Maternal Vit D supplementation in AMA mice and the role of Vit D/VDR signaling in the offspring's cognition.

To explore the molecular mechanism underlying the effect of maternal vitamin D (Vit D) supplementation before pregnancy in advanced maternal age (AMA) mice on the offspring's cognitive function.Thirty-two-week-old female mice either received 10 IU/g body weight vitamin D3 dissolved in 200 μl corn oil (32W+VD group), or 200 μl corn oil (32W group) per day for one week. Another group of eight-week-old female mice received the same amount of corn oil as 32W group was set as normal reproductive age control (8W group). Then the three groups of female mice were mating with ten-week-old male mice at 2:1 ratio, the offspring were weaned at the age of 3 weeks and housed until the age of 6 weeks. Vit D metabolites and enzymes involved in Vit D metabolism were measured in both mothers and their offspring. Vit D receptor (VDR) and synaptic markers were determined in the offspring hippocampus. Vit D response elements in HIF-1α promoter were predicted, and VDR transcriptional target genes and related signaling molecules were also detected.Vit D intervention markedly improved the serum 1,25 dihydroxy vitamin D3 (1,25(OH)2D3) concentration in early pregnancy, middle pregnancy and late pregnancy stages in AMA mice. The hippocampal 1,25(OH)2D3 levels in the offspring showed the similar pattern. Subsequently, the expression of Cyp27b1, the gene encoding enzyme that converts 25(OH)D3 to 1,25(OH)2D3, in the hippocampus of the offspring from AMA mice was significantly lower than that of the offspring from normal female mice, and was restored by Vit D supplementation. VDR (Vit D receptor), which mediates the cellular actions of active 1,25(OH)2D3, was also rescued by Vit D supplementation, especially in dentate gyrus (DG) region of hippocampus. Concurrently, the synaptic markers NR1, NR2A, and PSD-93 in the hippocampus were reversed in 32W+VD group. Finally, we found that Vit D supplementation may affect PI3K-AKT, PLC-ERK1/2, and p38-MAPK signaling molecules by mediating HIF1α expression via VDR.Our findings highlight the biological significance of maternal Vit D supplementation before pregnancy on Vit D metabolism, and signaling molecules in the offspring, underlying the potential mechanism of the cognitive impairment in the offspring born to AMA mice.