Perinatal α‐linolenic acid availability alters the expression of genes related to memory and to epigenetic machinery, and the Mecp2 DNA methylation in the whole brain of mouse offspring

Abstract

Many animal and human studies indicated that dietary ω-3 fatty acids could have beneficial roles on brain development, memory, and learning. However, the exact mechanisms involved are far from being clearly understood, especially for α-linolenic acid (ALA), which is the precursor for the ω-3 elongation and desaturation pathways. This study investigated the alterations induced by different intakes of flaxseed oil (containing 50% ALA), during gestation and lactation, upon the expression of genes involved in neurogenesis, memory-related molecular processes, and DNA methylation, in the brains of mouse offspring at the end of lactation (postnatal day 19, P19). In addition, DNA methylation status for the same genes was investigated. Maternal flaxseed oil supplementation during lactation increased the expression of Mecp2, Ppp1cc, and Reelin, while decreasing the expression of Ppp1cb and Dnmt3a. Dnmt1 expression was decreased by postnatal flaxseed oil supplementation but this effect was offset by ALA deficiency during gestation. Mecp2 DNA methylation was decreased by maternal ALA deficiency during gestation, with a more robust effect in the lactation-deficient group. In addition, linear regression analysis revealed positive correlations between Mecp2, Reelin, and Ppp1cc, between Gadd45b, Bdnf, and Creb1, and between Egr1 and Dnmt1, respectively. However, there were no correlations, in any gene, between DNA methylation and gene expression. In summary, the interplay between ALA availability during gestation and lactation differentially altered the expression of genes involved in neurogenesis and memory, in the whole brain of the offspring at the end of lactation. The Mecp2 epigenetic status was correlated with ALA availability during gestation. However, the epigenetic status of the genes investigated was not associated with transcript levels, suggesting that either the regulation of these genes is not necessarily under epigenetic control, or that the whole brain model is not adequate for the exploration of epigenetic regulation in the context of this study.

Multigenerational effects of parental prenatal exposure to famine on adult offspring cognitive function

“…Several recent studies suggest that adult cognitive function can be affected by early-life nutritional exposure through epigenetic modifications in the brain, such as DNA and histone methylation 5 6 . In addition, the epigenetic modification alterations induced by early-life nutrition can sometimes be transmitted to offspring 7 8 .…”

“…Recent studies suggested that epigenetic changes play key roles in brain development, maturation, and learning 3 4 . Early-life nutrition, such as choline and α-linolenic acid availability, can program brain development via DNA and histone methylation and then affect adult cognitive function 5 6 . Considering that epigenetic marks induced by early-life nutrition can sometimes be transmitted to offspring via gametes 7 8 , we hypothesized that the impaired cognitive functions induced by early-life malnutrition may be propagated across generations.…”

Early-life adversity programs emotional functions and the neuroendocrine stress system: the contribution of nutrition, metabolic hormones and epigenetic mechanisms

“…As in the case of stress, the effects of early nutrition might also be mediated by modulation of the epigenome (He et al, 2014;McNeil et al, 2008). This has mostly been addressed in the context of metabolic programming, which is in contrast to the scarce evidence of epigenetic effects of early nutritional manipulations in the brain.…”

Neurological and Epigenetic Implications of Nutritional Deficiencies on Psychopathology: Conceptualization and Review of Evidence

“…In a study involving rural Gambian women, who experience season nutrition changes, there were significant methylation changes on epialleles of offspring depending on the time of conception, based on differences in methyl-donor nutrient intake [ 64 ]. Additionally, a second potential mechanism whereby diet could alter DNA methylation involves direct effects on the expression of the DNA methylation machinery, namely the DNA methyltransferase system, as early life protein restriction [ 65 ] as well as α-linoleic acid supplementation [ 66 ] were both found to alter expression of DNMT1, as well as MeCP2, a methyl binding protein that binds methylated DNA and recruits additional transcriptional modifiers. DNA demethylation can also alter gene expression, whether by direct or indirect mechanisms such as changes in base excision repair or decreasing DNMT levels.…”