Metabolomic landscape of fetal organs development during late gestation in mice
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE299066 | GEO | 2025/08/23
REPOSITORIES: GEO
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Project description:Metabolomic landscape of fetal organs development during late gestation in mice
| PRJNA1272506 | ENA
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, Cushing’s disease and chronic stress.
2014-08-07 | GSE54237 | GEO
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)
2014-08-07 | E-GEOD-54237 | biostudies-arrayexpress
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. In previous studies of the intraventricular septum from these fetuses 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. We extended this investigation to the left ventricular free wall of these fetuses.le. Fewer genes were differentially regulated in left ventricle in the near term fetuses. In the LV of this cohort of fetuses, the nonredundant KEGG pathways represented by the DEG were insulin resistance and adipocytokine signaling pathway. GSEA analysis of the DEG in LV identified metabolic pathways as the nonredundant pathway altered. Comparison of the change in gene expression in biceps to that in cardiac intraventricular septum and left ventricle showed few common genes with little overlap in specific metabolic or signaling pathways, despite effects on mitochondria and metabolism in both heart and biceps. Our results suggest that glucocorticoid exposure affects nuclear genes important to mitochondrial activity and reactive oxygen in both cardiac and skeletal muscle tissues in a tissue specific manner.
2019-11-01 | GSE136315 | GEO
Project description:This study was designed to determine the effects of corticosteroids at MR in the late-gestation fetal lung. Since both the mineralocorticoid receptor (MR) and the glucocorticoid receptor (GR) are expressed at relatively high levels in the fetal lung, endogenous corticosteroids may act at MR as well as GR in the preterm fetal lung. The GR agonist, betamethasone, the MR agonist, aldosterone, or both were infused intravenously for 48 h in ovine fetuses of approximately 130 days gestation. Effects on airway pressures during stepwise inflation of the in situ lung, expression of ENaC alpha (SCNN1A), ENaC beta (SCNN1B), and Na,K ATPase (ATP1A1), and elastin and collagen content were determined after the infusions. We found that aldosterone significantly reduced the airway pressure measured during the initial step in inflation of the lung, although aldosterone had no overall effect on lung compliance, nor did aldosterone induce expression of ENaCα, ENaCβ or Na,K ATPaseα1. Betamethasone significantly increased expression of the epithelial sodium channel (ENaC) subunit mRNAs, and collagen and elastin content in the lungs, although this dose of betamethasone also had no effect on lung compliance. There was no synergy between effects of the MR and GR agonists. Transcriptomic analysis suggested that although aldosterone did not alter genes in pathways related to epithelial sodium transport, aldosterone did alter genes in pathways involved in cell proliferation in the lungs. The results are consistent with corticosteroid-induced fluid reabsorption at birth through GR rather than MR, but suggest that MR facilitates lung maturation, and may contribute to inflation with the first breaths via mechanisms distinct from known aldosterone effects in other epithelia.
| S-EPMC4187571 | biostudies-literature
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. In previous studies of the intraventricular septum from these fetuses 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. To investigate the effects on skeletal muscle, we extended the transcriptomic analyses to biceps femoralis. Transcriptomic modelling revealed that pathways related to mitochondrial metabolism were downregulated, whereas pathways suggestive of positive regulation of reactive oxygen species and activation of the apoptotic cascade were upregulated. Mitochondrial DNA (mt-DNA) and the protein levels of cytochrome C was significantly decreased in the biceps. RT- PCR validation of the pathways showed significant decrease in SLC2A4 mRNA levels, and a significant increase in PDK4, TXNIP, ANGPTL4 mRNA levels, consistent with reduced insulin sensitivity of the bicep muscles. Comparison of the change in gene expression in biceps to that in cardiac intraventricular septum and left ventricle showed few common genes with little overlap in specific metabolic or signaling pathways, despite reduction in mitochondria in both heart and biceps. Our results suggest that glucocorticoid exposure affects nuclear genes important to mitochondrial activity and reactive oxygen in both cardiac and skeletal muscle tissues in a tissue specific manner.
2019-11-01 | GSE136384 | GEO
Project description:BackgroundThe limited availability of donor organs has led to a search for alternatives to liver transplantation to restore liver function and bridge patients to transplantation. We have shown that the proliferation of late gestation (embryonic day 19) fetal rat hepatocytes is mitogen-independent and that mechanisms regulating mRNA translation, cell cycle progression, and gene expression differ from those of adult rat hepatocytes. In the present study, we investigated whether E19 fetal hepatocytes can engraft and repopulate an injured adult liver.MethodsFetal hepatocytes were isolated using a monoclonal antibody against a hepatic surface protein, leucine amino peptidase (LAP). LAP+ and LAP- fractions were analyzed by immunofluorescence and microarray. Immunopurified E19 liver cells from DPPIV+ rats were transplanted via splenic injection into partial hepatectomized DPPIV- rats that had been pretreated with mitomycin C.ResultsMore than a third of LAP+ fetal hepatocytes expressed ductal markers. Transcriptomic analysis revealed that these dual-expressing cells represent a population of less well-differentiated hepatocytes. Upon transplantation, LAP+ late gestation fetal hepatocytes formed hepatic, endothelial, and ductal colonies within 1 month. By 10 months, colonies derived from LAP+ cells increased so that up to 35% of the liver was repopulated by donor-derived cells.ConclusionsLate gestation fetal hepatocytes, despite being far along in the differentiation process, possess the capacity for extensive liver repopulation. This is likely related to the unexpected presence of a significant proportion of hepatocyte marker-positive cells maintaining a less well-differentiated phenotype.
| S-EPMC5605407 | biostudies-literature
Project description:The genetic programs responsible for pulmonary lymphatic maturation prior to birth are not known. To address this gap in knowledge, we developed a novel cell sorting strategy to collect fetal pulmonary lymphatic endothelial cells (PLECs) for global transcriptional profiling. We identified PLECs based on their unique cell surface immunophenotype (CD31+/Vegfr3+/Lyve1+/Pdpn+) and isolated them from murine lungs during late gestation (E16.5, E17.5, E18.5). Gene expression profiling was performed using whole-genome microarrays, and 1,281 genes were significantly differentially expressed with respect to time (FDR q < 0.05) and grouped into six clusters. Two clusters containing a total of 493 genes strongly upregulated at E18.5 were significantly enriched in genes with functional annotations corresponding to innate immune response, positive regulation of angiogenesis, complement & coagulation cascade, ECM/cell-adhesion, and lipid metabolism. Gene Set Enrichment Analysis identified several pathways coordinately upregulated during late gestation, the strongest of which was the type-I IFN-α/β signaling pathway. Upregulation of canonical interferon target genes was confirmed by qRT-PCR and in situ hybridization in E18.5 PLECs. We also identified transcriptional events consistent with a prenatal PLEC maturation program. This PLEC-specific program included individual genes (Ch25h, Itpkc, Pcdhac2 and S1pr3) as well as a set of chemokines and genes containing an NF-κB binding site in their promoter. Overall, this work reveals transcriptional insights into the genes, signaling pathways and biological processes associated with pulmonary lymphatic maturation in the fetal lung.
| S-EPMC6513083 | biostudies-literature
Project description:The most abundant form of estrogen circulating in fetal plasma is sulfo-conjugated estrogen; for example, estradiol-3-sulfate (E(2)SO(4)) is more highly abundant than estradiol (E(2)). The present study investigated the ontogeny of the deconjugating (steroid sulfatase [STS]) and conjugating (estrogen sulfotransferase [STF]) enzymes in ovine fetal brain and tested the hypothesis that treatment with E(2)SO(4) would alter the expression of one or both enzymes. Steroid sulfatase was more highly expressed than STF, and both changed as a function of gestational age. Estradiol-3-sulfate infused intracerebroventricularly (icv) significantly increased plasma adrenocorticotropic hormone (ACTH) and cortisol concentrations. Plasma E(2) and E(2)SO(4) were increased, and brain expression of estrogen receptor α was decreased. The proteins STS and STF were up- and downregulated, respectively. Pituitary proopiomelanocortin (POMC) and follicle-stimulating hormone (FSH) and hypothalamic corticotrophin-releasing hormone (CRH) messenger RNA (mRNA) was decreased. We conclude that E(2)SO(4) has complex actions on the fetal brain, which might involve deconjugation by STS, but that the net result of direct E(2)SO(4) icv infusion is more complex than can be accounted for by infusion of E(2) alone.
| S-EPMC3235910 | biostudies-literature
Project description:Key pointsFetal glucagon concentrations are elevated in the setting of placental insufficiency, hypoxia and elevated stress hormones. Chronically elevated glucagon concentrations in the adult result in profound decreases in amino acid concentrations and lean body mass. Experimental elevation of fetal glucagon concentrations in a late-gestation pregnant sheep results in lower fetal amino acid concentrations, lower protein accretion and lower fetal weight, in addition to decreased placental function. This study demonstrates a negative effect of glucagon on fetal protein accretion and growth, and also provides the first example of a fetal hormone that negatively regulates placental nutrient transport and blood flow.AbstractFetal glucagon concentrations are elevated in the setting of placental insufficiency and fetal stress. Postnatal studies have demonstrated the importance of glucagon in amino acid metabolism, and limited fetal studies have suggested that glucagon inhibits umbilical uptake of certain amino acids. We hypothesized that chronic fetal hyperglucagonaemia would decrease amino acid transfer and increase amino acid oxidation by the fetus. Late gestation singleton fetal sheep received a direct intravenous infusion of glucagon (GCG; 5 or 50 ng/kg/min; n = 7 and 5, respectively) or a vehicle control (n = 10) for 8-10 days. Fetal and maternal nutrient concentrations, uterine and umbilical blood flows, fetal leucine flux, nutrient uptake rates, placental secretion of chorionic somatomammotropin (CSH), and targeted placental gene expression were measured. GCG fetuses had 13% lower fetal weight compared to controls (P = 0.0239) and >28% lower concentrations of 16 out of 21 amino acids (P < 0.02). Additionally, protein synthesis was 49% lower (P = 0.0005), and protein accretion was 92% lower in GCG fetuses (P = 0.0006). Uterine blood flow was 33% lower in ewes with GCG fetuses (P = 0.0154), while umbilical blood flow was similar. Fetal hyperglucagonaemia lowered uterine uptake of 10 amino acids by >48% (P < 0.05) and umbilical uptake of seven amino acids by >29% (P < 0.04). Placental secretion of CSH into maternal circulation was reduced by 80% compared to controls (P = 0.0080). This study demonstrates a negative effect of glucagon on fetal protein accretion and growth. It also demonstrates that glucagon, a hormone of fetal origin, negatively regulates maternal placental nutrient transport function, placental CSH production and uterine blood flow.
| S-EPMC8249343 | biostudies-literature