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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.

SUBMITTER: Murray A

PROVIDER: S-EPMC8514544 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Prenatal alcohol exposure (PAE) can result in neurobehavioral anomalies, that may be exacerbated by co-occurring metabolic and immune system deficits. To test the hypothesis that the peripheral inflammation in adult PAE offspring is linked to poor glucose metabolism and neurocognitive deficits, pregnant Sprague-Dawley rats were exposed to ethanol vapor or ambient air during the latter half of gestation. We assessed, in adult offspring of both sexes, performance on a battery of neurocognitive behaviors, glucose tolerance, circulating and splenic immune cells by flow-cytometry, and circulating and tissue (liver, mesenteric adipose, and spleen) cytokines by multiplexed assays. PAE reduced both the ratio of spleen to body weight and splenic regulatory T-cell (Treg) numbers. PAE males, but not females exhibited an increase in circulating monocytes. Overall, PAE males exhibited a suppression of cytokine levels, while PAE females exhibited elevated cytokines in mesenteric adipose tissue (IL-6 and IL1α) and liver (IFN-γ, IL-1β, IL-13, IL-18, IL-12p70, and MCP-1), along with increased glucose intolerance. Behavioral analysis also showed sex-dependent PAE effects. PAE-males exhibited increased anxiety-like behavior while PAE-females showed decreased social interaction. PAE offspring of both sexes exhibited impaired recognition of novel objects. Multilinear regression modeling to predict the association between peripheral immune status, glucose intolerance and behavioral outcomes, showed that in PAE offspring, higher levels of adipose leptin and liver TNF- α predicted higher circulating glucose levels. Lower liver IL-1 α and higher plasma fractalkine predicted more time spent in the center of an open-field with sex being an additional predictor. Higher circulating and splenic Tregs predicted better social interaction in the PAE-offspring. Collectively, our data show that peripheral immune status is a persistent, sex-dependent predictor of glucose intolerance and neurobehavioral function in adult PAE offspring.

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

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