Maternal micronutrient imbalance alters gene expression of BDNF, NGF, TrkB and CREB in the offspring brain at an adult age.

Micronutrients like folate, vitamin B12, and fatty acids which are interlinked in the one carbon cycle play a vital role in mediating epigenetic processes leading to an increased risk for neurodevelopmental disorders in the offspring. Our earlier study demonstrates that a micronutrient imbalanced diet adversely affects docosahexaenoic acid (DHA) and protein levels of neurotrophins like brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF) in the brain and cognition in the offspring by 3 months of age. In this study we attempt to analyze if these effects are a consequence of a change in gene expression of these molecules. Further, we also examined the effect of either a postnatal control diet or a prenatal omega-3 fatty acid supplementation on gene expression in the cortex of the offspring. Pregnant rats were divided into control and five treatment groups at two levels of folic acid (normal and excess folate) in the presence and absence of vitamin B12. Omega-3 fatty acid (eicosapentaenoic acid - EPA+DHA) supplementation was given to vitamin B12 deficient groups. Following delivery, 8 dams from each group were shifted to control diet and remaining continued on the same treatment diet. Our results demonstrate that the imbalanced diet caused a marked reduction in the mRNA levels of BDNF, NGF, TrkB, and cAMP response element-binding protein (CREB). Prenatal omega-3 fatty acid supplementation to the maternal imbalanced diet was able to normalize the mRNA levels of all the above genes. This study demonstrates that a maternal diet imbalanced in micronutrients (folic acid, vitamin B12) influences gene expression of neurotrophins and their signalling molecules and thereby adversely affects the brain of the offspring.

Sable P ，Kale A ，Joshi A ，Joshi S ... -  《-》

Prenatal omega 3 fatty acid supplementation to a micronutrient imbalanced diet protects brain neurotrophins in both the cortex and hippocampus in the adult rat offspring.

Our earlier studies show that maternal diets imbalanced in micronutrients like folic acid and vitamin B12 reduced brain docosahexaenoic acid (DHA) and brain derived neurotrophic factor (BDNF) and nerve growth factor (NGF) in the offspring at birth and postnatal d21. This study followed the offspring till 3 months to examine the hypothesis that impaired brain neurotrophins at birth and d21 due to altered maternal micronutrients can be reversed by prenatal omega 3 fatty acid but not a postnatal control diet leading to altered cognition in adult life. Pregnant rats were divided into control and five treatment groups 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 the vitamin B12 deficient groups (NFBDO and EFBDO). Following delivery, 8 dams from each group were shifted to control and remaining continued on same diet. Imbalance in maternal micronutrients up to 3months decreased DHA, BDNF and NGF in cortex and only BDNF in the hippocampus and impaired cognitive performance. Postnatal control diet normalized BDNF in the cortex but not the hippocampus and also altered cognitive performance. Prenatal omega 3 fatty acid supplementation normalized DHA, BDNF and NGF while long term supplementation was not beneficial only when micronutrients were imbalanced. Patterns established at birth are not totally reversible by postnatal diets and give clues for planning intervention studies for improving brain functioning and cognitive abilities.

Sable PS ，Kale AA ，Joshi SR 《-》

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.

Sable PS ，Dangat KD ，Joshi AA ，Joshi SR ... -  《-》

Maternal micronutrients and brain global methylation patterns in the offspring.

Sable P ，Randhir K ，Kale A ，Chavan-Gautam P ，Joshi S ... -  《-》

Effect of maternal micronutrients (folic acid and vitamin B12) and omega 3 fatty acids on indices of brain oxidative stress in the offspring.

Our earlier studies have shown that a maternal diet imbalanced with micronutrients like folic acid, vitamin B12 has adverse effects on fatty acid metabolism, global methylation patterns and levels of brain neurotrophins in the offspring at birth. However, it is not clear if these effects are mediated through oxidative stress. The role of oxidative stress in influencing epigenetic mechanisms and thereby fetal programming is not well studied. Pregnant female rats were divided into six treatment groups at two levels of folic acid both in the presence and absence of vitamin B12. Omega 3 fatty acid supplementation was given to the vitamin B12 deficient groups. Following delivery, 8 dams from each group were randomly shifted back to control and the remaining 8 continued on the same treatment diet. Our results indicate for the first time that an imbalance in maternal micronutrients reduces the antioxidant enzymes superoxide dismutase (SOD) and glutathione peroxidase (GPx) (p<0.05 for both) at birth. At d21 of life, the levels of MDA and GPx (p<0.05 for both) in pup brain from the micronutrient imbalanced group were higher as compared to control while omega 3 fatty acid supplementation normalizes the levels of GPx. Our data shows that maternal micronutrient imbalance adversely affects antioxidant defense mechanisms while omega 3 fatty acid supplementation ameliorates some of the negative effects. Our study throws light on the role of oxidative stress in fetal brain programming and consequential risk for neurodegenerative disorders in later life.

Roy S ，Sable P ，Khaire A ，Randhir K ，Kale A ，Joshi S ... -  《-》