孕期维生素D缺乏与胎儿生长受限的关联及其机制研究

Vitamin D deficiency during pregnancy is a major international public health concern. The object of this project is to analyze the association between vitamin D status at different gestational stages and fetal growth restriction in Chinese population. This study is a population-based birth cohort study that recruited total 3000 eligible mother-and-singleton-offspring pairs from different districts in Anhui province. Serum 25(OH)D will be measured by radioimmunoassay. The rate and relative risk (RR) of small for gestational age (SGA) and low birth weight (LBW) infants will be calculated among subjects with vitamin D deficiency and insufficiency at different gestational stages. In this study, mice were fed with VitD-depleted diets to establish an animal model for fetal growth restriction. This study is to investigate the effects of vitamin D deficiency during pregnancy on placental inflammatory signaling and fetal programming. This study will explore whether down-regulation of placental VDR signaling and up-regulation of placental inflammatory signaling play a role in vitamin D deficiency-induced fetal growth restriction. This study is also to investigate whether vitamin D deficiency during pregnancy or silence of VDR gene impairs placental development and functions and to explore the mechanism through which down-regulation of placental VDR signaling and up-regulation of placental inflammatory signaling mediate fetal programming and growth restriction. To further verify the role of inflammation-mediated impairment of placental development and function, this study will compare the difference of maternal 25(OH)D level, placental VDR signaling, the level of inflammatory cytokines in placentas and cord blood, and placental development and function between SGA and appropriate for gestational age (AGA) infants. This study will provide the data on the association between vitamin D deficiency during pregnancy and fetal growth restriction.

孕期维生素D缺乏是重大公共卫生问题。本课题依托中国安徽出生队列3000对单胎母婴样本人群，分析孕期不同阶段维生素D缺乏与胎儿生长受限之间的关联和远期效应。用不含维生素D饲料喂养小鼠构建胎儿生长受限动物模型，观察孕期维生素D缺乏对胎盘炎性信号和胎儿宫内编程的调控作用，阐明VDR信号下调介导的胎盘炎症在维生素D缺乏所致宫内编程改变和胎儿生长受限中的作用；观察体内维生素D缺乏和体外VDR基因沉默对胎盘屏障、物质交换和内分泌功能的损害，阐明VDR信号下调所致胎盘炎症诱发宫内编程改变和胎儿生长受限的机理。依托马鞍山优生优育队列，采用巢式病例对照设计，分析小于胎龄儿与适于胎龄儿母血25（OH）D水平、胎盘VDR信号、胎盘和脐血炎性因子水平及胎盘功能发育状况的关联，验证炎症介导的胎盘发育受损和功能不全在维生素D缺乏所致胎儿生长受限中的关键作用。本课题为阐明孕期维生素D缺乏诱发胎儿生长受限的机理提供依据。

孕期维生素D缺乏是重大公共卫生问题。本课题依托中国安徽出生队列3000对单胎母婴样本人群，分析孕期不同阶段维生素D缺乏与胎儿生长受限之间的关联和远期效应。用不含维生素D饲料喂养小鼠构建胎儿生长受限动物模型，观察孕期维生素D缺乏对胎盘炎性信号和胎儿宫内编程的调控作用，阐明VDR信号下调介导的胎盘炎症在维生素D缺乏所致宫 内编程改变和胎儿生长受限中的作用；观察体内维生素D缺乏和体外VDR基因沉默对胎盘屏障、物质交换和内分泌功能的损害，阐明VDR信号下调所致胎盘炎症诱发宫内编程改变和胎儿生长受限的机理。依托马鞍山优生优育队列，采用巢式病例对照设计，分析小于胎龄 儿与适于胎龄儿母血25（OH）D水平、胎盘VDR信号、胎盘和脐血炎性因子水平及胎盘功能发育状况的关联，验证炎症介导的胎盘发育受损和功能不全在维生素D缺乏所致胎儿生长受限中的关键作用。主要研究发现：（1）孕期维生素D不足/缺乏增加早产、低出生体重和小于胎龄儿发生风险；（2）孕期维生素D缺乏通过损害胎盘发育间接引起胎儿生长受限，胎盘炎症是维生素D缺乏损害胎盘发育的机制之一；（3）孕期维生素D缺乏导致子代多器官和多系统发育长期损害，主要抑制II型肺泡上皮成熟、下调睾丸间质细胞睾酮合成酶、引起子代焦虑样行为、导致中年子代前列腺增生；（4）孕期补充维生素D3改善炎症所致早产、神经管畸形和生长受限，其主要机制是维生素D抑制胎盘炎症并改善胎盘叶酸转运；（5）全孕期补充高剂量维生素D3通过抑制胎盘滋养细胞增殖和间质样表型诱发胎儿生长受限。本课题为阐明孕期维生素D缺乏诱发不良妊娠结局的机理并制定预防对策提供理论依据。