Neonatal anesthesia and dysregulation of the epigenome†.
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ABSTRACT:
SUBMITTER: Cabrera OH
PROVIDER: S-EPMC8444668 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Preterm birth is the leading cause of infant morbidity and mortality. Necrotizing enterocolitis (NEC) is an inflammatory bowel disease affecting primarily premature infants, which can be lethal. Microbial intestinal colonization may alter epigenetic signatures of the immature gut establishing inflammatory and barrier properties predisposing to the development of NEC. We hypothesize that a crosstalk exists between the epigenome of the host and the initial intestinal colonizing microbiota at critical neonatal stages. By exposing immature enterocytes to probiotic and pathogenic bacteria, we showed over 200 regions of differential DNA modification, which were specific for each exposure. Reciprocally, using a mouse model of prenatal exposure to dexamethasone we demonstrated that antenatal treatment with glucocorticoids alters the epigenome of the host. We investigated the effects on the expression profiles of genes associated with inflammatory responses and intestinal barrier by qPCR-based gene expression array and verified the DNA modification changes in 5 candidate genes by quantitative methylation specific PCR (qMSP). Importantly, by 16S RNA sequencing-based phylogenetic analysis of intestinal bacteria in mice at 2 weeks of life, we showed that epigenome changes conditioned early microbiota colonization leading to differential bacterial colonization at different taxonomic levels. Our findings support a novel conceptual framework in which epigenetic changes induced by intrauterine influences affect early microbial colonization and intestinal development, which may alter disease susceptibility.
| S-EPMC4854540 | biostudies-literature
Project description:ContextAntenatal hyperglycemia is associated with increased risk of future adverse health outcomes in both mother and child. Variations in offspring's epigenome can reflect the impact and response to in utero glycemic exposure, and may have different consequences for the child.ObjectiveWe examined possible differences in associations of basal glucose status and glucose handling during pregnancy with both clinical covariates and offspring cord tissue DNA methylation.Research design and methodsThis study included 830 mother-offspring dyads from the Growing Up in Singapore Towards Healthy Outcomes cohort. The fetal epigenome of umbilical cord tissue was profiled using Illumina HumanMethylation450 arrays. Associations of maternal mid-pregnancy fasting (fasting plasma glucose [FPG]) and 2-hour plasma glucose (2hPG) after a 75-g oral glucose challenge with both maternal clinical phenotypes and offspring epigenome at delivery were investigated separately.ResultsMaternal age, prepregnancy body mass index, and blood pressure measures were associated with both FPG and 2hPG, whereas Chinese ethnicity (P = 1.9 × 10-4), maternal height (P = 1.1 × 10-4), pregnancy weight gain (P = 2.2 × 10-3), prepregnancy alcohol consumption (P = 4.6 × 10-4), and tobacco exposure (P = 1.9 × 10-3) showed significantly opposite associations between the 2 glucose measures. Most importantly, we observed a dichotomy in the effects of these glycemic indices on the offspring epigenome. Offspring born to mothers with elevated 2hPG showed global hypomethylation. CpGs most associated with the 2 measures also reflected differences in gene ontologies and had different associations with offspring birthweight.ConclusionsOur findings suggest that 2 traditionally used glycemic indices for diagnosing gestational diabetes may reflect distinctive pathophysiologies in pregnancy, and have differential impacts on the offspring's DNA methylome.
| S-EPMC8852163 | biostudies-literature
Project description:Maternal prenatal status, as encapsulated by that to which a mother is exposed through diet and environment, is a key determinant of offspring health and disease. Alterations in DNA methylation (DNAm) may be a mechanism through which suboptimal prenatal conditions confer disease risk later in life. One-carbon metabolism (OCM) is critical to both fetal development and in supplying methyl donors needed for DNAm. Plasma concentrations of one-carbon metabolites across maternal first trimester (M1), maternal term (M3), and infant cord blood (CB) at birth were tested for association with DNAm patterns in CB from the Michigan Mother and Infant Pairs (MMIP) pregnancy cohort. The Illumina Infinium MethylationEPIC BeadChip was used to quantitatively evaluate DNAm across the epigenome. Global and single-site DNAm and metabolite models were adjusted for infant sex, estimated cell type proportions, and batch as covariates. Change in mean metabolite concentration across pregnancy (M1 to M3) was significantly different for S-adenosylhomocysteine (SAH), S-adenosylmethionine (SAM), betaine, and choline. Both M1 SAH and CB SAH were significantly associated with the global distribution of DNAm in CB, with indications of a shift toward less methylation. M3 SAH and CB SAH also displayed significant associations with locus-specific DNAm in infant CB (FDR<0.05). Our findings underscore the role of maternal one-carbon metabolites in shifting the global DNAm pattern in CB and emphasizes the need to closely evaluate how dietary status influences cellular methylation potential and ultimately offspring health.
| S-EPMC8847320 | biostudies-literature
Project description:MicroRNAs (miRNAs), when subjected to environmental stimuli, can exhibit differential expression. As critical regulators of gene expression, differential miRNA expression has been implicated in numerous disorders of the nervous system. In this study, we focused on the effect of a general anesthetic, as an environmental stimulus, on miRNA expression of the developing brain. General anesthetics have potential long-lasting neurotoxic effects on the developing brain, resulting in behavioral changes in adulthood. We first carried out an unbiased profiling approach to examine the effect of single-episode neonatal general anesthetic, sevoflurance (sevo), exposure on miRNA expression of the brain. Neonatal sevo has a significant effect on the expression of specific miRNAs of the whole brain and the hippocampus that is both immediate - directly after neonatal treatment, as well as long-lasting - during adulthood. Functionally, neonatal sevo-associated miRNA gene-targets share potential neurodevelopmental pathways related to axon guidance, DNA transcription, protein phosphorylation and nervous system development. Our understanding on the role of miRNAs provides a putative epigenetic/molecular bridge that links neonatal general anesthetic's effect with its associated functional change.
| S-EPMC6045579 | biostudies-literature
Project description:BackgroundNeonatal adiposity is a risk factor for childhood obesity. Investigating contributors to neonatal adiposity is important for understanding early life obesity risk. Epigenetic changes of metabolic genes in cord blood may contribute to excessive neonatal adiposity and subsequent childhood obesity. This study aims to evaluate the association of cord blood DNA methylation patterns with anthropometric measures and cord blood leptin, a biomarker of neonatal adiposity.MethodsA cross-sectional study was performed on a multiethnic cohort of 114 full term neonates born to mothers without gestational diabetes at a university hospital. Cord blood was assayed for leptin and for epigenome-wide DNA methylation profiles via the Illumina 450K platform. Neonatal body composition was measured by air displacement plethysmography. Multivariable linear regression was used to analyze associations between individual CpG sites as well as differentially methylated regions in cord blood DNA with measures of newborn adiposity including anthropometrics (birth weight, fat mass and percent body fat) and cord blood leptin. False discovery rate was estimated to account for multiple comparisons.Results247 CpG sites as well as 18 differentially methylated gene regions were associated with cord blood leptin but no epigenetic changes were associated with birth weight, fat mass or percent body fat. Genes of interest identified in this study are DNAJA4, TFR2, SMAD3, PLAG1, FGF1, and HNF4A.ConclusionEpigenetic changes in cord blood DNA are associated with cord blood leptin levels, a measure of neonatal adiposity.
| S-EPMC6919608 | biostudies-literature
Project description:BACKGROUND:Awake regional anesthesia (RA) is a viable alternative to general anesthesia (GA) for infants undergoing lower abdominal surgery. Benefits include lower incidence of postoperative apnea and avoidance of anesthetic agents that may increase neuroapoptosis and worsen neurocognitive outcomes. The General Anesthesia compared to Spinal anesthesia study compares neurodevelopmental outcomes after awake RA or GA in otherwise healthy infants. The aim of the study is to describe success and failure rates of RA and report factors associated with failure. METHODS:This was a nested cohort study within a prospective, randomized, controlled, observer-blind, equivalence trial. Seven hundred twenty-two infants 60 weeks or less postmenstrual age scheduled for herniorrhaphy under anesthesia were randomly assigned to receive RA (spinal, caudal epidural, or combined spinal caudal anesthetic) or GA with sevoflurane. The data of 339 infants, where spinal or combined spinal caudal anesthetic was attempted, were analyzed. Possible predictors of failure were assessed including patient factors, technique, experience of site and anesthetist, and type of local anesthetic. RESULTS:RA was sufficient for the completion of surgery in 83.2% of patients. Spinal anesthesia was successful in 86.9% of cases and combined spinal caudal anesthetic in 76.1%. Thirty-four patients required conversion to GA, and an additional 23 patients (6.8%) required brief sedation. Bloody tap on the first attempt at lumbar puncture was the only risk factor significantly associated with block failure (odds ratio = 2.46). CONCLUSIONS:The failure rate of spinal anesthesia was low. Variability in application of combined spinal caudal anesthetic limited attempts to compare the success of this technique to spinal alone.
| S-EPMC4626278 | biostudies-literature
Project description:BackgroundThe majority of studies evaluating neurocognition in humans who had procedures under anesthesia early in life found long-term deficits even though the typical anesthesia duration normalized to the human life span is much shorter than that shown to induce developmental abnormalities in rodents. Therefore, we studied whether subsequent environmental stressors contribute to deficiencies programmed by a brief neonatal etomidate exposure.MethodsPostnatal days (P) 4, 5, or 6, Sprague-Dawley rats, pretreated with vehicle or the Na+-K+-2Cl- (NKCC1) inhibitor, bumetanide, received two injections of etomidate resulting in anesthesia for 2h. To simulate stress after anesthesia, the animals were exposed to a single maternal separation for 3h at P10. 3-7days after exposure to etomidate the rats had increased hypothalamic NKCC1 mRNA and corticotropin releasing hormone (CRH) mRNA and decreased K+-2Cl- (KCC2) mRNA levels with greater changes in males. In rats neonatally exposed to both etomidate and maternal separation, these abnormalities persisted into adulthood. These animals also exhibited extended corticosterone responses to restraint stress with increases in total plasma corticosterone more robust in males, as well as behavioral abnormalities. Pretreatment with the NKCC1 inhibitor ameliorated most of these effects.ConclusionsPost-anesthesia stressors may exacerbate/unmask neurodevelopmental abnormalities even after a relatively short anesthetic with etomidate, leading to dysregulated stress response systems and neurobehavioral deficiencies in adulthood. Amelioration by bumetanide suggests a mechanistic role for etomidate-enhanced gamma-aminobutyric acid type A receptor-mediated depolarization in initiating long-lasting alterations in gene expression that are further potentiated by subsequent maternal separation.
| S-EPMC5492971 | biostudies-literature
Project description:Changes in DNA methylation, is one mechanism by which genes are regulated. Aberrant methylation can lead to gene dysregulation, such as inactivation of tumour suppressor genes, and is observed in all cancers. Gene dysregulation via aberrant DNA methylation may be an important contributor to disease outcomes. Importantly, these marks are malleable in response to environmental exposures and contribute to phenotypic plasticity in the context of a fixed genotype. Many studies suggest maternal exposures during pregnancy can have a profound impact on the epigenome and so determine gene expression patterns and health throughout the life-course. Studies of altered epigenetic marking are of profound importance for mechanistic understanding of the role of exposures on health but especially for studies of the developmental origins of health. Historically collected neonatal blood spot samples represent a rich resource in which methylation at birth could be measured decades after being sampled and methylation patterns associated with recorded disease outcomes. Here we aimed to test the feasibility that methylation could be assessed in historically collected blood spot samples and assess if the time since sample collection affected methylation patterns. The Newcastle Haematology biobank houses blood spots collected routinely from neonates 5-8 days after birth between the years 1984-1994 in the local region. Samples were selected from across the collection period and cross referenced with the Northern region Children's malignant disease registry in an aim to exclude samples from children who had gone on to have a malignancy during childhood. Genome-wide DNA methylation profiling of neonatal blood spots was assessed using the Illumina Infinium® MethylationEPIC BeadChip platform. Extraction yield DNA of sufficient quality and quantity for successful analysis of DNA methylation. Time since collection was not found to significantly influence methylation in this sample. Data from this study could be utilised in future case-controls studies to investigate the relationship between methylation patterns and birth and disease outcomes.
2024-12-13 | GSE211591 | GEO
Project description:Background: The adult mammalian heart has limited capacity for regeneration following injury, whereas the neonatal heart can readily regenerate within a short period after birth. To uncover the molecular mechanisms underlying neonatal heart regeneration, we compared the transcriptomes and epigenomes of regenerative and non-regenerative mouse hearts over a 7-day time period following myocardial infarction. Methods: RNA-Seq, H3K27ac ChIP-Seq and H3K27me3 ChIP-Seq were performed on ventricular samples from regenerative P1 or non-regenerative P8 mouse hearts at +1.5d, +3d and +7d after MI or Sham surgery to assemble the transcriptome, active chromatin and repressed chromatin landscapes during neonatal heart regeneration. Dynamic enhancer landscapes from mouse hearts during cardiac development were analyzed using data from ENCODE. Effects on cardiomyocyte proliferation and cardiac function from selected factors identified in this study were tested using BrdU/EdU pulse-labeling or mouse models coupled with immunohistochemistry and echocardiography. Results: By integrating gene expression profiles with histone marks associated with active or repressed chromatin, we identified transcriptional programs underlying neonatal heart regeneration and the blockade to regeneration in later life. Our results reveal a unique immune response in regenerative hearts and an embryonic cardiogenic gene program that remains active during neonatal heart regeneration. Among the unique immune factors and embryonic genes associated with cardiac regeneration, we identified Ccl24, which encodes a cytokine, and Igf2bp3, which encodes an RNA-binding protein, as previously unrecognized regulators of cardiomyocyte proliferation. Conclusions: Our data provide insights into the molecular basis of neonatal heart regeneration and identify genes that might be modulated to promote heart regeneration.
2019-07-15 | GSE123867 | GEO
Project description:PurposeTo assess the feasibility of ferumoxytol-enhanced anesthesia-free cardiac MRI in neonates and young infants for complex congenital heart disease (CHD).Materials and methodsWith Institutional Review Board approval, 21 consecutive neonates and young infants (1 day to 11 weeks old; median age of 3 days) who underwent a rapid two-sequence (MR angiography [MRA] and four-dimensional [4D] flow) MRI protocol with intravenous ferumoxytol without sedation (n = 17) or light sedation (n = 4) at 3 Tesla (T) (except one case at 1.5T) between June 2014 and February 2016 were retrospectively identified. Medical records were reviewed for indication, any complications, if further diagnostic imaging was performed after MRI, and surgical findings. Two radiologists scored the images in two sessions on a 5-point scale for overall image quality and delineation of various anatomical structures. Confidence interval of proportions for likelihood of requiring additional diagnostic imaging after MRI was determined. For the possibility of reducing the protocol to a single rapid sequence, Wilcoxon-rank sum test was used to assess whether 4D flow and MRA significantly differed in anatomical delineation.ResultsOne of 21 patients (4.8%, 80% confidence interval 0-11%) required additional imaging, a computed tomography angiography to assess lung parenchyma and peripheral pulmonary arteries. Only 1 of 13 patients (7.7%) with operative confirmation had a minor discrepancy between radiology and operative reports (80% confidence interval 0-17%). 4D flow was significantly superior to MRA (P < 0.05) for the evaluation of systemic arteries, valves, ventricular trabeculae, and overall quality. Using Cohen's kappa coefficient, there was good interobserver agreement for the evaluation of systemic arteries by 4D flow (κ = 0.782), and systemic veins and pulmonary arteries by MRA (κ > 0.6). Overall 4D flow measurements (mean κ = 0.64-0.74) had better internal agreement compared with MRA (mean κ = 0.30-0.64).ConclusionFerumoxytol-enhanced cardiac MRI, without anesthesia, is feasible for the evaluation of complex CHD in neonates and young infants, with a low likelihood of need for additional diagnostic studies. The decreased risk by avoiding anesthesia must be balanced against the potential for adverse reactions with ferumoxytol.Level of evidence2 J. MAGN. RESON. IMAGING 2017;45:1407-1418.
| S-EPMC5373922 | biostudies-literature