Untargeted metabolomics reveals sex-specific differences in lipid metabolism of adult rats exposed to dexamethasone in utero

Abstract

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.

Figure 1

Triglyceride concentrations in the liver and plasma of saline and Dex exposed offspring. Levels of triglycerides were measured in the liver (a) and plasma (b) by the Triglyceride Quantification Assay (Abcam) in a colorimetric assay at 570 nm. For the livers, the triglyceride concentration was normalized to the weight of the tissue used for the analysis. The plasma samples were assay directly. The triglyceride concentrations in mM are represented graphically. Statistical significance between saline and Dex groups and sex was determined by one-way ANOVA with a post-hoc Tukey test. Data are presented as mean ± SEM (n = 8). Statistical significance between groups is shown by: * p < 0.05, ** p < 0.01, *** p < 0.001. The * indicates significance when compared to saline female group and the # indicates significance when compared to the saline male group.