No 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.

This study examined the relationship between glycans, metabolites, and development in C. elegans . Samples of N2 animals were synchronized and grown to five different time points ranging from L1 to a mixed population of adults, gravid adults, and offspring. Each time point was replicated seven times. The samples were each assayed by a large particle flow cytometer (Biosorter) for size distribution data, LC-MS/MS for targeted N - and O -linked glycans, and NMR for metabolites. The same samples were utilized for all measurements, which allowed for statistical correlations between the data. A new protocol was developed to correlate Biosorter developmental data with LC-MS/MS data to obtain stage-specific information of glycans. From the five time points, four distinct sizes of worms were observed from the Biosorter distributions, ranging from the smallest corresponding to L1 to adult animals. A network model was constructed using the four binned sizes of worms as starting nodes and adding glycans and metabolites that had correlations with r ≥ 0.5 to those nodes. The emerging structure of the network showed distinct patterns of N - and O -linked glycans that were consistent with previous studies. Furthermore, some metabolites that were correlated to these glycans and worm sizes showed interesting interactions. Of note, UDP-GlcNAc had strong positive correlations with many O -glycans that were expressed in the largest animals. Similarly, phosphorylcholine correlated with many N-glycans that were expressed in L1 animals.

Previous studies in our laboratory have suggested that the increase in stillbirth in pregnancies complicated by chronic maternal stress or hypercortisolemia is associated with cardiac dysfunction in late stages of labor and delivery. Transcriptomics analysis of the overly represented differentially expressed genes in the fetal heart of hypercortisolemic ewes indicated involvement of mitochondrial function. Sodium dichloroacetate (DCA) has been used to improve mitochondrial function in several disease states. We hypothesized that administration of DCA to laboring ewes would improve both cardiac mitochondrial activity and cardiac function in their fetuses. Four groups of ewes and their fetuses were studied: control, cortisol-infused (1 g/kg/d from 115 to term; CORT), DCA-treated (over 24h) or DCA+CORT-treated; oxytocin was delivered starting 48h before the DCA treatment. DCA significantly decreased cardiac lactate, alanine and glucose/glucose-6-phosphate and increased acylcarnitine/isobutyryl-carnitine. DCA increased mitochondrial activity, increasing oxidative phosphorylation (PCI, PCI+II)) per tissue weight or per unit of citrate synthase. DCA also decreased the duration of the QRS, attenuating the prolongation of the QRS observed in CORT fetuses. The effect to reduce QRS duration with DCA treatment correlated with increased glycerophosphocholine and serine and decreased phophocholine after DCA treatment. There were negative correlations of acylcarnitine/isobutyryl-carnitine to both HR and MAP. These results suggest that improvements in mitochondrial respiration with DCA produced changes in the cardiac lipid metabolism that favor improved conduction in the heart. DCA may therefore be an effective treatment of fetal cardiac metabolic disturbances in labor that can contribute to impairments of fetal cardiac conduction.