Abstract：
Air pollution (AP) is detrimental to pregnancies including increasing risk factors of gestational diabetes mellitus. We hypothesized that exposure to AP causes cardiovascular and metabolic disruption thereby altering placental gene expression, which in turn affects the placental phenotype and thereby embryonic/fetal development. To test this hypothesis, we investigated the impact of intra-nasal instilled AP upon gestational day 16-19 maternal mouse cardiovascular and metabolic status, placental nutrient transporters, and placental-fetal size and morphology. To further unravel mechanisms, we also examined placental total DNA 5\'-hydroxymethylation and bulk RNA sequenced gene expression profiles. AP exposed pregnant mice and fetuses were tachycardic with a reduction in maternal left ventricular fractional shortening and increased uterine artery with decreased umbilical artery systolic peak velocities. In addition, they were hyperglycemic, glucose intolerant and insulin resistant, with changes in placental glucose (Glut3) and fatty acid (Fatp1 & Cd36) transporters, and a spatial disruption of cells expressing Glut10 that imports L-dehydroascorbic acid in protecting against oxidative stress. Placentas revealed inflammatory cellular infiltration with associated cellular edema and necrosis, with dilated vascular spaces and hemorrhage. Placental and fetal body weights decreased in mid-gestation with a reduction in brain cortical thickness emerging in late gestation. Placental total DNA 5\'-hydroxymethylation was 2.5-fold higher, with perturbed gene expression profiles involving key metabolic, inflammatory, transcriptional, cellular polarizing and processing genes and pathways. We conclude that gestational exposure to AP incites a maternal inflammatory response resulting in features mimicking maternal gestational diabetes mellitus with altered placental DNA 5\'-hydroxymethylation, gene expression, and associated injury.
摘要：
空气污染（AP）对妊娠有害，包括增加妊娠糖尿病的危险因素。我们假设暴露于AP会导致心血管和代谢破坏，从而改变胎盘基因表达，这反过来影响胎盘表型，从而影响胚胎/胎儿发育。为了检验这个假设，我们调查了鼻内滴注AP对妊娠第16-19天母体小鼠心血管和代谢状态的影响，胎盘营养素转运蛋白，胎盘-胎儿大小和形态。为了进一步解开机制，我们还检查了胎盘总DNA5'-羟甲基化和大量RNA测序的基因表达谱。暴露于AP的怀孕小鼠和胎儿发生心动过速，母体左心室缩短率降低，子宫动脉增加，脐动脉收缩期峰值速度降低。此外,他们是高血糖，葡萄糖不耐受和胰岛素抵抗，随着胎盘葡萄糖（Glut3）和脂肪酸（Fatp1和Cd36）转运蛋白的变化，以及表达Glut10的细胞的空间破坏，Glut10导入L-脱氢抗坏血酸以防止氧化应激。胎盘显示炎性细胞浸润伴有细胞水肿和坏死，血管间隙扩张和出血.妊娠中期胎盘和胎儿体重下降，妊娠晚期出现大脑皮层厚度减少。胎盘总DNA5'-羟甲基化高2.5倍，涉及关键代谢的扰动基因表达谱，炎症，转录，细胞极化和加工基因和途径。我们得出的结论是，妊娠暴露于AP会引起母体炎症反应，从而导致模仿胎盘DNA5'-羟甲基化改变的母体妊娠糖尿病的特征。基因表达，和相关的伤害。
