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-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.

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-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。研究发现，孕期1-硝基芘（1-NP）暴露损害小鼠胎盘和胎鼠发育；孕期1-硝基芘暴露升高胎盘滋养细胞活性氧并激活小鼠胎盘内质网应激信号通路，活性氧介导的胎盘内质网应激至少部分参与1-硝基芘所致胎儿生长受限；孕期1-硝基芘暴露抑制胎盘滋养细胞增殖，活性氧介导的遗传毒性应激在1-硝基芘所致胎盘滋养细胞增殖阻滞和胎儿生长受限中起关键作用；孕期母体1-硝基芘暴露损害子代出生后生长和行为发育并导致子代哮喘易感性增加。进一步研究发现，急性1-硝基芘暴露通过激活不同炎性信号诱导肺上皮细胞炎性反应；长期1-硝基芘暴露诱发雄性小鼠睾丸内质网应激并抑制甾体激素合成。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。