Abstract
Docosahexaenoic acid (DHA) is critical for normal brain development and function. DHA is in danger of being significantly reduced in the human food supply, and the question of whether its metabolic precursor, the essential n-3 alpha linolenic acid (ALA) during pregnancy, can support fetal brain DHA levels for optimal neurodevelopment, is fundamental. Female mice were fed either ALA-enriched or Control diet during pregnancy and lactation. The direct effect of maternal dietary ALA on lipids was analyzed in liver, red blood cells, brain and brain vasculature, together with genes of fatty acid metabolism and transport in three-week-old offspring. The long-term effect of maternal dietary ALA on brain fatty acids and memory was studied in 19-week-old offspring. Three-week-old ALA offspring showed higher levels of n-3 fatty acids in liver, red blood cell, blood-brain barrier (BBB) vasculature and brain parenchyma, DHA enrichment in brain phospholipids and higher gene and protein expression of the DHA transporter, major facilitator superfamily domain containing 2a, compared to Controls. 19-week-old ALA offspring showed higher brain DHA levels and better memory performance than Controls. The increased brain DHA levels induced by maternal dietary ALA during pregnancy-lactation, together with the up-regulated levels of major facilitator superfamily domain containing 2a, may indicate a mode for greater DHA uptake with long-term impact on better memory in ALA offspring.
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Key Points
Studies based on cells and knockout mice supported the role of the transporter major facilitator superfamily domain containing 2a (Mfsd2a) as the primary mediator of DHA acquisition by the brain. The Mfsd2a transporter is expressed in the endothelium of the blood-brain barrier (BBB) and other abundant cell types within the brain. This transporter seems to be relatively specific to lysoPC DHA. However, the effect of maternal dietary ALA on the central nervous system, and specifically on brain DHA accretion, memory and Mfsd2a gene and protein expression in the offspring is unknown. In the present work, it was hypothesized that ALA enrichment in maternal diets during fetal development and weaning: (1) enhances Mfsd2a expression in brain vasculature and (2) improves cognitive functions in adult offspring, compared to control diet.
The present study found that maternal dietary ALA enrichment during pregnancy-lactation led to higher levels of n-3 LCPUFA– in particular DHA– in RBC, BBB vasculature and brain tissue, together with an elevated Mfsd2a transporter gene and protein expression in 3-week-old offspring, compared to Control. The lack of detectable DHA in the maternal diet, suggests that higher ALA, compared to LA, determined the higher DHA levels eventually accreted by the brain and measured in RBC. These results may support the additional findings discovered in 19-week-old offspring from ALA-fed mothers, such as the notably higher DHA levels and better memory skills than their Control counterparts. Altogether, the results in the present mouse model suggest an ALA-induced mechanism for higher DHA brain accretion at an early age, with beneficial long-term impact on cognitive functions. Dietary ALA enrichment during pregnancy leads to higher DHA brain levels, up-regulated expression of Mfsd2a gene and protein in 3-week-old mice offspring brain as well as higher brain DHA levels and better memory in 19-week-old offspring, compared to Control counterparts. Mfsd2a gene and protein up-regulation may indicate a mode for greater perinatal DHA accretion in this animal model. High n-3 LCPUFA, and particularly DHA brain content at early age, may “prime” for better memory in adult ALA-born offspring. ALA may be important as a dietary alternative due to its potential to provide n-3 LCPUFA suitable to metabolic needs. In addition, due to fishery decrease, mercury contamination and global warming, the use and production of n-3 DHA for human consumption is destined to be reduced. Increasing the plant source of ALA during perinatal nutrition may positively impact society’s dietary habits and economy, with significant health benefits.