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: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.

Project description:Prenatal exposure to synthetic corticosteroids can significantly alter postnatal development through changes in neurotransmitters, peptides and their receptors, and thus having long-lasting behavioral effects. Some of these changes have been observed in animal experiments, others also in humans prenatally exposed to synthetic corticosteroids. Here, we focused on transcriptomic changes within the ARC of rats prenatally exposed to either betamethasone or saline. The expression of transcriptome has been assessed by novel computational tools to determine complex changes that may have life-long effects on phenotype, i.e., behavior. Total of 18,094 unigenes were quantified in the hypothalamic ARC of P14 male and female rats prenatally exposed to betametasone used in this experiment. Out of these genes, Kyoto Encyclopedia for Genes and Genomes (http://www.genome.jp) selected 112 for the dopaminergic synapse, 75 for the GABAergic and 97 for the glutamatergic synapse. We further analyzed composition, topology and modulatory networks of the genomic fabric of the dopaminergic, GABAergic, and glutamatergic synapse (the transcriptome of the most interconnected and stably expressed gene network responsible for specific transmission). Finally we investigated the M-bM-^@M-^\transcriptomic landscapeM-bM-^@M-^] of the GSF in the ARC of P14 males (M) and females (F) prenatally (G15) exposed to betamethasone (B) or saline (S). We combined in one measure (PWR = Pair-Wise Relevance) expression levels, controls and coordination of all pairs that can be formed by synapse genes with the other synapse genes, higher PWRs indicating larger influence of that gene pair to the fabric modulation. We found that prenatal exposure to betamethasone caused sex-dependent changes in the dopaminergic/GABA/glutamatergic synapse genes:. In males, 10 dopaminergic (9%), 4 GABAergic (5%) and 5 glutamatergic synapse genes (5%) were down-regulated. While in females, 9 dopaminergic (8%), 3 GABAergic (4%) and 6 glutamatergic (6%) synapse genes were downregulated. The data indicate that in both sexes the dopaminergic synapse was the most affected. In contrast, in control animals, no significant differences between male and female were present in these synapse genes. Since the most noticeable transcritpomic changes were found in the transcriptome of DA glutamatergic synapse, we investigated the expression of tyrosine-hydroxylase (TH) NMDA receptor subunits in the ARC. The western blot analyses and immunohistochemistry confirmed the sex-specific differences between prenatally betamethasone-exposed and saline-exposed P15 rats. Accordingly to the changes in gene expression, prenatal exposure to synthetic corticosteroids was associated with postnatal changes in behavior and susceptibility to certain types of seizures. While we did not find any significant impairements in normal behavioral patterns (open field activity), there was a sex-specific change in the novel object recognition test. We found that behavioral lateralization in females is lost after prenatal betamethasone exposure and both male and female prenatally betamethasone exposed rats were avoiding novelty. This trait is similar to children with autism and suggests that certain elements of autistic behaviors can be present after prenatal exposure to synthetic corticosteroids. Additionally, there were changes in the search patterns in the Morris water maze as well as in the Barnes maze. In conclusion, our work is consistent with findings of profound reprogramming changes in the brain after prenatal corticosteroid exposure associated with alterations cognitive functions and seizure susceptibility. Two-sexes (M, F) x two-condition (B = betamethasone prenataly exposed vs S = saline prenataly exposed) experiment. Biological replicates: 4 MS, 4 FS, 4 MB, 4 FB.

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

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