胎盘内质网应激在镉诱发胎儿生长受限中的作用及其分子机理

Our preliminary result showed that pregnant women delivered with low-birth-weight newborns had significantly higher serum cadmium level when compared with the controls. To ascertain the correlation between maternal cadmium exposure during pregnancy and fetal growth restriction, the project will analyze the relevance between maternal serum cadmium level and neonatal birth weight from 3 658 mother-infant pairs with single fetus in Hefei Birth Cohort, which based on a exsisting research platform for China Anhui Birth Cohort (C-ABC). To investigate the regulatory effects of cadmium on three different ER stress-dependent signaling pathways, we will establish the mouse model of growth restriction in fetuses whose mothers were exposed to cadmium during the second and third trimester. To explore the role of placental ER stress in cadmium-induced fetal growth restriction (FGR), the present study will observe whether inhibition of ER stress via GRP78 overexpression and a chemical ER chaperone, phenylbutyric acid (PBA), can protect against cadmium-induced FGR. To explore the molecular mechanisms of placental trophoblastic ER stress mediated cadmium-induced FGR, the present study will observe whether inhibition of ER stress via GRP78 overexpression and PBA can prevent from cadmium-induced placental structural impairments and trophoblast dysfunction. To demonstrate the role of placental ER stress in cadmium-induced fetal growth restriction in human, the present study will compare placental ER stress between SGA group and the control group using a nested case-control study. This work will provide a theoretic basis for clarifying the molecular mechanisms in cadmium-impaired fetal development.

课题组前期研究发现，低出生体重儿母亲孕期血清镉水平明显高于对照组。本课题拟在前期成功建立中国安徽出生队列（C-ABC）基础上，检测合肥市3658对单胎母婴队列母亲孕期血镉水平，分析孕期镉暴露与胎儿生长受限的关联。用孕中晚期镉暴露方法构建胎儿生长受限小鼠模型，研究镉对胎盘内质网应激不同信号的调控作用。用GRP78过表达和内质网化学分子伴侣（PBA）抑制镉引起的胎盘内质网应激，观察GRP78过表达和PBA能否保护镉引起的胎儿生长受限，以阐明胎盘内质网应激在镉诱发胎儿生长受限中的作用；观察GRP78过表达和PBA能否对抗镉引起的小鼠胎盘结构受损和滋养细胞功能障碍，以阐明胎盘滋养细胞内质网应激介导镉诱发胎儿生长受限的分子机理。采用巢式病例-对照方法，对比小于胎龄儿和正常对照儿胎盘内质网应激反应，在人体验证胎盘内质网应激在镉诱发胎儿生长受限中的作用。本课题为阐明镉损害胎儿发育的分子机理提供理论依据。

孕期母体镉暴露与胎儿生长受限的关联尚存在争议。本项目基于中国安徽出生队列研究平台，用石墨炉原子吸收分光光度法检测孕妇血清镉水平，分析结果发现，孕期母体高镉暴露明显升高胎儿生长受限的发生风险。整体动物实验结果显示，母鼠孕中期镉暴露升高胎盘镉含量达60倍，而胚胎仅检测到极少量镉；进一步研究还发现，镉明显下调胎盘锌转运泵表达，降低胚胎锌和叶酸水平。上述结果提示胎盘功能障碍是镉诱发胎儿生长受限的重要原因。随后的动物和细胞实验研究发现，镉处理明显诱导小鼠胎盘和人胎盘滋养细胞内质网应激反应，抗氧化剂N-乙酰半胱氨酸预处理明显缓解小鼠胎盘内质网应激，减轻胎盘发育损伤和胎鼠生长受限。这些结果为最终阐明孕期镉暴露诱发胎儿生长受限的确切分子机理提供科学依据，也为今后探讨其它环境化学物对胎儿发育的损害效应及其机理并制定合理的防治对策提供参考。项目负责人以第一作者或通讯作者先后发表SCI论文10篇和中文论文1篇，获得安徽青年科技奖、安徽省科学技术奖（自然科学类）一等奖1项，成功申报青年皖江学者人才项目、省转化医学项目，以第二完成人成功申报国家自然科学基金重点项目1项。兼任中国毒理学会青年委员会常务委员、生化与分子毒理学专委会委员，担任环境与职业医学编委，Environment International、Toxicological Sciences、Journal of Endocrinology等多个杂志的审稿专家。