孕期1-硝基芘暴露与胎儿宫内生长受限的关联及其毒理学机制

1-硝基芘(1-NP) 是大气细颗粒物的关键组分。本课题采用孕期尿液1-NP代谢物为暴露标志评估1-NP暴露水平，识别孕期1-NP暴露与胎儿生长受限之间关联强度。建立1-NP胎儿生长受限小鼠模型，用化学分子伴侣（PBA）抑制胎盘内质网应激并观察其能否抑制1-NP诱发宫内编程改变和胎儿生长受限，阐明活性氧介导的胎盘内质网应激在1-NP诱发宫内编程改变和胎儿生长受限中的作用；通过观察内质网化学分子伴侣和IRE1α基因沉默对1-NP所致小鼠胎盘发育受损和人胎盘细胞功能不全的拮抗效应，阐明1-NP启动胎盘内质网应激、诱发宫内编程改变和胎儿生长受限的机制。采用巢式病例对照设计，分析小于胎龄儿与适于胎龄儿两组间尿液1-NP代谢物水平、胎盘内质网应激信号和胎盘功能指标之间的差异，验证内质网应激介导的胎盘功能不全在1-NP所致胎儿生长受限中的作用。本课题为阐明大气细颗粒物关键组分的发育毒理机制提供资料。

1-nitropyrene (1-NP) is one of the key constituents in atmospheric fine particles. The present study will measure urinary 1-NP metabolites as biomarkers of gestational 1-NP exposure and analyze the association between maternal 1-NP exposure at different gestational periods and fetal intra-uterine growth restriction. We will establish a mouse model of 1-NP-induced fetal growth restriction. To investigate the role of ROS-mediated endoplasmic reticulum stress (ER stress) on 1-NP-induced alteration of Intrauterine reprogramming and fetal growth restriction, PBA, a chemical chaperone, is used to inhibit 1-NP-induced placental ER stress and observe its protective effect of 1-NP-induced fetal growth restriction. To explore the mechanism by which ER stress is involved in 1-NP-induced intrauterine reprogramming and fetal growth restriction, IRE1 gene in JEG-3, a human trophoblast, is silenced using siRNA. The effects of PBA, a chemical chaperone, and knockdown of IRE1 gene, on 1-NP-induced functional insufficiency in mouse placenta and down-regulation of genes for placental functions will be analyzed. Finally, urinary 1-NP metabolites, placental ER stress signaling and biomarkers of placental functions will be compared between subjects with SGA and AGA infants to verify the role of ER stress on 1-NP-induced intrauterine reprogramming and fetal growth restriction. The present study will provide the data for elucidating atmospheric fine particles induced fetal growth restriction and its toxicological mechanism.