Brain α-Tocopherol Concentration and Stereoisomer Profile Alter Hippocampal Gene Expression in Weanling Mice

Abstract

Background Alpha-tocopherol (αT), the bioactive constituent of vitamin E, is essential for fertility and neurological development. Synthetic αT (8 stereoisomers; all rac-αT) is added to infant formula at higher concentrations than natural αT (RRR-αT only) to adjust for bio-potency differences, but its effects on brain development are poorly understood. Objectives The objective was to determine the impact of bio-potency–adjusted dietary all rac-αT versus RRR-αT, fed to dams, on the hippocampal gene expression in weanling mice. Methods Male/female pairs of C57BL/6J mice were fed AIN 93-G containing RRR-αT (NAT) or all rac-αT (SYN) at 37.5 or 75 IU/kg (n = 10/group) throughout gestation and lactation. Male pups were euthanized at 21 days. Half the brain was evaluated for the αT concentration and stereoisomer distribution. The hippocampus was dissected from the other half, and RNA was extracted and sequenced. Milk αT was analyzed in separate dams. Results A total of 797 differentially expressed genes (DEGs) were identified in the hippocampi across the 4 dietary groups, at a false discovery rate of 10%. Comparing the NAT-37.5 group to the NAT-75 group or the SYN-37.5 group to the SYN-75 group, small differences in brain αT concentrations (10%; P < 0.05) led to subtle changes (<10%) in gene expression of 600 (NAT) or 487 genes (SYN), which were statistically significant. Marked differences in brain αT stereoisomer profiles (P < 0.0001) had a small effect on fewer genes (NAT-37.5 vs. SYN-37.5, 179; NAT-75 vs. SYN-75, 182). Most of the DEGs were involved in transcription regulation and synapse formation. A network analysis constructed around known vitamin E interacting proteins (VIPs) revealed a group of 32 DEGs between NAT-37.5 vs. SYN-37.5, explained by expression of the gene for the VIP, protein kinase C zeta (Pkcz). Conclusions In weanling mouse hippocampi, a network of genes involved in transcription regulation and synapse formation was differentially affected by dam diet αT concentration and source: all rac-αT or RRR-αT.

α-Tocopherol Stereoisomer Profiles in Matched Human Maternal and Umbilical Cord Plasma

“…We believe these finding to be important for several reasons beyond the well-documented differences in vitamin E activity between RRR -αT and S-αT ( 5 ). αT has increasingly been found to influence gene expression ( 30 – 35 ), and more recently, evidence is accumulating that S-αT stereoisomers and RRR -αT have differential impacts on gene expression in the brain ( 20 , 36 , 37 ). In addition, improved maternal αT status appears to positively influence fetal growth ( 19 , 38 – 42 ), but recently cord plasma αT concentration was reported to be negatively related to neonate 5-min Apgar (physician ratings of the newborn infant's appearance, pulse, grimace, activity, respiration) ( 38 ).…”

Dietary share of ultra-processed foods and its association with vitamin E biomarkers in Brazilian lactating women

“…Even so, the of this study highlight the effects of the consumption of ultra-processed foods during lactation on both mother and infant as maternal serum α-tocopherol levels are associated with low circulating levels in the child, even without maternal deficient serum levels (20) . Moreover, a reduced supply of vitamin E in the breast milk or maternal concentration can cause greater oxidative damage due to reduced antioxidant protection in the infant provided by vitamin E (42) and gene expression genes involved in transcription regulation and synapse formation in the hippocampus are very sensitive to subtle changes in α-tocopherol concentration (43) . This in turn makes the infant, particularly premature babies, more susceptible to the development of clinical complications related to VED, such as hemolytic anaemia, retrolental fibroplasia, intracranial haemorrhage and bronchopulmonary dysplasia (42) .…”

α-Tocopherol: New Perspectives and Challenges for Achieving the Sustainable Development Goals (SDG) Target

“…In addition, time-course bioaccumulation of natural vs. synthetic α-Toc in tissues of young marginally VE-deficient mice showed that bioaccumulation of α-Toc over time varied substantially depending on α-Toc source and tissue type; Natural α-Toc showed higher accumulation levels in heart, lungs, kidney, brain and adipose tissue than synthetic one 43) . Besides, in mice, natural and synthetic VEs modulate transcription of different genes, suggesting in vivo effects are related to the fine structure of the molecules 44,45) . It is claimed that although RRR-α-Toc is the predominant stereoisomer in human milk, synthetic (all-rac) -α-Toc is commonly used in infant formulas 46) .…”