Corwin Elizabeth, Dunlop Anne L, Fernandes Jolyn, Li Shuzhao, Pearce Bradley, Jones Dean P
Columbia University, United States.
Emory University School of Medicine and School of Nursing, Emory University, United States.
Compr Psychoneuroendocrinol. 2020 Feb-May;1-2. doi: 10.1016/j.cpnec.2020.100001. Epub 2020 Mar 30.
Glucocorticoid resistance (GR) is associated with exposure to chronic stress and an increased risk of metabolic and inflammatory disorders in both animal and human populations. Studies on ethnic disparities highlight the African-American (AA) population as having a high propensity to both GR and chronic stress exposure. Glucocorticoids and inflammation play a very important role in pregnancy outcome and fetal development. To date, however, the metabolites and metabolic pathways associated with GR during pregnancy have not been identified, obscuring the mechanisms by which adverse health consequences arise, and thus impeding targeted therapeutic intervention. The objective of this study was to perform untargeted high-resolution metabolomics (HRM) profiling on 273 pregnant AA women, to identify metabolites and metabolic pathways associated with GR during the first trimester of pregnancy and to evaluate their cross-sectional association with birth outcomes and psychosocial variables related to chronic stress exposure. For this study, GR was determined by the concentration of dexamethasone required for 50% inhibition (Dex IC50) of the cytokine tumor-necrosis factor alpha (TNF-alpha) release in response to a standard dose of lipopolysaccharide. The results for Metabolome-Wide Association Studies (MWAS) and pathway enrichment analysis for serum metabolic associations with Dex IC50, showed energy (nicotinamide and TCA cycle), amino acid, and glycosphingolipid metabolism as top altered pathways. Bioinformatic analysis showed that GR, as indicated by elevated Dex IC50 in the pregnant women, was associated with increased inflammatory metabolites, oxidative stress related metabolites, increased demand for functional amino acids to support growth and development, and disruption in energy-related metabolites. If confirmed in future studies, targeting these physiologically significant metabolites and metabolic pathways may lead to future assessment and intervention strategies to prevent inflammatory and metabolic complications observed in pregnant populations.
糖皮质激素抵抗（GR）与长期应激暴露以及动物和人类群体中代谢和炎症性疾病风险增加有关。关于种族差异的研究表明，非裔美国人（AA）群体极易出现糖皮质激素抵抗和长期应激暴露。糖皮质激素和炎症在妊娠结局和胎儿发育中起着非常重要的作用。然而，迄今为止，尚未确定孕期与糖皮质激素抵抗相关的代谢物和代谢途径，这使得不良健康后果产生的机制变得模糊不清，从而阻碍了有针对性的治疗干预。本研究的目的是对273名怀孕的非裔美国女性进行非靶向高分辨率代谢组学（HRM）分析，以识别妊娠早期与糖皮质激素抵抗相关的代谢物和代谢途径，并评估它们与出生结局以及与长期应激暴露相关的心理社会变量之间的横断面关联。在本研究中，糖皮质激素抵抗通过细胞因子肿瘤坏死因子α（TNF-α）释放受到标准剂量脂多糖刺激后50%抑制所需的地塞米松浓度（地塞米松IC50）来确定。代谢组全关联研究（MWAS）结果以及血清代谢物与地塞米松IC50的通路富集分析显示，能量（烟酰胺和三羧酸循环）、氨基酸和糖鞘脂代谢是变化最显著的通路。生物信息学分析表明，孕妇中地塞米松IC50升高所表明的糖皮质激素抵抗与炎症代谢物增加、氧化应激相关代谢物增加、支持生长发育所需的功能性氨基酸需求增加以及能量相关代谢物紊乱有关。如果在未来研究中得到证实，针对这些具有生理意义的代谢物和代谢途径可能会带来未来的评估和干预策略，以预防在孕妇群体中观察到的炎症和代谢并发症。
