Chronic maternal cortisol excess during late gestation leads to metabolic alterations in the newborn heart

Abstract

Our laboratory has previously shown in an ovine model of pregnancy that abnormal elevations in maternal cortisol during late gestation lead to increased fetal cardiac arrhythmias and mortality during peripartum. Furthermore, transcriptomic analysis of the fetal heart suggested alterations in TCA cycle intermediates and lipid metabolites in animals exposed to excess cortisol in utero. Therefore, we utilized a sheep model of pregnancy to determine how chronic increases in maternal cortisol alter maternal and fetal serum before birth and neonatal cardiac metabolites and lipids at term. Ewes were either infused with 1 mg·kg−1·day−1 of cortisol starting at gestational day 115 ( n = 9) or untreated ( n = 6). Serum was collected from the mother and fetus (gestational day 125), and hearts were collected following birth. Proton nuclear magnetic resonance (1H-NMR) spectroscopy was conducted to measure metabolic profiles of newborn heart specimens as well as fetal and maternal serum specimens. Mass spectrometry was conducted to measure lipid profiles of newborn heart specimens. We observed alterations in amino acid and TCA cycle metabolism as well as lipid and glycerophospholipid metabolism in newborn hearts after excess maternal cortisol in late gestation. In addition, we observed alterations in amino acid and TCA cycle metabolites in fetal but not in maternal serum during late gestation. These results suggest that fetal exposure to excess maternal cortisol alters placental and fetal metabolism before birth and limits normal cardiac metabolic maturation, which may contribute to increased risk of peripartum cardiac arrhythmias observed in these animals or later life cardiomyopathies.

A Transcriptomic Model of Postnatal Cardiac Effects of Prenatal Maternal Cortisol Excess in Sheep

“…There is some suggestion that triglyceride uptake and production is altered; increased expression of DGAT2, encoding an enzyme responsible for de novo synthesis of triglycerides, as well as LSR, encoding the protein responsible for uptake of triglycerides, was identified in the IVS. In our previous study of the newborn cardiac metabolome after maternal cortisol exposure, we found higher levels of di and triglycerides (Walejko et al, 2019). DGAT2 expression is linked to insulin resistance in muscle fibers (Levin et al, 2007).…”

“…The peroxisomal pathway genes upregulated in the LV were associated with fatty acid production [PEX13, important in peroxisomal biogenesis (Maxwell et al, 2003); SLC27A, acyl CoA synthetase [Reviewed in Soupene and Kuypers (2008)]; and ACACB, catalyzing production of malonyl CoA, a negative regulator of acyl CoA uptake (Brownsey et al, 2006)]. In a study in our laboratory in newborn lambs born to ewes treated continuously with 1 mg/kg/d cortisol, cardiac levels of plasmenyl-phosphatidylcholines (plasmenyl-PC), plasmanyl-phosphatidylethanolamines (plasmanyl-PE), and cardiolipins (CL) were reduced whereas triglycerides and diglycerides were elevated (Walejko et al, 2019). Oxidized plasmalogen products are elevated in a porcine model of myocardial infarction, and are thought to play a role in protection against oxidative stress in the heart and in the brain (Schmid and Takahashi, 1968; Dudda et al, 1996; Brosche and Platt, 1998).…”

“…In our sheep model, a chronic doubling of maternal cortisol over the last month of fetal life was associated with a dramatic increase in stillbirth in the immediate perinatal period (Keller-Wood et al, 2014), and with significantly lower heart rate in the last hour before birth (Antolic et al, 2017). The newborns of cortisol-treated ewes also have changes in the cardiac transcriptome and in the cardiac and serum metabolomes (Antolic et al, 2019; Walejko et al, 2019); these data have suggested that metabolism of lipids and the TCA cycle are altered in the fetuses of ewes with higher than normal cortisol concentrations. Transcriptomic modeling of pathways in the heart altered after maternal cortisol treatment also indicated increased expression of genes associated with the TGFβ pathway, consistent with the observed increase in collagen deposition and wall thickness of the left ventricular free wall in the newborns after maternal cortisol treatment (Antolic et al, 2019).…”

Myocardium Metabolism in Physiological and Pathophysiological States: Implications of Epicardial Adipose Tissue and Potential Therapeutic Targets

“…However, 11β-HSD2 is expressed in a number of tissues [75]. Then, a chronic stressful situation in our life may produce true diseases [76] and, during pregnancy, can produce metabolic alteration in newborn heart [77]. Cortisol binds to glucocorticoids receptors, which are expressed in adipose tissue [78].…”

Proton Nuclear Magnetic Resonance Metabolomics Corroborates Serine Hydroxymethyltransferase as the Primary Target of 2-Aminoacrylate in a ridA Mutant of Salmonella enterica

“…specific cellular process in this complex network requires both global and local knowledge, acquired by the integration of multidisciplinary approaches (1,2). Metabolomics approaches have been successful in accelerating the elucidation of complex metabolic and physiological states of an organism and help complement biochemical and genetic approaches that can require significant resources and time (1,(3)(4)(5)(6)(7). Metabolomics has the benefit of providing a snapshot of all metabolic changes in a system without requiring that these differences produce an observable (growth) phenotype.…”