Maternal n-3 polyunsaturated fatty acid deprivation during pregnancy and lactation affects neurogenesis and apoptosis in adult offspring: associated with DNA methylation of brain-derived neurotrophic factor transcripts.

In this study, we hypothesized that n-3 polyunsaturated fatty acid (PUFA) deficiency during pregnancy and lactation will make a lasting impact on brain neurogenesis and apoptosis of the adult offspring and that these harmful effects cannot be reversed by n-3 PUFA supplementation after weaning. Moreover, the underlying mechanisms may be attributable to the epigenetic changes of brain-derived neurotrophic factor (BDNF). C57BL/6J female mice were fed with n-3 PUFA-deficient diet (n-3 def) or n-3 PUFA-adequate diet (n-3 adq) throughout pregnancy and lactation. At postnatal 21 days, equal numbers of male pups from both groups were fed the opposite diet, and the remaining male pups were fed with the same diets as their mothers until 3 months of age. Feeding the n-3 adq diet to pups from the maternal n-3 def group significantly increased the n-3 PUFA concentration but did not change expressions of calretinin, Bcl2, and Bax in the hippocampus. Feeding the n-3 def diet to pups from the maternal n-3 adq group significantly reduced the n-3 PUFA concentration but did not reduce expressions of calretinin and Bcl2. Similarly, BDNF levels, especially mRNA expressions of BDNF transcripts IV and IX, were also reduced by maternal n-3 def and not reversed by n-3 PUFA supplementation after weaning. The decrease in BDNF expression by maternal n-3 def diet was associated with greater DNA methylation at special CpG sites. These results suggested that the maternal n-3 PUFA deficiency during pregnancy and lactation imprints long-term changes of brain development in adult offspring.

Fan C ，Fu H ，Dong H ，Lu Y ，Lu Y ，Qi K ... -  《-》

DIETARY RATIOS OF N-6/N-3 POLYUNSATURATED FATTY ACIDS DURING MATERNAL PREGNANCY AFFECT HIPPOCAMPAL NEUROGENESIS AND APOPTOSIS IN MOUSE OFFSPRING.

although n-3 polyunsaturated fatty acids (PUFAs) play crucial roles in brain development and function, neither the optimal level of n-3 PUFAs nor the optimal ratio of n-6/n-3 PUFAs in the maternal diet are well defined. In this study, we investigated the effects of dietary n-6/n-3 PUFA ratios during pregnancy on neurogenesis and apoptosis in the brains of mouse offspring. Metods: female C57BL/6J mice were fed one of three diets with high, medium and low ratios of n-6/n-3 PUFAs (15.7:1, 6.3:1, 1.6:1), as well as a high fish oil diet with a n-6/n-3 ratio of 1:5.7; an n-3 PUFA-deficient diet served as control. The feeding regimens began two months before mouse conception and continued for the duration of the pregnancy. The neurogenesis and apoptosis of hippocampal CA3 area in the offspring were detected. compared to the n-3 PUFA-deficient diet, n-3 PUFA-containing diets, particularly those with n-6/n-3 PUFA ratios of 6.3:1 and 1.6:1, significantly increased both phosphorylation of histone H3 at ser 10 (p-H3ser10) and calretinin-positive cells in hippocampus CA3 of the offspring. Furthermore, increased expression of Bcl2 protein, decreased expression of Bax protein, and reduced caspase 3 activity and numbers of TUNEL apoptotic cells were found in the three diets with high, medium and low n-6/n-3 PUFA ratios. However, there were no differences in any of these parameters between the high fish oil diet group and the n-3 PUFA-deficient diet group. these data suggest that a higher intake of n-3 PUFAs with a lower ratio of n-6/n-3 PUFAs of between about 6:1 to 1:1, supplied to mothers during pregnancy, may benefit brain neurogenesis and apoptosis in offspring. However, excessive maternal intake of n-3 PUFAs may exert a negative influence on brain development in the offspring.

Fan C ，Sun W ，Fu H ，Dong H ，Xia L ，Lu Y ，Deckelbaum RJ ，Qi K ... -  《-》

Brain histological changes in young mice submitted to diets with different ratios of n-6/n-3 polyunsaturated fatty acids during maternal pregnancy and lactation.

N-3 polyunsaturated fatty acids (n-3 PUFAs) are essential for brain development and function, but the appropriate quantity of dietary n-3 PUFAs and ratio of n-6/n-3 PUFAs have not been clearly determined. In this study, we investigated the effects of different dietary ratios of n-6/n-3 PUFAs on the brain structural development in mice and the expression of associated transcription factors. C57 BL/6J mice were fed with one of two categories of n-3 PUFA-containing diets (a flaxseed oil diet and a flaxseed/fish oil mixed diet) or an n-3 PUFA-deficient diet. For each of the n-3 PUFA diets, flaxseed oil or flaxseed/fish oil was combined with other oils to yield three different n-6/n-3 ratios, which ranged from 15.7:1 to 1.6:1. The feeding regimens began two months before mouse conception and continued throughout lactation for new pups. As compared with the n-3 PUFA-deficient diet, both the flaxseed oil n-3 PUFA diets and the flaxseed/fish oil n-3 PUFA diets significantly increased the expression levels of brain neuron-specific enolase, glial fibrillary acidic protein and myelin basic protein, somewhat dose-dependently, in new pup mice at 21 d and 42 d of age. The expression of PPAR-γ in the brains of pup mice was increased only at 7 d of age with the n-3 PUFA diet, and no changes in the expression of PPAR-α and PPAR-β were found among all the diet groups. These results suggest that the higher intake amount of n-3 PUFAs with a low ratio of n-6/n-3 PUFAs at about 1-2:1, supplied during both maternal pregnancy and lactation, may be more beneficial for early brain development, and PPAR-γ may act in one of the pathways by which n-3 PUFAs promote early brain development.

Tian C ，Fan C ，Liu X ，Xu F ，Qi K ... -  《-》

The cognitive impairment induced by zinc deficiency in rats aged 0∼2 months related to BDNF DNA methylation changes in the hippocampus.

Hu YD ，Pang W ，He CC ，Lu H ，Liu W ，Wang ZY ，Liu YQ ，Huang CY ，Jiang YG ... -  《-》

Maternal diet high in Omega-3 fatty acids upregulate genes involved in neurotrophin signalling in fetal brain during pregnancy in C57BL/6 mice.

Neurotrophins play a critical role in the development, maintenance, and proper function of the brain. We investigated the effects of maternal diet high in omega (n)-3 polyunsaturated fatty acids (PUFA) on fatty acids composition and the gene expression of neurotrophins in fetal brain at different gestation stages. Female C57BL/6 mice (7-weeks old, n = 8/group) were fed a diet containing high, low or very low n-3 PUFA (9, 3 or 1% w/w, respectively), with an n-6:n-3 PUFA of 5:1, 20:1 and 40:1, respectively, for two weeks before mating and throughout pregnancy. Animals were sacrificed during pregnancy at gestation day 12.5 and 18.5 to determine placental and fetal-brain fatty acids composition. The gene expressions of endothelial lipase (EL) and plasma membrane fatty acid-binding protein (FABPpm) were measured in the placenta, while major facilitator superfamily domain-containing 2a (Mfsd2a), brain-derived neurotrophic factor (BDNF), tropomyosin-receptor kinase (TrK)-B, and cAMP response element-binding protein (CREB) were measured in fetal-brain, using qPCR. The protein expression of phosphorylated CREB (pCREB) was determined using ELISA. The high n-3 PUFA diet increased the mRNA expression of EL, FABPpm, and Mfsd2a at both gestation days, compared to other groups. Docosahexaenoic acid (DHA) and total n-3 PUFA were significantly higher in the high n-3 PUFA group, compared to the other groups at both gestation days. The high n-3 PUFA diet also increased the mRNA expressions of BDNF, TrKB and CREB, as well as the protein concentration of pCREB as gestation progressed, compared to the other groups. Our findings show for the first time that maternal diet high in n-3 PUFA increased the mRNA expression of Mfsd2a, which correlated with an increase in DHA accretion in the fetal-brain. A diet high in n-3 PUFA increased neurotrophin signalling in fetal-brain as gestation progressed, demonstrating the importance of n-3 PUFA during brain development.

Akerele OA ，Cheema SK 《-》