Metabolites and metabolic pathways associated with glucocorticoid resistance in pregnant African-American women
Metabolites and metabolic pathways associated with glucocorticoid resistance in pregnant African-American women
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DOI：
10.1016/j.cpnec.2020.100001
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发表时间：
2020-02-01
影响因子：
--
通讯作者：
Jones, Dean P.
中科院分区：
文献类型：
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作者：
Corwin, Elizabeth;Dunlop, Anne L.;Jones, Dean P.
糖皮质激素抵抗（GR）与暴露于慢性应激以及动物和人类群体中代谢和炎症性疾病的风险增加有关。关于种族差异的研究强调，非洲裔美国人（AA）人口对GR和慢性压力暴露具有很高的倾向。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，尚未确定妊娠期间与GR相关的代谢物和代谢途径，从而模糊了不良健康后果产生的机制，从而阻碍了靶向治疗干预。本研究的目的是对273名AA孕妇进行非靶向高分辨率代谢组学（HRM）分析，以确定妊娠前三个月期间与GR相关的代谢物和代谢途径，并评估其与出生结局和与慢性应激暴露相关的心理社会变量的横截面关联。对于本研究，GR通过响应于标准剂量的脂多糖的细胞因子肿瘤坏死因子α（TNF-α）体外释放的50%抑制（Dex IC 50）所需的地塞米松浓度来确定。全代谢组关联研究（MWAS）和Dex IC 50血清代谢关联的途径富集分析结果显示，能量（烟酰胺和TCA循环）、氨基酸和鞘糖脂代谢是最重要的改变途径。生物信息学分析表明，妊娠女性中Dex IC 50升高表明GR与炎症代谢产物、氧化应激相关代谢产物增加、支持生长和发育的功能性氨基酸需求增加以及能量相关代谢产物破坏相关。如果在未来的研究中得到证实，靶向这些生理上重要的代谢物和代谢途径可能会导致未来的评估和干预策略，以预防在妊娠人群中观察到的炎症和代谢并发症。
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. Gluco-corticoids 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 vitro 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.