Northern Ontario School of Medicine, Laurentian University, 935 Ramsey Lake Rd, Sudbury, ON, P3E 2C6, Canada.
Department of Biology, Laurentian University, Sudbury, ON, P3E 2C6, Canada.
Sci Rep. 2021 Oct 13;11(1):20342. doi: 10.1038/s41598-021-99598-x.
Prenatal stress through glucocorticoid (GC) exposure leads to an increased risk of developing diseases such as cardiovascular disease, metabolic syndrome and hypertension in adulthood. We have previously shown that administration of the synthetic glucocorticoid, dexamethasone (Dex), to pregnant Wistar-Kyoto dams produces offspring with elevated blood pressures and disrupted circadian rhythm signaling. Given the link between stress, circadian rhythms and metabolism, we performed an untargeted metabolomic screen on the livers of offspring to assess potential changes induced by prenatal Dex exposure. This metabolomic analysis highlighted 18 significantly dysregulated metabolites in females and 12 in males. Pathway analysis using MetaboAnalyst 4.0 highlighted key pathway-level metabolic differences: glycerophospholipid metabolism, purine metabolism and glutathione metabolism. Gene expression analysis revealed significant upregulation of several lipid metabolism genes in females while males showed no dysregulation. Triglyceride concentrations were also found to be significantly elevated in female offspring exposed to Dex in utero, which may contribute to lipid metabolism activation. This study is the first to conduct an untargeted metabolic profile of liver from GC exposed offspring. Corroborating metabolic, gene expression and lipid profiling results demonstrates significant sex-specific lipid metabolic differences underlying the programming of hepatic metabolism.
产前应激通过糖皮质激素（GC）暴露会增加成年后患心血管疾病、代谢综合征和高血压等疾病的风险。我们之前的研究表明，给怀孕的 Wistar-Kyoto 母鼠注射合成糖皮质激素地塞米松（Dex）会导致后代血压升高和昼夜节律信号紊乱。鉴于应激、昼夜节律和代谢之间的联系，我们对后代的肝脏进行了非靶向代谢组学筛选，以评估产前 Dex 暴露引起的潜在变化。这项代谢组学分析突出了 18 种在雌性后代中显著失调的代谢物和 12 种在雄性后代中失调的代谢物。使用 MetaboAnalyst 4.0 进行的途径分析突出了关键的代谢途径水平差异：甘油磷脂代谢、嘌呤代谢和谷胱甘肽代谢。基因表达分析显示，雌性后代中几个脂质代谢基因显著上调，而雄性后代则没有失调。还发现暴露于 Dex 的雌性后代的甘油三酯浓度显著升高，这可能导致脂质代谢激活。这项研究是首次对 GC 暴露后代的肝脏进行非靶向代谢谱分析。代谢、基因表达和脂质分析结果的相互印证表明，GC 暴露后代肝脏代谢的编程存在显著的性别特异性脂质代谢差异。
