Mechanisms of in utero cortisol effects on the newborn heart revealed by transcriptomic modeling
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PROVIDER: PRJNA433835 | ENA |
REPOSITORIES: ENA
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Project description:We have identified effects of elevated maternal cortisol on fetal cardiac maturation and function in an ovine model. Whereas short term exposure, produced by maternal infusion (1 mg/kg/d) from 115-130d gestation increased fetal heart wall thickness and weight, myocyte proliferation and Purkinje fiber apoptosis, when cortisol exposure continued until term (~145 days of gestation), there was a profound increase in perinatal stillbirth. Further study indicated increases in P-R and R-R interval of the ECG and increased incidence of arrhythmias at birth, suggesting that these changes in the fetal heart contribute to the stillbirth. We have used systems biology to statistically model the transcriptomic changes in hearts at 130 days and near term. In the current study, we used this approach to test for effects on pathways related to metabolism and cardiac structure in the left ventricle and septum from newborn lambs. Cortisol altered genes in pathways involved in cardiac architecture in the left ventricle, including SMAD and BMP; cortisol also increased collagen deposition. Genes in pathways involved in metabolism and actin filament assembly were affected within the septum. Comparison of the effects of cortisol to the effects of normal maturation from day 140 to birth revealed that only 1% of the genes changed by cortisol in the LV and 18% in the septum were consistent with the normal maturational changes in gene expression. These results indicate that chronic in utero exposure to elevated cortisol concentrations alters the normal maturation of the fetal myocardium, adversely impacting perinatal cardiac function.
2019-01-04 | GSE110470 | GEO
Project description:We have identified effects of elevated maternal cortisol (induced by maternal infusion 1 mg·kg-1·day-1) on fetal cardiac maturation and function using an ovine model. Whereas short-term exposure (115-130-day gestation) increased myocyte proliferation and Purkinje fiber apoptosis, infusions until birth caused bradycardia with increased incidence of arrhythmias at birth and increased perinatal death, despite normal fetal cortisol concentrations from 130 days to birth. Statistical modeling of the transcriptomic changes in hearts at 130 and 140 days suggested that maternal cortisol excess disrupts cardiac metabolism. In the current study, we modeled pathways in the left ventricle (LV) and interventricular septum (IVS) of newborn lambs after maternal cortisol infusion from 115 days to birth. In both LV and IVS the transcriptomic model indicated over-representation of cell cycle genes and suggested disruption of cell cycle progression. Pathways in the LV involved in cardiac architecture, including SMAD and bone morphogenetic protein ( BMP) were altered, and collagen deposition was increased. Pathways in IVS related to metabolism, calcium signaling, and the actin cytoskeleton were altered. Comparison of the effects of maternal cortisol excess to the effects of normal maturation from day 140 to birth revealed that only 20% of the genes changed in the LV were consistent with normal maturation, indicating that chronic elevation of maternal cortisol alters normal maturation of the fetal myocardium. These effects of maternal cortisol on the cardiac transcriptome, which may be secondary to metabolic effects, are consistent with cardiac remodeling and likely contribute to the adverse impact of maternal stress on perinatal cardiac function.
| S-EPMC6483213 | biostudies-literature
Project description:Cortisol administration during late gestation in ewes, modeling maternal stress, resulted in transcriptomic changes suggesting altered maturation and metabolic changes to the offspring heart. Pregnant ewes were treated with 0.5 mg/kg/day cortisol from 115 days gestation to term lambs were studied over the next 2 weeks. Left ventricular free wall (LV) and intraventricular septum (IVS) were collected at 2 weeks of age (lambs of control, untreated ewes: n=8, lambs of ewes treated with 0.5 mg/kg/day: n=8). In this model we found that neonatal plasma glucose was increased and plasma insulin was decreased compared to those in the control group. LV free wall thickness was increased in the 2 week old lamb. In this study, we have used transcriptomic modeling to better understand the programming effect of this maternal cortisolemia in the 2 week old hearts. This is a time when both terminal differentiation and a shift in the metabolism of the heart from carbohydrates to lipid oxidation are thought to be complete. The transcriptomics indicates downregulation of RNA related pathways, but upregulation of ubiquitin-mediated proteolysis and protein targeting to the mitochondria in in the intraventricular septum (IVS) and left ventricle (LV) in lambs of cortisol-infused ewes compared to untreated control ewes. In IVS pathways the AMPK pathway and adipocytokine signaling pathways were also modeled as downregulated in lambs of cortisl-treated ewes Genes for peroxisomal activity are modeled as decreased in LV and IVS; our previous metabolomic study of the newborn hearts from the 1 mg/kg/d study indicated changes in the plasmogens and phospholipids that are peroxisomal products. Our results suggest that pathways for lipid metabolismas well as cell proliferation and cardiac remodeling have altered activity postnatally after the in utero cortisol exposure. Together, this model is consistent with the observed increase in cardiac wall thickness at necropys and altered glucose metabolism observed in vivo, and predicts that in utero exposure to excess maternal cortisol causes postnatal cardiac hypertrophy and altered responses to oxidative stress.
2019-07-10 | GSE131537 | GEO
Project description:Cardiac tissue from newborn hearts from animals exposed to excess maternal cortisol in late gestation and untreated was compared via MS lipidomic analysis
2018-11-30 | ST001106 | MetabolomicsWorkbench
Project description:Cardiac tissue from newborn hearts from animals exposed to excess maternal cortisol in late gestation and untreated was compared via NMR metabolomic analysis
2018-12-04 | ST001107 | MetabolomicsWorkbench
Project description:Cortisol administration during late gestation in ewes, modeling maternal stress, resulted in transcriptomic changes suggesting altered maturation and metabolic changes to the offspring heart. This study investigates the effects of cortisol on epicardial adipose tissue (EAT), a visceral fat pad associated with adverse cardiovascular conditions in adults. Pregnant ewes were treated with either 1 or 0.5 mg/kg/day cortisol from 115 days gestation to term and EAT collected from term fetuses (control: n=8, maternal cortisol 1 mg/kg/day: n=6) or two-week-old lambs (control: n=7, maternal cortisol 0.5mg/kg/day: n=9). Transcriptomic modeling was used to identify pathways altered by maternal cortisol over-exposure. Transcriptomic modeling confirmed the brown fat phenotype of EAT at term and a transition towards white fat at two weeks of age in EAT of control fetuses/lambs, and highlighted a role of immune responses, including complement-coagulation, and serotonin in this transition. Maternal cortisol (1mg/kg/day) increased the lipid peroxidation product 4-hydroxynonenal in EAT of term fetuses, but did not affect the number of activated macrophages or size of the lipid droplets in the depot; transcriptomics suggested an earlier metabolic maturation of EAT via, in part, increased immune responses. Conversely the transcriptomics in EAT of two-week-old lambs of ewes treated with a lower dose of cortisol (0.5mg/kg/day) suggested decreased metabolism of several substrates through both mitochondrial and cytosolic actions, and delayed maturation of EAT associated with a longer period of adipogenesis and angiogenesis.
2019-07-10 | GSE119254 | GEO
Project description:Background: Zidovudine remains the cornerstone drug for prophylaxis to prevent mother-to-child HIV-1 transmission. A mild but long-lasting hematological multilineage defect is observed in children exposed in utero. Objectives: To evaluate the effects of zidovudine-based ARV combinations on newborn cord blood cells. Methods: Cord blood-derived mononuclear cells from 22 HIV-1-uninfected newborn exposed in utero to a zidovudine-based ARV combination and from 20 healthy unexposed newborn were investigated by immunophenotyping, gene expression analysis, cytogenetic studies and functional capacity testing. To evaluate the effects of zidovudine-based ARV combinations on newborn cord blood cells.
2012-05-02 | E-GEOD-37748 | biostudies-arrayexpress
Project description:Background: Zidovudine remains the cornerstone drug for prophylaxis to prevent mother-to-child HIV-1 transmission. A mild but long-lasting hematological multilineage defect is observed in children exposed in utero. Objectives: To evaluate the effects of zidovudine-based ARV combinations on newborn cord blood cells. Methods: Cord blood-derived mononuclear cells from 22 HIV-1-uninfected newborn exposed in utero to a zidovudine-based ARV combination and from 20 healthy unexposed newborn were investigated by immunophenotyping, gene expression analysis, cytogenetic studies and functional capacity testing.
2012-05-03 | GSE37748 | GEO
Project description:Transcriptional profiling of log and stationary phases of S. Typhimurium, comparing untreated controls with cortisol-treated samples. Each array used labelled cDNA against a common genomic DNA reference. Triplicate arrays were carried out for each of the 4 conditions: untreated log phase, untreated stationary phase, cortisol treated log phase and cortisol treated stationary phase.
2011-07-25 | E-GEOD-30923 | biostudies-arrayexpress
Project description:Effects of in utero exposure to caloric restriction on the heart proteome of the foetus
2021-08-01 | PXD011407 | Pride