Kamini Dangat

Effects of altered maternal folic acid, vitamin B12 and docosahexaenoic acid on placental global DNA methylation patterns in Wistar rats.

Potential adverse effects of excess maternal folic acid supplementation on a vegetarian population deficient in vitamin B12 are poorly understood. We have previously shown in a rat model that maternal folic acid supplementation at marginal protein levels reduces brain omega-3 fatty acid levels in the adult offspring. We have also reported that reduced docosahexaenoic acid (DHA) levels may result in diversion of methyl groups towards DNA in the one carbon metabolic pathway ultimately resulting in DNA methylation. This study was designed to examine the effect of normal and excess folic acid in the absence and presence of vitamin B12 deficiency on global methylation patterns in the placenta. Further, the effect of maternal omega 3 fatty acid supplementation on the above vitamin B12 deficient diets was also examined. Our results suggest maternal folic acid supplementation in the absence of vitamin B12 lowers plasma and placental DHA levels (p<0.05) and reduces global DNA methylation levels (p<0.05). When this group was supplemented with omega 3 fatty acids there was an increase in placental DHA levels and subsequently DNA methylation levels revert back to the levels of the control group. Our results suggest for the first time that DHA plays an important role in one carbon metabolism thereby influencing global DNA methylation in the placenta.

Fatty acids, antioxidants, and oxidative stress in pre-eclampsia

To investigate whether free radical‐mediated membrane lipid peroxidation may be implicated in the pathogenesis of pre‐eclampsia.

Maternal micronutrients (folic acid and vitamin B12) and omega 3 fatty acids: Implications for neurodevelopmental risk in the rat offspring

Altered maternal micronutrients (folic acid, vitamin B(12)) are suggested to be at the heart of intra-uterine programming of adult diseases. We have recently described interactions of folic acid, vitamin B(12) and docosahexaenoic acid in one carbon metabolism that is considered to play a key role in regulation oxidative stress and chromatin methylation. However its impact on fetal oxidative stress and brain fatty acid levels has been relatively unexplored. The present study examined the effect of imbalance in maternal micronutrients (folic acid and vitamin B(12)) and maternal omega 3 fatty acid supplementation on oxidative stress parameters and brain fatty acids and in the offspring at birth. Pregnant female rats were divided into six groups at two levels of folic acid both in the presence and absence of vitamin B(12). Both the vitamin B(12) deficient groups were supplemented with omega 3 fatty acid. Oxidative stress marker (malondialdehyde) and polyunsaturated fatty acid profiles in plasma and brain were analyzed in dam and offspring at d20. Our results for the first time indicate that imbalance in maternal micronutrients (excess maternal folic acid supplementation on a B(12) deficient diet) increases (p<0.01) oxidative stress in both mother and pups. This increased maternal oxidative stress resulted in lower (p<0.01) fetal brain DHA levels. Omega 3 fatty acid supplementation was able to restore (p<0.05) the levels of brain DHA in both the vitamin B(12) deficient groups. Our data has implications for implications for neurodevelopmental disorders since micronutrients and DHA are important modulators for neural functioning.

Association of omega-3 fatty acids and homocysteine concentrations in pre-eclampsia.

BACKGROUND & AIMS The present study examines the associations of folic acid, vitamin B₁₂ and omega-3 fatty acids and increased homocysteine which are implicated in the pathology of pre-eclampsia. METHODS 49 Pre-eclamptic and 57 normotensive women were recruited at Bharati hospital, Pune, India. Plasma folate, vitamin B₁₂, homocysteine and erythrocyte omega-3 and omega-6 fatty acids were analyzed. RESULTS Homocysteine concentrations were higher in pre-eclamptic than in normotensive women (14.28±7.31 vs. 11.03±4.38 μmol/l, p<0.01) despite similar levels of folic acid and vitamin B₁₂. In the pre-eclamptic group, plasma folate levels were positively associated with erythrocyte omega-6 fatty acids (p<0.05) while erythrocyte docosahexaenoic acid levels were negatively associated with plasma homocysteine levels (p<0.01). CONCLUSIONS Our study provides evidence for the associations of altered omega-3 fatty acids especially docosahexaenoic acid and the resultant increased homocysteine concentrations in pre-eclampsia. Future studies need to examine if docosahexaenoic acid supplementation during pregnancy reduces homocysteine levels and ameliorates the risk of developing pre-eclampsia.

Long chain polyunsaturated fatty acids in mothers and term babies

Abstract Aim: To establish the levels of docosahexaenoic acid (DHA) and arachidonic acid (AA) in both plasma and erythrocytes of maternal and cord blood as well as in breast milk of mothers delivering babies at term. Methods: A total of 148 mothers delivering babies at term were recruited from Bharati Medical Hospital, Pune, India. Results: Levels of DHA and AA in both plasma and erythrocyte were higher in cord blood compared to levels in maternal blood (P<0.001). Maternal plasma and erythrocyte DHA levels had a positive association with the respective levels in cord blood (P<0.001). However, such an association was not seen for AA levels. Maternal plasma omega 3 and omega 6 fatty acids were positively associated with the respective milk fatty acids (P<0.01). Conclusions: Our results indicate that milk long-chain polyunsaturated fatty acids (LCPUFA) status reflects the concentrations of maternal LCPUFA in women delivering babies at term. Improving the maternal LCPUFA status throughout pregnancy and lactation may improve the milk LCPUFA status and ultimately benefit the infant.

Maternal omega 3 fatty acid supplementation during pregnancy to a micronutrient-imbalanced diet protects postnatal reduction of brain neurotrophins in the rat offspring

An altered one carbon cycle (folic acid, vitamin B(12)) and omega 3 fatty acid metabolism during pregnancy can increase the risk for neurodevelopmental disorders in the offspring. Our earlier studies have shown that a maternal diet imbalanced with micronutrients like folic acid, vitamin B(12) reduces levels of brain docosahexaenoic acid (DHA) and neurotrophins in the offspring at birth. The present study examines whether these effects can be reversed by a postnatal diet. Pregnant female rats were divided into six treatment groups at two levels of folic acid both in the presence and absence of vitamin B(12). Omega 3 fatty acid supplementation was given to the vitamin B(12)-deficient groups. Following delivery, eight dams from each group were randomly shifted back to control and remaining eight continued on the same treatment diet. Plasma homocysteine levels could be normalized by a postnatal control diet. Brain DHA levels were similar in all the groups irrespective of the diet consumed during lactation. Brain-derived nerve growth factor (BDNF) and nerve growth factor (NGF) levels were lower in both the vitamin B(12)-deficient groups even after consuming a diet with normal levels of vitamin B(12) during lactation (p<0.05 for all) indicating that the effects of maternal programing with respect to neurotrophins cannot be reversed by a postnatal diet. Our findings for the first time suggest that omega 3 fatty acid supplementation to a micronutrient-imbalanced diet, during pregnancy and lactation protects the levels of BDNF and NGF. This may have significant implications in the development of psychiatric disorders/cognitive deficits in later life.

High Maternal Plasma Antioxidant Concentrations Associated with Preterm Delivery

Background/Aims: Our earlier study has shown that increased maternal oxidative stress and reduced antioxidants like vitamin E and C play an important role in fetal growth in preeclampsia. However, the role of antioxidants and their effects on gestation and birth outcome in normotensive pregnancies are not conclusive. The present study examined plasma malondialdehyde as a marker of oxidative stress and antioxidant concentrations (vitamins E and C) in maternal as well as in cord blood samples in normotensive women who delivered both preterm and at term. Methods: 140 normotensive pregnant women were recruited at Bharati Medical Hospital, Pune, India, during the year 2007. Maternal and cord samples were examined for oxidative stress levels and vitamin C and E concentrations in women who delivered preterm (n = 40) and at term (n = 100). Mean values were compared with those of women delivering at term using the t test. Results: Increased (p < 0.05) oxidative stress was seen in preterm mothers as well as in cord samples. Preterm mothers had higher vitamin C concentrations (p < 0.05), and these were positively associated with oxidative stress (p = 0.02). Vitamin E levels were comparable between groups. Conclusions: Increased maternal circulating vitamin C concentrations and increased oxidative stress are associated with preterm delivery.

Altered brain neurotrophins at birth: consequence of imbalance in maternal folic acid and vitamin B12 metabolism

Folic acid fortification to pregnant women is suggested to mask vitamin B₁₂ deficiency leading to adverse neurologic consequences. The present study examines the effect of maternal folic acid supplementation at normal and excess levels both in the presence and absence of vitamin B₁₂ on levels and expression of brain neurotrophins in Wistar Albino rats. Pregnant female rats were assigned to six dietary groups with varying levels of folic acid and vitamin B₁₂, that is, (NFB: 2 mg folic acid+B₁₂; NFBD: 2 mg folic acid-B₁₂; EFB: 8 mg folic acid+B₁₂; EFBD: 8 mg folic acid-B₁₂; NFBDO: 2 mg folic acid-B₁₂+DHA and EFBDO: 8 mg folic acid-B₁₂+DHA). On day 20 of gestation pup brain samples were collected to assess protein and mRNA levels of brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF). Brain BDNF protein and mRNA levels were reduced (P<0.01 for both) in the EFBD group as compared to control. However, NGF protein levels were reduced (P<0.05) only in the EFBD group in comparison to EFB and control. Maternal supplementation of DHA improved pup brain NGF protein levels only in the NFBDO (P<0.05) and EFBDO (P<0.05) groups compared to NFBD and EFBD respectively. Our results suggest that maternal micronutrients during pregnancy play an important role in regulating protein and mRNA levels of neurotrophins. Maternal DHA supplementation to a micronutrient imbalanced diet could ameliorate the negative effects only for NGF but not for BDNF.

Long-chain polyunsaturated fatty acid composition of breast milk in pre-eclamptic mothers.

Background: Maternal fatty acid nutrition during pregnancy and lactation determines the transfer of long-chain polyunsaturated fatty acids via the placenta and through human milk. Neural maturation of breast-fed infants is known to be linked to breast-milk long-chain polyunsaturated fatty acid concentrations. In spite of this, the fatty acid composition of breast milk in pre-eclamptic mothers is poorly understood. Objectives: To compare the fatty acid composition of breast milk of pre-eclamptic (n = 45) with normotensive (n = 85) mothers and examine the association of breast-milk fatty acids with plasma fatty acids. Methods: Milk and plasma fatty acid methyl esters were prepared and analyzed by the modified method of Manku and colleagues using gas chromatography. Results: Docosahexaenoic acid (DHA) concentrations were significantly increased (p < 0.01) in breast milk in spite of lower maternal plasma DHA concentrations (p < 0.05) in pre-eclamptic women. However, there was no difference in arachidonic acid levels between groups in spite of reduced maternal plasma arachidonic acid levels. Conclusions: The data suggest that in pre-eclampsia, the relation between plasma and milk DHA is altered. The resulting higher milk DHA concentrations are beneficial for infants.

Maternal micronutrients and omega 3 fatty acids affect placental fatty acid desaturases and transport proteins in Wistar rats.

Adequate supply of LCPUFA from maternal plasma is crucial for fetal normal growth and development. The present study examines the effect of maternal micronutrients (folic acid and vitamin B12) and omega 3 fatty acids on placental mRNA levels of fatty acid desaturases (Δ5 and Δ6) and transport proteins. Pregnant female rats were divided into 6 groups at 2 levels of folic acid both in the presence and absence of vitamin B12. Both the vitamin B12 deficient groups were supplemented with omega 3 fatty acid. Maternal vitamin B12 deficiency reduced placental mRNA and protein levels of Δ5 desaturase, mRNA levels of FATP1 and FATP4 (p<0.05 for all) as compared to control while omega 3 fatty acid supplementation normalized the levels. Our data for the first time indicates that altered maternal micronutrients and omega 3 fatty acids play a key role in regulating fatty acid desaturase and transport protein expression in placenta.