Maternal hypercortisolemia alters placental metabolism: a multiomics view

Abstract

Previous studies have suggested that increases in maternal cortisol or maternal stress in late pregnancy increase the risk of stillbirth at term. In an ovine model with increased maternal cortisol over the last 0.20 of gestation, we have previously found evidence of disruption of fetal serum and cardiac metabolomics, and of expression of genes related to mitochondrial function and metabolism in biceps femoris, diaphragm and cardiac muscle. The present studies were designed to test for effects of chronically increased maternal cortisol on gene expression and metabolomics in placentomes near term. We hypothesized that changes in placenta may underlie or contribute to the alterations in fetal serum metabolomics, and thereby contribute to changes in striated muscle metabolism. Placentomes were collected from pregnancies in early labor (143±1 d gestation) of control ewes (n=7) or ewe treated with cortisol (1 mg/kg/d iv; n=5) starting at day 115 of gestation. Transcriptomics and metabolomics were performed using an ovine gene expression microarray (Agilent 019921) and HR-MAS NMR, respectively. Multi-omic analysis indicates that amino acid metabolism, particularly of branched chain amino acids and glutamate occur in placenta; changes in amino acid metabolism, degradation or biosynthesis in placenta were consistent with changes in valine, isoleucine, leucine and glycine in fetal serum. The analysis also indicates changes in glycerophospholipid metabolism and suggests changes in ER stress and antioxidant status in the placenta. These findings suggest that changes in placental function occurring with excess maternal cortisol in late gestation may contribute to metabolic dysfunction in the fetus at birth.

Integrated Metabolomic and Lipidomic Analysis in the Placenta of Preeclampsia

“…PS is synthesized in the endoplasmic reticulum (ER) by head exchange from PC and PE (Butler et al, 2020). Choline and ethanolamine are major contributors to the production of membrane lipids (Joseph et al, 2020). Previous studies have reported that maternal choline supplementation modulates the expression of amino acid transporters and improves angiogenesis in the placenta of mice (Kwan et al, 2017).…”

Metabolic Consequences of Glucocorticoid Exposure before Birth

“…There is an increase in the urea concentration of fetal sheep after 10 days of maternal cortisol infusion, indicative of increased amino acid deamination and oxidative use of amino acids [ 61 ]. Transcriptome and metabolome analyses of the ovine placenta after 25 days of maternal cortisol infusion also indicate that there are changes in amino acid metabolism that involve glutamate and the degradation and biosynthesis of branched chain amino acids [ 64 ]. Similar changes in the metabolism of branched chain amino acids are also seen in ovine cardiac and skeletal muscle before and at birth after prolonged maternal hypercortisolemia [ 65 , 94 ].…”

“…In contrast with the effect of short term administration, GC exposure over longer periods appears to suppress mitochondrial respiratory capacity in fetal tissues [ 41 , 60 , 64 , 65 ]. Maternal cortisol infusion for last 25 days of ovine pregnancy reduces mitochondrial content and abundance of specific ETS complexes and adenine nucleotide transporters in fetal cardiac and skeletal muscle at term [ 65 ].…”

High‐resolution magic angle spinning NMR for intact biological specimen analysis: Initial discovery, recent developments, and future directions

“…Based on our survey, during 2016-2020, on average, 18.6 publications specified metabolomics as the study target, representing a 38.8% increase from the annual average of 13.4 publications from 2011 to 2015. Similarly, in the past 5 years, on average, more than four reports combined HRMAS NMR with measurements of other methodologies, including mass spectroscopy, [28][29][30][31][32][33][34][35][36][37] microarrays, [38][39][40] immunoassays, 41 genomics, [42][43][44][45][46][47] and the imaging of positron emission tomography (PET) 48,49 and diffusion tensor imaging (DTI). 50 By contrast, from 2011 to 2015, our review found only one such study reported; it combined HRMAS NMR with mass spectroscopy in 2013.…”