High oxygen prevents fetal lethality due to lack of catecholamines
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE10341 | GEO | 2008/06/03
SECONDARY ACCESSION(S): PRJNA105581
REPOSITORIES: GEO
Similar Datasets
Project description:The catecholamine norepinephrine is required for fetal survival, but its essential function is unknown. When catecholamine-deficient [tyrosine hydroxylase (Th) null] mouse fetuses die at E13.5-E14.5, they resemble wild type fetuses exposed to hypoxia. They exhibit bradycardia (28% reduction in heart rate), thin ventricular myocardium (20% reduction in tissue), epicardial detachment, and death with vascular congestion, hemorrhage and edema. At E12.5, prior to the appearance of morphological deficits associated with Th deletion, catecholamine-deficient fetuses are preferentially killed by experimentally-induced hypoxia and have lower tissue pO2 than wild type siblings. Catecholamine-deficient fetuses also induced HIF-1 target genes to a greater extent than wild type siblings, supporting the notion that null fetuses experience greater hypoxia or have an enhanced response to hypoxia. Hypoxia induces a 13-fold increase in plasma norepinephrine levels, which would be expected to increase heart rate, thereby, improving oxygen delivery in wild type mice. Surprisingly, increasing maternal oxygen (FiO2 33% or 63%) prevents the effects of catecholamine-deficiency, restoring heart rate, myocardial mass and survival of Th null fetuses. We suggest that norepinephrine mediates fetal survival by maintaining oxygen homeostasis as vulnerability to constitutive hypoxia increases as fetal growth accelerates during normal development. Keywords: Comparative with respect to genotype and oxygen conditions The first aim was to compare gene expression of E12.5 mouse fetuses between wild type (Th+/+) versus tyrosine hydroxylase null (Th-/-) animals from normoxic dams. This resulted in 6 arrays. The second aim compared wild type and tyrosine hydroxylase null E12.5 fetuses from dam exposed to hypoxia (8% oxygen) for 6 hours prior to sacrifice at E12.5 of gestation. This resulted in 6 arrays. The third aim was to compare HIF-1 targets behind wt and null fetuses
2008-06-03 | E-GEOD-10341 | biostudies-arrayexpress
Project description:The study objective was to determine differentially expressed mRNA transcripts in pancreatic islets from fetal sheep exposed to persistent elevations in stress hormone norepinephrine to isolate effects of chronic adrenergic signaling on fetal islets. Ultimately, these data can be compared to islets from fetuses with placental insufficiency-induced intrauterine growth restriction, where there is known increases in norepinephrine.
2018-09-05 | GSE106440 | GEO
Project description:Fetuses respond to transient hypoxia (a common stressor in utero) with cellular responses that are appropriate for promoting survival of the fetus. The present experiment was performed to identify the acute genomic responses of the fetal hypothalamus to transient hypoxia. Three fetal sheep were exposed to 30 min of hypoxia and hypothalamic mRNA extracted from samples collected 30 min after return to normoxia. These samples were compared to those from 4 normoxic control fetuses using the Agilent 019921 ovine array. Differentially-regulated genes were analyzed by network analysis and by gene ontology analysis, identifying statistically significant overrepresentation of biological processes. Real-time PCR of selected genes supported the validity of the array data. Hypoxia induced increased expression of genes involved in response to oxygen stimulus, RNA splicing, anti-apoptosis, vascular smooth muscle proliferation, and positive regulation of Notch receptor target. Downregulated genes were involved in metabolism, antigen receptor-mediated immunity, macromolecular complex assembly, S-phase, translation elongation, RNA splicing, protein transport, and post-transcriptional regulation. We conclude that these results emphasize that the cellular response to hypoxia involves reduced metabolism, the involvement of the fetal immune system, and the importance of glucocorticoid signaling. 3 Ventilatory Hypoxia (VH) and 4 Control (con) fetuses. All fetuses were chronically catheterized and in late gestation. Hypoxia produced by low PO2 in maternal inspired gas for 30 min, followed by normoxia recovery for 30 min. Control fetuses maintained at normoxia for 30 min, followed by another 30 min of normoxia. Hypothalami collected for mRNA at end of normoxic recovery period.
2014-01-16 | E-GEOD-43371 | biostudies-arrayexpress
Project description:Fetuses respond to transient hypoxia (a common stressor in utero) with cellular responses that are appropriate for promoting survival of the fetus. The present experiment was performed to identify the acute genomic responses of the fetal hypothalamus to transient hypoxia. Three fetal sheep were exposed to 30 min of hypoxia and hypothalamic mRNA extracted from samples collected 30 min after return to normoxia. These samples were compared to those from 4 normoxic control fetuses using the Agilent 019921 ovine array. Differentially-regulated genes were analyzed by network analysis and by gene ontology analysis, identifying statistically significant overrepresentation of biological processes. Real-time PCR of selected genes supported the validity of the array data. Hypoxia induced increased expression of genes involved in response to oxygen stimulus, RNA splicing, anti-apoptosis, vascular smooth muscle proliferation, and positive regulation of Notch receptor target. Downregulated genes were involved in metabolism, antigen receptor-mediated immunity, macromolecular complex assembly, S-phase, translation elongation, RNA splicing, protein transport, and post-transcriptional regulation. We conclude that these results emphasize that the cellular response to hypoxia involves reduced metabolism, the involvement of the fetal immune system, and the importance of glucocorticoid signaling.
2014-01-16 | GSE43371 | GEO
Project description:The physiological response to hypoxia in the fetus has been extensively studied with regard to redistribution of fetal combined ventricular output and sparing of oxygen delivery to fetal brain and heart. However, little is known about the biochemical and molecular response of the fetal brain to transient hypoxia. The present study was designed to use transcriptomics and systems biology modeling to identify major biological responses of the fetal hypothalamus to transient hypoxia. We also investigated the effect of ketamine, an FDA approved anesthetic that has anti-inflammatory properties in various tissues. Chronically catheterized fetal sheep (122±5 days gestation) were subjected to 30 min hypoxia (relative reduction in PaO2 ~50 %) caused by infusion of nitrogen into the inspired gas of the pregnant ewe. Messenger RNA was isolated from fetal hypothalamus collected 24 hours after hypoxia, and was analyzed for gene expression using the Agilent 15.5k ovine microarray. Hypoxia increased expression of 280 and decreased expression of 357 genes. Genes increased by hypoxia were associated with immune responses, consistent with stimulation by lipopolysaccharide. Pretreatment of the fetuses with ketamine reduced immune/inflammation responses. Immunohistochemical analysis revealed that the number of microglia/macrophages in the anterior hypothalamus was increased by hypoxia and that the increase was blunted by ketamine. We conclude that transient hypoxia stimulates an inflammatory/immune response in the fetal hypothalamus and that transcriptomics/systems biology modeling is a useful and valid tool for investigation of biological function in the fetal sheep.
2017-07-31 | GSE82016 | GEO
Project description:Transient hypoxia in pregnancy stimulates a physiological reflex response that redistributes blood flow and defends oxygen delivery to the fetal brain. The chemoreceptor reflex that is responsible for this physiological response is dependent on glutamatergic neurotransmission which, in times of vigorous activity, could produce cell death secondary to calcium uptake. We designed the present experiment to test the hypotheses that transient hypoxia produces damage of the cerebral cortex and that ketamine, an antagonist of NMDA receptors, reduces the damage. Late-gestation, chronically catheterized fetal sheep were subjected to a 30 min period of ventilatory hypoxia that decreased fetal PaO2 from 17±1 to 10±1 mm Hg, or normoxia (PaO2 17±1 mm Hg), with or without pretreatment (10 min before hypoxia/normoxia) with ketamine (3 mg/kg, iv). One day (24 h) after hypoxia/normoxia, fetal cerebral cortex was removed and mRNA extracted for transcriptomics and systems biology analysis. Hypoxia stimulated a transcriptomics response consistent with a reduction in cellular metabolism and an increase in inflammation. Ketamine pretreatment reduced both of these responses. The inflammation response modeled with transcriptomic system biology was validated by immunohistochemistry and showed increased abundance of microglia/macrophages after hypoxia in the cerebral cortical tissue that ketamine significantly reduced. We conclude that transient hypoxia produces inflammation of the fetal cerebral cortex and that ketamine, in a standard clinical dose, reduces the inflammation response. 4 groups: hypoxia, hypoxia plus ketamine, normoxia, normoxia plus ketamine. Hypoxia produced by low PO2 in maternal inspired gas for 30 min, followed by normoxia recovery for 23.5 hours. Control fetuses maintained at normoxia for 30 min, followed by another 23.5 h of normoxia. Fetal frontal cerebral cortex collected for mRNA at end of 23.5 h recovery period.
2016-04-06 | E-GEOD-76110 | biostudies-arrayexpress
Project description:Parathyroid hormone (PTH) plays an essential role in regulating calcium and bone homeostasis in the adult, but whether PTH is required at all for regulating fetal-placental mineral homeostasis is uncertain. To address this we treated Pth-null mice in utero with 1 nmol PTH (1-84) or saline and examined placental calcium transfer 90 minutes later. It was found that placental calcium transfer increased in Pth-null fetuses treated with PTH as compared to Pth-null fetuses treated with saline. Subsequently, to determine the effect of PTH treatment on placental gene expression, in a separate experiment, 90 minutes after the fetal injections the placentas were removed for subsequent RNA extraction and microarray analysis.
2010-03-01 | GSE16983 | GEO
Project description:Maternal overnutrition affects offspring susceptibility to nonalcoholic steatohepatitis (NASH). Male offspring from high-fat diet (HFD)-fed dams developed a severe form of NASH, leading to highly vascular tumor formation. The cancer/testis antigen HORMA domain containing protein 1 (HORMAD1), one of 146 upregulated differentially expressed genes in fetal livers from HFD-fed dams, was overexpressed with hypoxia-inducible factor 1 alpha (HIF-1alpha) in hepatoblasts and in NASH-based hepatocellular carcinoma (HCC) in offspring from HFD-fed dams at 15 weeks old. Hypoxia substantially increased Hormad1 expression in primary mouse hepatocytes. Despite the presence of three putative hypoxia response elements within the mouse Hormad1 gene, the Hif-1alpha siRNA only slightly decreased hypoxia-induced Hormad1 mRNA expression. In contrast, N-acetylcysteine, but not rotenone, inhibited hypoxia-induced Hormad1 expression, indicating its dependency on nonmitochondrial reactive oxygen species production. Synchrotron-based phase-contrast micro-CT of the fetuses from HFD-fed dams showed significant enlargement of the liver accompanied by a consistent size of the umbilical vein, which may cause hypoxia in the fetal liver. Based on these findings, a maternal HFD induces fetal origins of NASH/HCC via hypoxia, and HORMAD1 is a potential therapeutic target for NASH/HCC.
2022-07-29 | GSE183360 | GEO
Project description:Although the effects of thyroid hormones (TH) on the brain development have been extensively studied perinatally, effects of TH of maternal origin on the fetal brain development have been largely unexplored. We applied a high throughput study on the mouse models with aberrant TH levels on gestation day (GD) 16, before the onset of fetal thyroid function. Although 3 day treatment with methimazole (MMI) and perchlorate significantly decreased TH levels in fetal cerebral cortex, few changes in the abundance of mRNA were revealed by the microarray analysis. Injection TH to dams 12 hours before sacrifice on GD 16 induced 161 genes significantly changed in fetal cortex. Nine out of 10 selected genes were confirmed with RT-PCR, including known TH responsive gene Klf9 and other novel TH responsive genes such as Appbp2, Ppap2b and Fgfr1op2. TH regulation of the expression of these genes was also confirmed with cultured N2a? cells. Thyroid responsive elements (TREs) in the promoters of these genes were identified using electrophoresis mobility shift assay. TH effect on microRNA (miRNA) expression in developing cortex on GD 16 and postnatal day (PND) 15 was investigated with microarray and RT-PCR. Some of miRNAs and precursors decreased in fetal cortex from the dams injected with TH on GD 16, including miR-16 and miR-106. Using 3’ untranslate region reporter vector, we identified Klf9 is one of the target genes of miR-106, while Ppap2b is the target of miR-16. These results indicated that TH regulation on gene expression could through TR-TRE interaction and through regulating target miRNA expression. This study is the first report to identify TH responsive genes and miRNAs genome wide in the early fetal brain; it provides evidence to further understand the mechanism of TH effect on brain development. Timed-pregnant C57BL/6 mice (n=20; Harlan, Indianapolis, IN) arrived on gestational day (GD) 11 and were housed individually in plastic cages under a 12:12 light cycle (0600 h–1800 h) with food available ad libitum. Mice were divided randomly into one of 4 groups (control, hypo, hypo+ and hyper; 5 per group) . Mice in the control and hyper groups were provided with fresh drinking water containing 2% sucrose from GD 13 to GD 16 until sacrifice. Mice in hypo and hypo+ were provided with fresh drinking water daily containing 1% Perchlorate (Per) and 0.025% Methimazole (MMI) supplemented with 2% sucrose (to mask bitterness) from GD 13 to sacrifice on GD 16. Twelve hours prior to sacrifice on GD 16 all mice received a single subcutaneous injection. Control and hypo mice received vehicle (0.9% saline in 100 µl volume); the hypo+ group received 25.0 µg/100g body weight thyroxine (T4) with 2.5 µg/100g body weight T3 to restore a physiological level of TH; the hyper group received 100.0 µg/100g body weight T4 with 10.0 µg/100g body weight T3 to model hyperthyroidism. Dams were killed by exposure to CO2. Fetuses were dissected from the uterine horn and embryonic membranes then frozen on pulverized dry ice. Tissue samples were taken from the fetuses to determine sex using PCR for SRY (Yang J and RT Zoeller, 2002). Fetal cerebral cortices were removed from each mouse and used for microarray and RT-PCR analysis. Total RNA was extracted from half cortices of individual female fetuses using RNeasy Lipid tissue Mini kits (Qiagen, Germantown, MD) according to the manufacturer's instructions. The quality of total RNA was evaluated by A260/A280 ratio (found to be at least 1.8 for each sample) and by electrophoresis on the Agilent Bioanalyzer. The Yale Center for the Neuroscience Microarray Consortium carried out the Affymetrix microarray analysis using The GeneChip Rat Genome 230 2.0 Array. Preparation of labeled cRNA for hybridization onto Affymetrix GeneChips followed the recommended Affymetrix protocol. Control versus each of the three treatment groups: hyper, hypo, and hypo+. 1 of 20 samples removed due to poor quality.
2014-02-04 | E-GEOD-43927 | biostudies-arrayexpress
Project description:Pregnant women and their fetuses are particularly susceptible to respiratory pathogens. How they respond to SARS-CoV-2 infection is still under investigation. Here, we studied the transcriptome and phenotype of umbilical cord blood cells in pregnant women infected or not with SARS-CoV-2. We found that symptomatic maternal COVID-19 was associated with a transcriptional erythroid cell signature as compared with asymptomatic and uninfected mothers. We observed an expansion of fetal hematopoietic progenitors skewed towards erythroid differentiation and displaying increased clonogenicity. We found no difference in inflammatory cytokines in the cord blood upon SARS-CoV-2 infection. Interestingly, we showed an activation of hypoxia pathway in cord blood cells from symptomatic COVID-19 mothers, suggesting that maternal hypoxia may be triggering this fetal stress erythropoiesis. Overall, these results show a fetal hematopoietic response to symptomatic COVID-19 in pregnant mothers in the absence of vertically transmitted SARS-CoV-2 infection, which is likely to be a mechanism of fetal adaptation to maternal infection and reduced oxygen supply.
2023-08-10 | GSE224063 | GEO