Li Dao, Xu Yawen, Wang Kai, Yang Zhuanhong, Li Hui, Lei Sijia, Wang Suqing
Department of Preventive Medicine, School of Health Sciences, Wuhan University Wuhan 430071, Hubei, China.
Fundamental Medical Center, Wuhan City College Wuhan 430071, Hubei, China.
Am J Transl Res. 2021 Nov 15;13(11):12650-12661. eCollection 2021.
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 D 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 D (1,25(OH)D) concentration in early pregnancy, middle pregnancy and late pregnancy stages in AMA mice. The hippocampal 1,25(OH)D levels in the offspring showed the similar pattern. Subsequently, the expression of Cyp27b1, the gene encoding enzyme that converts 25(OH)D to 1,25(OH)D, 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)D, 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.
探讨高龄妊娠（AMA）小鼠孕前补充母源维生素D（Vit D）对后代认知功能影响的分子机制。
32周龄雌性小鼠每天接受溶解于200 μl玉米油中的10 IU/g体重维生素D（32W + VD组），或每天接受200 μl玉米油（32W组），持续一周。将另一组8周龄雌性小鼠接受与32W组相同量的玉米油作为正常生育年龄对照组（8W组）。然后将三组雌性小鼠以2:1的比例与10周龄雄性小鼠交配，后代在3周龄时断奶并饲养至6周龄。检测母鼠及其后代中Vit D代谢产物和参与Vit D代谢的酶。测定后代海马中的Vit D受体（VDR）和突触标记物。预测HIF-1α启动子中的Vit D反应元件，并检测VDR转录靶基因和相关信号分子。
Vit D干预显著提高了AMA小鼠孕早期、孕中期和孕晚期血清1,25-二羟基维生素D（1,25(OH)D）浓度。后代海马中的1,25(OH)D水平呈现相似模式。随后，AMA小鼠后代海马中编码将25(OH)D转化为1,25(OH)D的酶的Cyp27b1基因表达显著低于正常雌性小鼠后代，且通过补充Vit D得以恢复。介导活性1,25(OH)D细胞作用的VDR（Vit D受体）也通过补充Vit D得到挽救，尤其是在海马齿状回（DG）区域。同时，32W + VD组海马中的突触标记物NR1、NR2A和PSD-93得到逆转。最后，我们发现补充Vit D可能通过VDR介导HIF1α表达来影响PI3K-AKT、PLC-ERK1/2和p38-MAPK信号分子。
我们的研究结果突出了孕前补充母源Vit D对Vit D代谢及后代信号分子的生物学意义，揭示了AMA小鼠所产后代认知障碍的潜在机制。
