Metabolites and metabolic pathways associated with glucocorticoid resistance in pregnant African-American women

Abstract

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 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.