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

ABSTRACT: In utero treatment with glucocorticoids have been suggested to reprogram postnatal cardiovascular function and stress responsiveness. However, little is known about the effects of prenatal exposure to the natural corticosteroid, cortisol, on postnatal cardiovascular system or metabolism. We have demonstrated an increased incidence of stillbirth in sheep pregnancies in which there is mild maternal hypercortisolemia caused by infusion of 1 mg/kg/d cortisol. In order to model corticosteroid effects in the neonate, we created a second model in which cortisol was infused for 12 h per day for a daily infusion of 0.5 mg/kg/d. In this model we had previously found that neonatal plasma glucose was increased and plasma insulin was decreased compared to those in the control group, and that neonatal ponderal index and kidney weight were reduced and left ventricular 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 hypercortisolemia in these 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 transcriptomic model indicates suppression of genes in pathways for fatty acid and ketone production and upregulation of genes in pathways for angiogenesis in the epicardial adipose fat (EAT). The transcriptomic model indicates that RNA related pathways are overrepresented by downregulated genes, but ubiquitin-mediated proteolysis and protein targeting to the mitochondria are overrepresented by upregulated genes in the intraventricular septum (IVS) and left ventricle (LV). In IVS the AMPK pathway and adipocytokine signaling pathways were also modeled based on overrepresentation by downregulated genes. Peroxisomal activity is modeled as increased in EAT, but decreased in LV and IVS. Our results suggest that pathways for lipids as 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 necropsy and altered glucose metabolism observed in vivo, and predicts that in utero exposure to excess maternal cortisol will cause postnatal cardiac hypertrophy and altered responses to oxidative stress.

SUBMITTER: Antolic A

PROVIDER: S-EPMC6616147 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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

Antolic Andrew A Richards Elaine M EM Wood Charles E CE Keller-Wood Maureen M

Frontiers in physiology 20190703

<i>In utero</i> treatment with glucocorticoids have been suggested to reprogram postnatal cardiovascular function and stress responsiveness. However, little is known about the effects of prenatal exposure to the natural corticosteroid, cortisol, on postnatal cardiovascular system or metabolism. We have demonstrated an increased incidence of stillbirth in sheep pregnancies in which there is mild maternal hypercortisolemia caused by infusion of 1 mg/kg/d cortisol. In order to model corticosteroid ...[more]

PMID: 31333485

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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.

Project description:ObjectiveThe aim of the study was to investigate prospective, longitudinal associations between maternal prenatal cortisol response to an interpersonal stressor and child health for the subsequent 3 years.MethodsOne hundred twenty-three women expecting their first child provided salivary cortisol samples between 12 and 32 weeks of gestation (M (SD) = 22.4 (4.9) weeks) before and after a videotaped couple conflict discussion with their partner. Mothers reported on overall child health and several indicators of child illness (sick doctor visits, fevers, ear, and respiratory infections) when children were 6 months (n = 114), 1 (n = 116), and 3 (n = 105) years old. Associations between maternal prenatal cortisol reactivity and recovery and later child health at each of the three time points were analyzed using longitudinal regression models.ResultsGreater cortisol reactivity in response to the couple conflict discussion was associated with maternal self-report of better overall child health (p = .016, 95% CI = 0.06-1.30, Cohen's f = 0.045) across the study period. Greater cortisol reactivity was also associated with lower incidence rate ratios for maternal reports of sick doctor visits (incidence rate ratio 95% CI = 0.25-0.83, p = .006), fevers (95% CI = 0.25-0.73, p = .002), ear infections (95% CI = 0.25-0.58, p < .001), and respiratory infections (95% CI = 0.08-1.11, p = .073). Cortisol recovery was unrelated to study outcomes (all p's > 0.05). Maternal prenatal depressive symptoms moderated the association between cortisol reactivity and overall child health (p = .034, 95% CI = 0.07-1.87 for interaction term) but no other health outcomes (p's > 0.05). Among women with lower depressive symptoms, cortisol reactivity was not associated with overall child health; among women with higher levels of depressive symptoms, greater cortisol reactivity was associated with better overall child health.ConclusionsThis study provides longitudinal evidence that greater maternal cortisol reactivity to a salient interpersonal stressor during pregnancy is associated with fewer child health problems and better maternal report of overall child health during infancy and into early childhood.Trial registrationClinicaltrials.gov ID NCT01901536.

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

Publications

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

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