Department of Pediatrics & the UCLA Children's Discovery and Innovation Institute, David Geffen School of Medicine at UCLA, 10833 Le Conte Ave, Los Angeles, CA 90095-1752, USA.
Department of Pathology, David Geffen School of Medicine at UCLA, 10833 Le Conte Ave, Los Angeles, CA 90095-1752, USA.
Reprod Toxicol. 2024 Sep;128:108657. doi: 10.1016/j.reprotox.2024.108657. Epub 2024 Jul 16.
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.
空气污染（AP）对妊娠有害，包括增加妊娠糖尿病的风险因素。我们假设，暴露于 AP 会导致心血管和代谢紊乱，从而改变胎盘基因表达，进而影响胎盘表型，从而影响胚胎/胎儿发育。为了验证这一假设，我们研究了在妊娠第 16-19 天经鼻腔内注入 AP 对母鼠心血管和代谢状态、胎盘营养转运体以及胎盘-胎儿大小和形态的影响。为了进一步揭示机制，我们还检查了胎盘总 DNA 5'-羟甲基化和批量 RNA 测序的基因表达谱。AP 暴露的孕鼠和胎儿出现心动过速，左心室缩短分数降低，子宫动脉增加，脐动脉收缩峰速度降低。此外，它们还出现高血糖、葡萄糖耐量和胰岛素抵抗，胎盘葡萄糖（Glut3）和脂肪酸（Fatp1 和 Cd36）转运体发生变化，表达 Glut10 的细胞空间分布紊乱，Glut10 可导入 L-脱氢抗坏血酸以防止氧化应激。胎盘出现炎症细胞浸润，伴有细胞水肿和坏死，血管空间扩张和出血。胎盘和胎儿体重在妊娠中期下降，妊娠晚期大脑皮质厚度减少。胎盘总 DNA 5'-羟甲基化增加了 2.5 倍，涉及关键代谢、炎症、转录、细胞极化和加工基因和途径的基因表达谱发生了紊乱。我们的结论是，妊娠期间暴露于 AP 会引发母体炎症反应，导致类似于母体妊娠糖尿病的特征，伴有胎盘 DNA 5'-羟甲基化、基因表达和相关损伤的改变。
