Brown Amy G, Tulina Natalia M, Barila Guillermo O, Hester Michael S, Elovitz Michal A
Maternal Child Health Research Center, Department of Obstetrics and Gynecology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.
PLoS One. 2017 Oct 19;12(10):e0186656. doi: 10.1371/journal.pone.0186656. eCollection 2017.
Exposure to prenatal inflammation is associated with diverse adverse neurobehavioral outcomes in exposed offspring. The mechanism by which inflammation negatively impacts the developing brain is poorly understood. Metabolomic profiling provides an opportunity to identify specific metabolites, and novel pathways, which may reveal mechanisms by which exposure to intrauterine inflammation promotes fetal and neonatal brain injury. Therefore, we investigated whether exposure to intrauterine inflammation altered the metabolome of the amniotic fluid, fetal and neonatal brain. Additionally, we explored whether changes in the metabolomic profile from exposure to prenatal inflammation occurs in a sex-specific manner in the neonatal brain.
CD-1, timed pregnant mice received an intrauterine injection of lipopolysaccharide (50 μg/dam) or saline on embryonic day 15. Six and 48 hours later mice were sacrificed and amniotic fluid, and fetal brains were collected (n = 8/group). Postnatal brains were collected on day of life 1 (n = 6/group/sex). Global biochemical profiles were determined using ultra performance liquid chromatography/tandem mass spectrometry (Metabolon Inc.). Statistical analyses were performed by comparing samples from lipopolysaccharide and saline treated animals at each time point. For the P1 brains, analyses were stratified by sex.
RESULTS/CONCLUSIONS: Exposure to intrauterine inflammation induced unique, temporally regulated changes in the metabolic profiles of amniotic fluid, fetal brain and postnatal brain. Six hours after exposure to intrauterine inflammation, the amniotic fluid and the fetal brain metabolomes were dramatically altered with significant enhancements of amino acid and purine metabolites. The amniotic fluid had enhanced levels of several members of the (hypo) xanthine pathway and this compound was validated as a potential biomarker. By 48 hours, the number of altered biochemicals in both the fetal brain and the amniotic fluid had declined, yet unique profiles existed. Neonatal pups exposed to intrauterine inflammation have significant alterations in their lipid metabolites, in particular, fatty acids. These sex-specific metabolic changes within the newborn brain offer an explanation regarding the sexual dimorphism of certain psychiatric and neurobehavioral disorders associated with exposure to prenatal inflammation.
孕期暴露于炎症环境与子代出现多种不良神经行为结局有关。炎症对发育中大脑产生负面影响的机制尚不清楚。代谢组学分析为识别特定代谢物和新途径提供了机会，这可能揭示宫内炎症暴露促进胎儿和新生儿脑损伤的机制。因此，我们研究了宫内炎症暴露是否会改变羊水、胎儿和新生儿大脑的代谢组。此外，我们还探讨了产前炎症暴露引起的代谢组变化在新生儿大脑中是否存在性别特异性。
在胚胎第15天，对定时受孕的CD-1小鼠进行宫内注射脂多糖（50μg/只）或生理盐水。6小时和48小时后处死小鼠，收集羊水和胎儿大脑（每组n = 8）。出生后第1天收集新生鼠大脑（每组/性别n = 6）。使用超高效液相色谱/串联质谱（Metabolon公司）测定整体生化谱。通过比较脂多糖和生理盐水处理动物在每个时间点的样本进行统计分析。对于出生后第1天的大脑，分析按性别分层。
结果/结论：宫内炎症暴露导致羊水、胎儿大脑和出生后大脑的代谢谱发生独特的、随时间变化的改变。宫内炎症暴露6小时后，羊水和胎儿大脑代谢组发生显著改变，氨基酸和嘌呤代谢物显著增加。羊水中（次）黄嘌呤途径的几种成分水平升高，该化合物被确认为潜在生物标志物。到48小时时，胎儿大脑和羊水中改变的生化物质数量减少，但仍存在独特的谱。暴露于宫内炎症的新生鼠脂质代谢物，特别是脂肪酸，有显著改变。新生大脑内这些性别特异性的代谢变化为与产前炎症暴露相关的某些精神和神经行为障碍的性别差异提供了解释。
