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Mechanisms of in utero cortisol effects on the newborn heart revealed by transcriptomic modeling

ABSTRACT: 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.

ORGANISM(S): Ovis aries

PROVIDER: GSE110470 | GEO | 2019/01/04

REPOSITORIES: GEO

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Project description:We have previously shown in sheep that 10 days of modest chronic increase in maternal cortisol result in fetal heart enlargement and Purkinje cell apoptosis. In subsequent studies in which we extended the duration of cortisol infusion (1mg/kg/d) to term, we found a dramatic incidence of stillbirth in the pregnancies with chronically increased cortisol and associated maternal hyperglycemia. To investigate the effects on the heart, transcriptomic analyses were performed on the septa using ovine microarrays and Webgestalt and Cytoscape programs for pathway inference. Analyses of the effects of 10 days of maternal cortisol infusion (130d-cortisol vs 130d control), ~25 days (term at ~140d-cortisol vs 140d control), normal maturation (140d-control vs 130d control) were performed. In all analyses gene ontology (GO) terms related to immune function and cytokine actions were significantly over-represented. After 10 days of cortisol, growth factor and muscle cell apoptosis pathways were significantly over-represented, consistent with our previous findings. We found significantly differentially regulated genes in the term fetuses (ie after ~25 days of cortisol) in pathways consistent with altered metabolism in the heart, particularly in mitochondria, associated with responses to hypoxia and to nutrient. Analysis of mitochondrial number by quantitative real-time PCR confirmed a significant decrease. These pathways were different from those modeled following the normal increase in cortisol in late gestation which contributes to normal maturation of the heart, and thus may be indicative of the fetal heart pathophysiologies seen in pregnancies complicated by diabetes, CushingM-bM-^@M-^Ys disease and chronic stress. 2 cohorts of singleton sheep fetuses at 129-131d gestation or 139-144d gestation (approximately term) were used. The first cohort received maternal cortisol infusion of 1mg/kg/day or vehicle for 10 days until approximately day 130 of gestation (n=6/group), the second cohort received the same dose of cortisol for approximately 25 days until near term (n=7, cortisol; n=7ewes, n=8 fetuses due to one set of twins, control)

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.

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Mechanisms of in utero cortisol effects on the newborn heart revealed by transcriptomic modeling

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