Oral dosing for antenatal corticosteroids in the rhesus macaque
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ABSTRACT:
ORGANISM(S): Macaca mulatta
PROVIDER: GSE131194 | GEO | 2019/09/25
REPOSITORIES: GEO
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Project description:Purpose: Evaluate fetal lung maturation and transcriptome after clinical treatment with antenatal corticosteroids compared to an alternative treatment with a slow release low-dose formulation. Methods: Lung mRNA profiles of rhesus macaques were generated by RNA sequencing. Reads that met quality thresholds were aligned to the rhesus macaque genome and number of reads per gene was counted. RNA-sequencing of the hippocampus was done. Differential expression analysis was done using read counts. Results: A relatively low dose of Beta-Ac increased lung compliance, surfactant concentration and relative airspace of the fetal lung equivalent to the clinical drug. By transcriptome analyses, the early suppression of genes associated with immune responses and the downregulation of genes associated with developmental pathways were less changed by Beta-Ac than the clinical drug. There were no significant differences between Beta-Ac and control while the clinical drug suppressed maturational pathways including genes involved in neurogenesis, neuronal differentiation and stem cell fate commitment. Conclusions: We report that low-dose betamethasone-acetate has decreased impact on lung transcriptome compared to the clinical treatment.
2019-06-21 | GSE118438 | GEO
Project description:[Background] Antenatal steroid (ACS) therapy conveys lifesaving benefits to the preterm fetus. However, current treatments are associated with increased risk of growth, endocrine, and neurodevelopmental abnormalities. [Objectives] To inform ACS therapy optimisation we used a sheep model of pregnancy to test whether adverse fetal brain effects were independent of respiratory benefit and ACS pharmacokinetics. [Study Design] Ewes carrying a single fetus received intramuscular injections of either: i) 2 x 12mg dexamethasone phosphate 12 hourly (DexP) (Dex High); ii) 4 x 1.5mg DexP 12 hourly (Dex Low); iii) 1 x 0.125mg/kg betamethasone acetate (Beta-Acetate); or iv) Saline (Negative Control). Lambs were delivered for ventilation after 48 hours. Hippocampal and lung tissues were subjected to RNA sequencing. [Results] Dex High treatment did not mature the preterm ovine lung. Pulsatile (Dex High and Dex Low) treatments caused hippocampal RNA changes consistent with neuronal death. Constant, low-amplitude treatment (Beta Acetate) significantly improved lung function, with few adverse RNA transcriptional changes in the fetal hippocampus. [Conclusions] All ACS exposures caused significant alterations in fetal homeostasis. Pulsatile exposures caused dose-independent neurodegenerative changes in the fetal hippocampus. These data highlight the importance of considering magnitude, duration and stability of fetal glucocorticoid exposures in optimising ACS therapy.
2024-09-13 | GSE248786 | GEO
Project description:Purpose: Our goal was to evaluate the pathways through which chorioamnionitis induces fetal lung maturation and how it interacts with a low-dose treatment with antenatal corticosteroids to further enhance fetal lung maturation. Methods: We treated pregnant rhesus macaque at 132 days (80% gestation) with intre-amniotic bacterla lipopolissacharide to model chorioamnionitis or a low-dose antenatal corticosteroids treatment with betamethasone-acetate (Beta-Ac 0.125mg/kg) or both treatments. Fetuses were delivered by c-section after 5 days and RNA-sequencing of whole lung tissue was performed. Another group of fetuses exposed to LPS was delivered 16h after treatment. Preterm controls were delivered at 132 days and term controls were delivered at 155 days and received no intervention. Results: Treatment with Beta-Ac in the setting of chorioamnionitis improves lung compliance and increases surfactant production relative to either treatment alone. RNA sequencing shows that these changes are mediated by suppression of proliferation and induction of mesenchymal cellular death. The combined exposure results in a mature-like transcriptomic profile with inhibition of extracellular matrix development by suppression of collagen genes and regulators of lung development. ACS and inflammation also suppressed signature genes associated with proliferative mesenchymal progenitors similar to the term lung. Conclusion: Treatment with ACS in the setting of inflammation may result in early respiratory advantage to preterm infants, but this advantage may come at a cost of abnormal extracellular matrix development which may be associated with increased risk of chronic lung disease.
2021-02-01 | GSE148645 | GEO
Project description:Oral dosing for antenatal corticosteroids in the rhesus macaque
| PRJNA542881 | ENA
Project description:Study investigating responses of lung to sub-clinical antenatal steroid (betamethasone phosphate) exposure Microarray was used to determine the inflammatory transcriptome in homogenised lung tissue samples
2016-09-22 | GSE87151 | GEO
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.
2013-03-06 | E-GEOD-44858 | biostudies-arrayexpress
Project description:Prenatal exposure to synthetic corticosteroids can significantly alter postnatal development through changes in neurotransmitters 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 prefrontal cortex of female rats prenatally exposed to either betamethasone or saline. The transcriptome has been assessed by novel computational tools to determine complex changes that may have life-long effects on phenotype, i.e., behavior. We analyzed how 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) are afected by the prenatal exposure to corticosteroids and postnatal ketamine-induced seizures. One sex (F) x two prenatal exposures (B = betamethasone, S = saline) x two postnatal treatments (K = ketamine, S = saline). Biological replicates: 4 FSS, 4 FBS, 4 FBK.
2016-01-09 | E-GEOD-76694 | biostudies-arrayexpress
Project description:The late-gestation fetal lung has relatively high levels of expression of the mineralocorticoid receptor (MR) as well as the glucocorticoid receptor (GR), suggesting that endogenous corticosteroids may act in the lung through binding at MR as well as GR. This study was designed to determine the effects of physiologically relevant increases in steroids on MR and GR in the late-gestation lung. The GR agonist, betamethasone, the MR agonist, aldosterone, or both agonists were infused intravenously for 48 hours in ovine fetuses of approximately 130 days gestation. Effects on airway pressures during stepwise inflation of the in situ lung, expression of ENaC and Na,K ATPase, and elastin and collagen content were determined at the end of the infusions. We found that aldosterone significantly reduced the initial airway pressures measured in situ during inflation. This effect did not occur with betamethasone alone or in combination with aldosterone. Conversely, betamethasone, but not aldosterone, significantly increased expression of the epithelial sodium channel (ENaC) subunit mRNAs, and collagen and elastin content in the lungs. Aldosterone altered novel gene pathways in the fetal lung, suggesting effects on lung compliance via genes which influence immune pathways and lung stiffness. The results are consistent with corticosteroid-induced fluid reabsorption at birth through GR rather than MR, but suggest that MR contributes effects facilitating lung inflation with the first breaths via nonclassical mechanisms. 4 sets of twin sheep fetuses at approximately 130d gestation (term is 147d) were used. One twin was infused with 0.2 mg aldosterone for 48 h, the other received vehicle.
2014-08-07 | E-GEOD-53048 | biostudies-arrayexpress
Project description:Antenatal corticosteroids (ANS) are the major intervention to decrease respiratory distress syndrome and mortality from premature birth and are standard of care. The use of ANS is expanding to include new indications and gestational ages, although the recommended dosing was never optimized. The most widely used treatment is two intramuscular doses of a 1:1 mixture of betamethasone-phosphate (Beta-P) and betamethasone-acetate (Beta-Ac) - the clinical drug. We tested in a primate model the efficacy of the slow release Beta-Ac alone for enhancing fetal lung maturation and to reduce fetal corticosteroid exposure and potential toxic effects. Pregnant rhesus macaques at 127 days of gestation (80% of term) were treated with either the clinical drug (0.25 mg/kg) or Beta-Ac (0.125 mg/kg). Beta-Ac alone increased lung compliance and surfactant concentration in the fetal lung equivalently to the clinical drug. By transcriptome analyses the early suppression of genes associated with immune responses and developmental pathways were less affected by Beta-Ac than the clinical drug. Promoter and regulatory analysis prediction identified differentially expressed genes targeted by the glucocorticoid receptor in the lung. At 5 days the clinical drug suppressed genes associated with neuronal development and differentiation in the fetal hippocampus compared to control, while low dose Beta-Ac alone did not. A low dose ANS treatment with Beta-Ac should be assessed for efficacy in human trials.
| S-EPMC6588577 | biostudies-literature
Project description:The late-gestation fetal lung has relatively high levels of expression of the mineralocorticoid receptor (MR) as well as the glucocorticoid receptor (GR), suggesting that endogenous corticosteroids may act in the lung through binding at MR as well as GR. This study was designed to determine the effects of physiologically relevant increases in steroids on MR and GR in the late-gestation lung. The GR agonist, betamethasone, the MR agonist, aldosterone, or both agonists were infused intravenously for 48 hours in ovine fetuses of approximately 130 days gestation. Effects on airway pressures during stepwise inflation of the in situ lung, expression of ENaC and Na,K ATPase, and elastin and collagen content were determined at the end of the infusions. We found that aldosterone significantly reduced the initial airway pressures measured in situ during inflation. This effect did not occur with betamethasone alone or in combination with aldosterone. Conversely, betamethasone, but not aldosterone, significantly increased expression of the epithelial sodium channel (ENaC) subunit mRNAs, and collagen and elastin content in the lungs. Aldosterone altered novel gene pathways in the fetal lung, suggesting effects on lung compliance via genes which influence immune pathways and lung stiffness. The results are consistent with corticosteroid-induced fluid reabsorption at birth through GR rather than MR, but suggest that MR contributes effects facilitating lung inflation with the first breaths via nonclassical mechanisms.
2014-08-07 | GSE53048 | GEO