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

Alyssa Murray,T C Tai,Sujeenthar Tharmalingam,Phong Nguyen

doi:10.1038/s41598-021-99598-x

Alyssa Murray, T C Tai + Show 2 more

Open Access

https://doi.org/10.1038/s41598-021-99598-x

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Journal: Scientific Reports	Publication Date: Oct 13, 2021
Citations: 5	License type: open-access

Affiliation: Laurentian University, NOSM University

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.

Highlights

Prenatal stress through glucocorticoid (GC) exposure leads to an increased risk of developing diseases such as cardiovascular disease, metabolic syndrome and hypertension in adulthood
Circadian disruption is strongly associated with metabolic imbalance and an increased risk of metabolic syndrome; which currently describes a group of disorders that often co-occur such as central obesity, insulin resistance dyslipidemia, hyperglycemia and h ypertension[19,20]
Given the strong link between circadian rhythm and metabolism[19], the impact the prenatal environment has on the development of cardio-metabolic d isorders[2,32] and the monumental role of the liver in metabolism, we wanted to examine if prenatal Dex exposure results in changes to postnatal adult liver metabolism

Summary

Introduction

Prenatal stress through glucocorticoid (GC) exposure leads to an increased risk of developing diseases such as cardiovascular disease, metabolic syndrome and hypertension in adulthood. 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. Circadian disruption is strongly associated with metabolic imbalance and an increased risk of metabolic syndrome; which currently describes a group of disorders that often co-occur such as central obesity, insulin resistance dyslipidemia, hyperglycemia and h ypertension[19,20] Factors such as nutrient-lacking high-energy foods along with decreased energy expenditure and a sedentary life-style contribute to metabolic disorders[21]. The body is remarkable in its ability to maintain its energy equilibrium but when energy intake exceeds energy expenditure, metabolic fuel is stored as liver glycogen, muscle protein and adipose t issue[19]

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