ii) vitamin B12 deficient (BD), iii) vitamin B12 deficient + omega-3 fatty acid (BDO), iv) vitamin B12 supplemented (BS) and v) vitamin B12 supplemented + omega-3 fatty acid (BSO). The BD group demonstrated lower (p < 0.01) NGF in the cortex but not BDNF levels although the cognition was impaired (p < 0.01). In contrast, in the BDO group, higher NGF levels were observed in the hippocampus and animals demonstrated improved (p < 0.01) cognitive performance. Vitamin B12 supplementation showed comparable BDNF levels in the hippocampus while their levels were lower in the cortex as compared to the control (p < 0.05). These animals showed more reference and working memory errors (p < 0.01) as compared to the control group. A combined supplementation of vitamin B12 and omega-3 fatty acid showed higher (p < 0.01) levels of DHA and NGF in the hippocampus, higher BDNF in both hippocampus and cortex and improved cognitive performance. Our findings have implications for fortification of foods with vitamin B12 and omega-3 fatty acids in improving brain development.

A combined supplementation of vitamin B12 and omega-3 fatty acids across two generations improves cardiometabolic variables in rats.

Our earlier studies indicate that micronutrients (vitamin B12, folic acid) and omega-3 fatty acids especially docosahexaenoic acid (DHA) are interlinked in one carbon cycle. The present study examines the effects of a sustained vitamin B12 deficiency/supplementation in the presence of omega-3 fatty acids across two generations on the pregnancy outcome and cardiometabolic profile [blood pressure, plasma lipid profile (cholesterol and triglycerides), plasma/liver fatty acid profile and hepatic lipid metabolism] in the second generation adult Wistar rat offspring. Two generations of animals were fed the following diets: control; vitamin B12 deficient; vitamin B12 supplemented; vitamin B12 deficient diet supplemented with omega-3 fatty acids; vitamin B12 and omega-3 fatty acid supplemented diets. Male offspring were sacrificed at 3 months of age. Vitamin B12 deficiency lowered the weight gain (p < 0.01) during pregnancy, increased systolic (p < 0.05) and diastolic (p < 0.01) blood pressure, and lowered the levels of plasma/liver DHA (p < 0.05 for both) but did not affect the lipid profile. Vitamin B12 supplementation showed weight gain, blood pressure and the fatty acid profile similar to the control. However, it increased (p < 0.05) the levels of plasma triglycerides. Omega-3 fatty acid supplementation to the vitamin B12 deficient group lowered the weight gain although the levels of cardiometabolic variables were comparable to the control. Omega-3 fatty acid supplementation in the presence of vitamin B12 improved the pregnancy outcome and all cardio-metabolic variables. Our study highlights the adverse effects of sustained vitamin B12 deficiency across two generations on the pregnancy outcome, fatty acid profile and blood pressure while a combined supplementation of vitamin B12 and omega-3 fatty acids is beneficial.

Supplementation of maternal omega-3 fatty acids to pregnancy induced hypertension Wistar rats improves IL10 and VEGF levels.

OBJECTIVES: Our recent study demonstrates the beneficial effect of a combined supplementation of vitamin B12, folic acid, and docosahexaenoic acid in reducing the severity of pregnancy induced hypertension (PIH). It is also known to be associated with angiogenic imbalance and inflammation. The current study examines whether the individual/combined supplementation of folic acid, vitamin B12 and omega-3 fatty acid during pregnancy can ameliorate the inflammatory markers and restore the angiogenic balance in a rat model of PIH. MATERIALS AND METHODS: There were total of six groups, control and five treatment groups: PIH Induced; PIH+vitamin B12; PIH+folic acid; PIH+Omega-3 fatty acids and PIH+combined micronutrient supplementation (vitamin B12+folic acid+omega-3 fatty acids). Hypertension during pregnancy was induced using L- Nitroarginine methylester (L-NAME; 50mg/kg body weight/day). Dams were dissected at d20 of gestation and placental tissues were collected for further analysis. RESULTS: Animals from the PIH induced group demonstrated lower (p<0.01 for both) IL-10 and VEGF levels as compared to control. However, PIH induction did not alter the protein levels of eNOS, IL-6, Flt and mRNA levels of VEGF and VEGFR-1/ Flt-1. Individual micronutrient supplementation of vitamin B12 and folate did not offer benefit. In contrast individual omega-3 fatty acid as well as combined micronutrient supplementation showed IL-10 and VEGF levels comparable to that of control. CONCLUSION: Omega 3 fatty acid supplementation plays a key role in reducing inflammation in pregnancy induced hypertension.

Novel insights into the effect of vitamin B12 and omega-3 fatty acids on brain function.

The prevalence of psychiatric disorders which are characterized by cognitive decline is increasing at an alarming rate and account for a significant proportion of the global disease burden. Evidences from human and animal studies indicate that neurocognitive development is influenced by various environmental factors including nutrition. It has been established that nutrition affects the brain throughout life. However, the mechanisms through which nutrition modulates mental health are still not well understood. It has been suggested that the deficiencies of both vitamin B12 and omega-3 fatty acids can have adverse effects on cognition and synaptic plasticity. Studies indicate a need for supplementation of vitamin B12 and omega-3 fatty acids to reduce the risk of cognitive decline, although the results of intervention trials using these nutrients in isolation are inconclusive. In the present article, we provide an overview of vitamin B12 and omega-3 fatty acids, the possible mechanisms and the evidences through which vitamin B12 and omega-3 fatty acids modulate mental health and cognition. Understanding the role of vitamin B12 and omega-3 fatty acids on brain functioning may provide important clues to prevent early cognitive deficits and later neurobehavioral disorders.

Beneficial effects of omega-3 fatty acids and vitamin B12 supplementation on brain docosahexaenoic acid, brain derived neurotrophic factor, and cognitive performance in the second-generation Wistar rats.

In vegetarian population, vitamin B12 deficiency coexists with suboptimal levels of omega-3 fatty acids. Studies indicate a need for supplementation/fortification of vitamin B12 and omega-3 fatty acids to reduce the risk of brain disorders. We have described the effects of vitamin B12 and omega-3 fatty acid supplementation on brain development in F1 generation animals. The current study investigates the effects of vitamin B12 and omega-3 fatty acids supplementation on brain function and cognition. Pregnant Wistar rats were assigned the following groups: control, vitamin B12 deficient (BD), vitamin B12 deficient + omega-3 fatty acid (BDO), vitamin B12 supplemented (BS), vitamin B12 supplemented + omega-3 fatty acid (BSO). The same diets were continued for two generations. BDO group showed higher (P < 0.05) levels of BDNF (brain derived neurotrophic factor) and DHA (docosahexaenoic acid) in the cortex and hippocampus as compared with the BD group. The cognitive performance was also normalized in this group. BS showed comparable levels of DHA, BDNF (protein and mRNA), and CREB mRNA (cAMP response element-binding protein) to that of control group while Tropomyosin receptor kinase mRNA levels were higher. The combined vitamin B12 and omega-3 fatty acid supplementation further enhanced the levels of DHA (P < 0.05) and BDNF (P < 0.05) in the hippocampus and CREB mRNA (P < 0.01) in the cortex as compared with BS group. The cognitive performance of these animals was higher (P < 0.05) as compared with BS group. Our data indicates the beneficial effects of vitamin B12 and omega-3 fatty acid supplementation across two generations on brain development and function.

Vitamin B12 and omega-3 fatty acids together regulate lipid metabolism in Wistar rats.

Our recent study indicates that maternal vitamin B12 and omega-3 fatty acid status influence plasma and erythrocyte fatty acid profile in dams. The present study examines the effects of prenatal and postnatal vitamin B12 and omega-3 fatty acid status on lipid metabolism in the offspring. Pregnant dams were divided into five groups: Control; Vitamin B12 deficient (BD); Vitamin B12 supplemented (BS); Vitamin B12 deficient group supplemented with omega-3 fatty acids (BDO); Vitamin B12 supplemented group with omega-3 fatty acids (BSO). The offspring were continued on the same diets till 3 month of age. Vitamin B12 deficiency increased cholesterol levels (p<0.01) but reduced docosahexaenoic acid (DHA) (p<0.05), liver mRNA levels of acetyl CoA carboxylase-1 (ACC-1) (p<0.05) and carnitine palmitoyltransferase-1 (CPT-1) (p<0.01) in the offspring. Omega-3 fatty acid supplementation to this group normalized cholesterol but not mRNA levels of ACC-1 and CPT-1. Vitamin B12 supplementation normalized the levels cholesterol to that of control but increased plasma triglyceride (p<0.01) and reduced liver mRNA levels of adiponectin, ACC-1, and CPT-1 (p<0.01 for all). Supplementation of both vitamin B12 and omega-3 fatty acid normalized triglyceride and mRNA levels of all the above genes. Prenatal and postnatal vitamin B12 and omega-3 fatty acids together play a crucial role in regulating the genes involved in lipid metabolism in adult offspring.

Maternal omega-3 fatty acids and micronutrients modulate fetal lipid metabolism: A review.

It is well established that alterations in the mother's diet or metabolism during pregnancy has long-term adverse effects on the lipid metabolism in the offspring. There is growing interest in the role of specific nutrients especially omega-3 fatty acids in the pathophysiology of lipid disorders. A series of studies carried out in humans and rodents in our department have consistently suggested a link between omega-3 fatty acids especially docosahexaenoic acid and micronutrients (vitamin B12 and folic acid) in the one carbon metabolic cycle and its effect on the fatty acid metabolism, hepatic transcription factors and DNA methylation patterns. However the association of maternal intake or metabolism of these nutrients with fetal lipid metabolism is relatively less explored. In this review, we provide insights into the role of maternal omega-3 fatty acids and vitamin B12 and their influence on fetal lipid metabolism through various mechanisms which influence phosphatidylethanolamine-N-methyltransferase activity, peroxisome proliferator activated receptor, adiponectin signaling pathway and epigenetic process like chromatin methylation. This will help understand the possible mechanisms involved in fetal lipid metabolism and may provide important clues for the prevention of lipid disorders in the offspring.

Maternal omega-3 fatty acid supplementation to a vitamin B12 deficient diet normalizes angiogenic markers in the pup brain at birth.

Vitamin B12 and omega-3 fatty acids are critical for normal brain development and function and their deficiencies during pregnancy could have adverse effects on cognitive performance in children. Our earlier studies indicate that both maternal vitamin B12 and omega-3 fatty acids influence brain development by regulating the levels of neurotrophins. Literature suggests that there exists a cross talk between neurotrophins like nerve growth factor (NGF) and angiogenic factors like vascular endothelial growth factor (VEGF). It remains to be established whether maternal nutrients like vitamin B12 and omega-3 fatty acids influence the levels of angiogenic markers like VEGF and NGF in the brain of the offspring. Therefore the present study examines the effect of maternal vitamin B12 and omega-3 fatty acids on protein and mRNA levels of VEGF, HIF-1 alpha (hypoxia inducible factor alpha) and NGF in the pup brain at birth. Pregnant Wistar rats were divided into five dietary groups (n=8 each): control, vitamin B12 deficient, vitamin B12 deficient+omega-3 fatty acid, vitamin B12 supplemented, vitamin B12 supplemented+omega-3 fatty acid. At birth the pups were dissected to collect the brain tissue. Maternal vitamin B12 deficiency showed lower (p<0.05) pup brain mRNA and protein levels (p<0.01) of VEGF, higher (p<0.01) HIF-1 alpha protein levels, lower (p<0.05) NGF protein levels while NGF mRNA levels were not altered. Omega-3 fatty acid supplementation to a vitamin B12 deficient group normalized the VEGF mRNA levels, NGF protein levels and HIF-1 alpha protein levels. Vitamin B12 supplementation showed similar protein and mRNA levels of VEGF and NGF as well as HIF-1 alpha protein levels as compared to control. Omega-3 fatty acid supplementation to the vitamin B12 supplemented group showed higher (p<0.01) protein and mRNA levels of NGF but the protein and mRNA levels of VEGF were comparable to control. In conclusion maternal vitamin B12 and omega-3 fatty acids both influence the levels and expression of neurotrophins and angiogenic factors in the offspring brain suggesting a possible benefit of combined maternal supplementation of these vital nutrients.

Maternal micronutrients and brain global methylation patterns in the offspring.

OBJECTIVES: Studies have established the association of maternal nutrition and increased risk for non-communicable diseases. It has been suggested that this involves epigenetic modifications in the genome. However, the role of maternal micronutrients in the one-carbon cycle in influencing brain development of the offspring through methylation is unexplored. It is also unclear whether epigenomic marks established during early development can be reversed by a postnatal diet. The present study reports the effect of maternal micronutrients and omega-3 fatty acids on global DNA methylation patterns in the brain of the Wistar rat offspring at three timepoints (at birth, postnatal day 21, and 3 months of age). METHOD: Pregnant rats were divided into control (n = 8) and five treatment groups (n = 16 dams in each group) at two levels of folic acid (normal and excess folate) in the presence and absence of vitamin B12 (NFBD, EFB, and EFBD). Omega-3 fatty acid supplementation was given to vitamin B12 deficient groups (NFBDO and EFBDO). Following delivery, eight dams from each group were shifted to control diet and remaining continued on the same treatment diet. RESULTS: Our results demonstrate that maternal micronutrient imbalance results in global hypomethylation in the offspring brain at birth. At adult age the cortex of the offspring displayed hypermethylation as compared with control, in spite of a postnatal control diet. In contrast, prenatal omega-3 fatty acid supplementation was able to normalize methylation at 3 months of age. DISCUSSION: Our findings provide clues for the role of omega-3 fatty acids in reversing methylation patterns thereby highlighting its contribution in neuroprotection and cognition.

Supplementation with omega-3 fatty acids during gestation and lactation to a vitamin B12-deficient or -supplemented diet improves pregnancy outcome and metabolic variables in Wistar rats.

Maternal vitamin B12 deficiency leads to an adverse pregnancy outcome and increases the risk for developing diabetes and metabolic syndrome in mothers in later life. Our earlier studies have demonstrated that vitamin B12 and n-3 polyunsaturated fatty acids (PUFA) are interlinked in the one carbon cycle. The present study for the first time examines the effect of maternal n-3 PUFA supplementation to vitamin B12 deficient or supplemented diets on pregnancy outcome, fatty-acid status and metabolic variables in Wistar rats. Pregnant dams were assigned to one of the following groups: control, vitamin B12 deficient, vitamin B12 supplemented, vitamin B12 deficient + n-3 PUFA or vitamin B12 supplemented + n-3 PUFA. The amount of vitamin B12 in the supplemented group was 0.50 µg kg(-1) diet and n-3 PUFA was alpha linolenic acid (ALA) 1.68, eicosapentaenoic acid 5.64, docosahexaenoic acid (DHA) 3.15 (g per 100g fatty acids per kg diet). Our findings indicate that maternal vitamin B12 supplementation did not affect the weight gain of dams during pregnancy but reduced litter size and weight and was ameliorated by n-3 PUFA supplementation. Vitamin B12 deficiency or supplementation resulted in a low percentage distribution of plasma arachidonic acid and DHA. n-3 PUFA supplementation to these diets improved the fatty-acid status. Vitamin B12 deficiency resulted in higher homocysteine and insulin levels, which were normalised by supplementation with either vitamin B12 or n-3 PUFA. Our study suggests that maternal vitamin B12 status is critical in determining pregnancy outcome and metabolic variables in dams and that supplementation with n-3 PUFA is beneficial.