Leonard Katherine M, Schmiedecke Stacey S, Talley Rebecca L, Damicis Jennifer R, Walton Robert B, Burd Irina, Napolitano Peter G, Ieronimakis Nicholas
Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, Madigan Army Medical Center, Tacoma, WA (Leonard, Schmiedecke, Walton, and Ieronimakis).
Department of Clinical Investigation, Madigan Army Medical Center, Tacoma, WA (Talley, Damicis, and Ieronimakis).
AJOG Glob Rep. 2024 Jun 12;4(3):100361. doi: 10.1016/j.xagr.2024.100361. eCollection 2024 Aug.
Preterm birth from intrauterine infection is a leading cause of neonatal neurologic morbidity. Likewise, maternal obesity is associated with intra-amniotic infection and inflammation. Whether maternal obesity is a risk factor for fetal brain injury that occurs with premature birth remains unknown. This study hypothesized that maternal obesity intensifies fetal neuroinflammation in the setting of premature delivery.
This study aimed to examine the influence of maternal obesity on perinatal neuroinflammatory responses that arise with preterm birth using a murine model.
Dams with obesity were generated via a high-fat diet that was maintained throughout pregnancy. In parallel, dams without obesity (normal) received a control diet. All dams were paired with males on normal diet. Pregnant dams were randomized to receive an intrauterine administration of bacterial endotoxin (lipopolysaccharide) or the vehicle (phosphate-buffered saline) on embryo day 15.5 of what is typically a 19- to 21-day gestation. Fetal brains were harvested 6 hours after intrauterine administrations, and the expressions of key inflammatory cytokines (, and ) and panels of metabolic, immune, and inflammatory genes were analyzed.
With the phosphate-buffered saline, there was no difference in gene expression related to maternal obesity. There were substantial differences in and immune/inflammatory expression profiles in fetal brains from dams with obesity vs normal dams that received lipopolysaccharide. Few differences were observed among the metabolic genes examined under these conditions. The gene expression pattern associated with maternal obesity correlated with pathways related to white matter injury.
The expression of neuroinflammatory markers instigated by bacterial endotoxin via intrauterine lipopolysaccharide was greater in embryo brains obtained from dams with obesity. Expression profiles suggest that in combination with intrauterine inflammation, maternal obesity may increase the risk of fetal white matter injury. Further investigation is warranted to understand the relationship between maternal health and neurologic outcomes associated with prematurity.
宫内感染导致的早产是新生儿神经功能障碍的主要原因。同样，孕妇肥胖与羊膜腔内感染及炎症有关。孕妇肥胖是否是早产时胎儿脑损伤的危险因素仍不清楚。本研究假设孕妇肥胖会在早产情况下加剧胎儿神经炎症。
本研究旨在使用小鼠模型研究孕妇肥胖对早产时围产期神经炎症反应的影响。
通过在整个孕期维持高脂饮食来构建肥胖母鼠。同时，非肥胖（正常）母鼠给予对照饮食。所有母鼠与正常饮食的雄鼠配对。在通常为19至21天妊娠期的胚胎第15.5天，将怀孕母鼠随机分为两组，一组经子宫内给予细菌内毒素（脂多糖），另一组给予载体（磷酸盐缓冲盐水）。子宫内给药6小时后采集胎儿大脑，分析关键炎性细胞因子（、和）以及一系列代谢、免疫和炎性基因的表达。
给予磷酸盐缓冲盐水时，与孕妇肥胖相关的基因表达没有差异。在接受脂多糖的肥胖母鼠与正常母鼠所产胎儿大脑中，和免疫/炎性表达谱存在显著差异。在这些条件下检测的代谢基因之间几乎没有差异。与孕妇肥胖相关的基因表达模式与白质损伤相关通路有关。
通过子宫内脂多糖由细菌内毒素引发的神经炎性标志物在肥胖母鼠所产胚胎大脑中的表达更高。表达谱表明，与子宫内炎症相结合，孕妇肥胖可能会增加胎儿白质损伤的风险。有必要进一步研究以了解孕妇健康与早产相关神经结局之间的关系。
