Your browser doesn't support javascript.
loading
Show: 20 | 50 | 100
Results 1 - 10 de 10
Filter
Add more filters










Publication year range
1.
Article in English | MEDLINE | ID: mdl-34615670

ABSTRACT

Here we describe for the first time double paternal uniparental isodisomy (iUPD) 7 and 15 in a baby boy with features in the Beckwith-Wiedemann syndrome spectrum (BWSp) (placentomegaly, hyperinsulinism, enlarged viscera, hemangiomas, and earlobe creases) in addition to conjugated hyperbilirubinemia. His phenotype was also reminiscent of genome-wide paternal uniparental isodisomy. We discuss the most likely origin of the UPDs: a maternal double monosomy 7 and 15 rescued by duplication of the paternal chromosomes after fertilization. So far, paternal UPD7 is not associated with an abnormal phenotype, whereas paternal UPD15 causes Angelman syndrome. Methylation analysis for other clinically relevant imprinting disorders, including BWSp, was normal. Therefore, we hypothesized that the double UPD affected other imprinted genes. To look for such effects, patient fibroblast RNA was isolated and analyzed for differential expression compared to six controls. We did not find apparent transcription differences in imprinted genes outside Chromosomes 7 and 15 in patient fibroblast. PEG10 (7q21.3) was the only paternally imprinted gene on these chromosomes up-regulated beyond double-dose expectation (sixfold). We speculate that a high PEG10 level could have a growth-promoting effect as his phenotype was not related to aberrations in BWS locus on 11p15.5 after DNA, RNA, and methylation testing. However, many genes in gene sets associated with growth were up-regulated. This case broadens the phenotypic spectrum of UPDs but does not show evidence of involvement of an imprinted gene network.


Subject(s)
Beckwith-Wiedemann Syndrome , Beckwith-Wiedemann Syndrome/genetics , DNA Methylation , Genomic Imprinting , Humans , Male , Phenotype , Uniparental Disomy
2.
J Perinat Med ; 47(1): 114-124, 2018 Dec 19.
Article in English | MEDLINE | ID: mdl-30020889

ABSTRACT

Background 8-Oxoguanine DNA-glycosylase 1 (OGG1) and mutY DNA glycosylase (MUTYH) are crucial in the repair of the oxidative DNA lesion 7,8-dihydro-8-oxoguanine caused by hypoxia-reoxygenation injury. Our objective was to compare the gene expression changes after hypoxia-reoxygenation in neonatal Ogg1-Mutyh double knockout mice (OM) and wildtype mice (WT), and study the gene response in OM after hyperoxic reoxygenation compared to normoxic. Methods Postnatal day 7 mice were subjected to 2 h of hypoxia (8% O2) followed by reoxygenation in either 60% O2 or air, and sacrificed right after completed reoxygenation (T0h) or after 72 h (T72h). The gene expression of 44 a priori selected genes was examined in the hippocampus/striatum and lung. Results We found that OM had an altered gene response compared to WT in 21 genes in the brain and 24 genes in the lung. OM had a lower expression than WT of inflammatory genes in the brain at T0h, and higher expression at T72h in both the brain and lung. In the lung of OM, five genes were differentially expressed after hyperoxic reoxygenation compared to normoxic. Conclusion For the first time, we report that Ogg1 and Mutyh in combination protect against late inflammatory gene activation in the hippocampus/striatum and lung after neonatal hypoxia-reoxygenation.


Subject(s)
DNA Glycosylases/metabolism , Hyperoxia , Hypoxia , Oxidative Stress/physiology , Animals , Animals, Newborn , DNA Repair , Female , Gene Expression Profiling/methods , Hippocampus/metabolism , Hyperoxia/etiology , Hyperoxia/metabolism , Hypoxia/metabolism , Hypoxia/therapy , Lung/metabolism , Mice , Mice, Knockout , Oxygen/administration & dosage , Pregnancy
3.
Neonatology ; 111(1): 45-54, 2017.
Article in English | MEDLINE | ID: mdl-27529351

ABSTRACT

BACKGROUND: One out of four children with neonatal asphyxia has lung involvement. Still, there has been little research on injury mechanisms of hypoxia-reoxygenation in the neonatal lung. OBJECTIVES: To make a temporal profile of the gene expression changes of 44 a priori selected genes after hypoxia-reoxygenation in the newborn mouse lung, and to compare the changes after hyperoxic and normoxic reoxygenation. METHODS: Postnatal day 7 mice were randomized to 2-hour hypoxia (8% O2) and 30-min reoxygenation in either 60% O2 or air. After 0-72 h of observation, gene expression changes and protein concentrations in whole lung homogenates were examined. RESULTS: Immediately after completed reoxygenation, 7 genes of mediators of inflammation were downregulated, and there was an antiapoptotic gene expression pattern. Three DNA glycosylases were downregulated, while genes involved in cell cycle renewal indicated both increased and decreased cell cycle arrest. Sod1 (T2.5h median H60: 1.01, H21: 0.88, p = 0.005; T5h median H60: 1.04, H21: 0.85, p = 0.038) and Il1b (T0h median H60: 0.86, H21: 1.08, p = 0.021) were significantly differentially expressed when comparing hyperoxic and normoxic reoxygenation. CONCLUSION: In this newborn mouse lung hypoxia-reoxygenation model, we found downregulation of genes of mediators of inflammation, an antiapoptotic gene expression pattern, and downregulation of DNA glycosylases. Sod1 and Il1b were significantly differentially expressed when comparing reoxygenation using 60% O2 with air.


Subject(s)
Asphyxia Neonatorum/genetics , DNA Glycosylases/genetics , Interleukin-1beta/genetics , Oxygen/therapeutic use , Superoxide Dismutase-1/genetics , Transcriptome/genetics , Animals , Animals, Newborn , Apoptosis/genetics , Asphyxia Neonatorum/therapy , DNA Repair , Disease Models, Animal , Hyperoxia/metabolism , Hypoxia/metabolism , Lung/metabolism , Mice , Mice, Inbred C57BL , Random Allocation
4.
Pediatr Res ; 77(2): 326-33, 2015 Feb.
Article in English | MEDLINE | ID: mdl-25423075

ABSTRACT

BACKGROUND: Hyperoxic reoxygenation following hypoxia increases the expression of inflammatory genes in the neonatal mouse brain. We have therefore compared the temporal profile of 44 a priori selected genes after hypoxia and hyperoxic or normoxic reoxygenation. METHODS: Postnatal day 7 mice were subjected to 2 h of hypoxia (8% O2) and 30 min reoxygenation with 60% or 21% O2. After 0 to 72 h observation, mRNA and protein were examined in the hippocampus and striatum. RESULTS: There were significantly higher gene expression changes in six genes after hyperoxic compared to normoxic reoxygenation. Three genes had a generally higher expression throughout the observation period: the inflammatory genes Hmox1 (mean difference: 0.52, 95% confidence interval (CI): 0.15-1.01) and Tgfb1 (mean difference: 0.099, CI: 0.003-0.194), and the transcription factor Nfkb1 (mean difference: 0.049, CI: 0.011-0.087). The inflammatory genes Cxcl10 and Il1b, and the DNA repair gene Neil3, had a higher gene expression change after hyperoxic reoxygenation at one time point only. Nineteen genes involved in inflammation, transcription regulation, apoptosis, angiogenesis, and glucose transport had significantly different gene expression changes with time in all intervention animals. CONCLUSION: We confirm that hyperoxic reoxygenation induces a stronger inflammatory gene response than reoxygenation with air.


Subject(s)
Corpus Striatum/metabolism , Gene Expression Regulation/physiology , Hippocampus/metabolism , Hyperoxia/metabolism , Hypoxia/physiopathology , Inflammation/metabolism , Oxygen/metabolism , Analysis of Variance , Animals , Animals, Newborn , Apoptosis/genetics , Gene Expression Profiling , Heme Oxygenase-1/metabolism , Inflammation/genetics , Membrane Proteins/metabolism , Mice , NF-kappa B p50 Subunit/metabolism , Oxygen/administration & dosage , Real-Time Polymerase Chain Reaction , Reverse Transcriptase Polymerase Chain Reaction , Transforming Growth Factor beta1/metabolism
5.
Invest Ophthalmol Vis Sci ; 55(3): 1393-401, 2014 Mar 10.
Article in English | MEDLINE | ID: mdl-24458145

ABSTRACT

PURPOSE: Resuscitation of newborns is one of the most frequent procedures in neonatal medicine. The use of supplementary oxygen during resuscitation of the asphyxiated newborn has been shown to be detrimental to vulnerable tissues. We wanted to assess transcriptional changes in ocular tissue after the acute use of oxygen in the delivery room in a hypoxia-reoxygenation model of the newborn mouse. METHODS: C57BL/6 mice (n = 57), postnatal day 7, were randomized to receive either 120 minutes of hypoxia, at 8% O2, followed by 30 minutes of reoxygenation with 21, 40, 60, or 100% O2 or to normoxia followed by 30 minutes of 21% or 100% O2. Whole ocular homogenates were analyzed by Affymetrix 750k expression array, and RT-PCR was performed for validation. Bayesian analysis of variance for microarray data (BAMarray) was used to identify single significant genes, and Gene Set Enrichment Analysis (GSEA) was applied to reveal significant pathway systems. RESULTS: In total, ∼ 92% of the gene expression changes were altered in response to reoxygenation with 60% or 100% O2 compared to expression at the lower percentages of 21% and 40%. After 100% O2 treatment, genes involved in inflammation (Ccl12), angiogenesis (Igfr1, Stat3), and metabolism (Hk2) were upregulated. Pathway analyses after hypoxia-reoxygenation revealed significant alterations of six pathways which included apoptosis, TGF-beta signaling, oxidative phosphorylation, voltage-gated calcium channel complex, mitochondrion, and regulation of RAS protein signal transduction. CONCLUSIONS: Hypoxia-reoxygenation can induce immediate transcriptional responses in ocular tissue involving inflammation, angiogenesis, energy failure, and Ras signaling.


Subject(s)
Gene Expression Regulation, Developmental , Hyperoxia/genetics , Hypoxia/genetics , Monocyte Chemoattractant Proteins/genetics , Oxidative Stress/genetics , RNA/genetics , STAT3 Transcription Factor/genetics , Animals , Animals, Newborn , Disease Models, Animal , Hyperoxia/metabolism , Hypoxia/metabolism , Mice , Mice, Inbred C57BL , Microarray Analysis , Monocyte Chemoattractant Proteins/biosynthesis , Real-Time Polymerase Chain Reaction , STAT3 Transcription Factor/biosynthesis , Signal Transduction
6.
Pediatr Res ; 75(4): 517-26, 2014 Apr.
Article in English | MEDLINE | ID: mdl-24375083

ABSTRACT

BACKGROUND: Supplemental oxygen used during resuscitation can be detrimental to the newborn brain. The aim was to determine how different oxygen therapies affect gene transcription in a hypoxia-reoxygenation model. METHODS: C57BL/6 mice (n = 56), postnatal day 7, were randomized either to 120 min of hypoxia 8% O2 followed by 30 min of reoxygenation with 21, 40, 60, or 100% O2, or to normoxia followed by 30 min of 21 or 100% O2. Affymetrix 750k expression array was applied with RT-PCR used for validation. Histopathology and immunohistochemistry 3 d after hypoxia-reoxygenation compared groups reoxygenated with 21 or 100% O2 with normoxic controls (n = 22). RESULTS: In total, ~81% of the gene expression changes were altered in response to reoxygenation with 60 or 100% O2 and constituted many inflammatory-responsive genes (i.e., C5ar2, Stat3, and Ccl12). Oxidative phosphorylation was downregulated after 60 or 100% O2. Iba1(+) cells were significantly increased in the striatum and hippocampal CA1 after both 21 and 100% O2. CONCLUSION: In the present model, hypoxia-reoxygenation induces microglial accumulation in subregions of the brain. The transcriptional changes dominating after applying hyperoxic reoxygenation regimes include upregulating genes related to inflammatory responses and suppressing the oxidative phosphorylation pathway.


Subject(s)
Brain/metabolism , Gene Expression Profiling , Hyperoxia/metabolism , Hypoxia/metabolism , Inflammation/metabolism , Transcriptome , Animals , Animals, Newborn , Cluster Analysis , Energy Metabolism/genetics , Mice , Mice, Inbred C57BL , Oligonucleotide Array Sequence Analysis
7.
PLoS One ; 8(10): e78585, 2013.
Article in English | MEDLINE | ID: mdl-24194948

ABSTRACT

RATIONALE: Bronchopulmonary dysplasia is one of the most serious complications observed in premature infants. Thanks to microarray technique, expression of nearly all human genes can be reliably evaluated. OBJECTIVE: To compare whole genome expression in the first month of life in groups of infants with and without bronchopulmonary dysplasia. METHODS: 111 newborns were included in the study. The mean birth weight was 1029 g (SD:290), and the mean gestational age was 27.8 weeks (SD:2.5). Blood samples were drawn from the study participants on the 5th, 14th and 28th day of life. The mRNA samples were evaluated for gene expression with the use of GeneChip® Human Gene 1.0 ST microarrays. The infants were divided into two groups: bronchopulmonary dysplasia (n=68) and control (n=43). RESULTS: Overall 2086 genes were differentially expressed on the day 5, only 324 on the day 14 and 3498 on the day 28. Based on pathway enrichment analysis we found that the cell cycle pathway was up-regulated in the bronchopulmonary dysplasia group. The activation of this pathway does not seem to be related with the maturity of the infant. Four pathways related to inflammatory response were continuously on the 5(th), 14(th) and 28(th) day of life down-regulated in the bronchopulmonary dysplasia group. However, the expression of genes depended on both factors: immaturity and disease severity. The most significantly down-regulated pathway was the T cell receptor signaling pathway. CONCLUSION: The results of the whole genome expression study revealed alteration of the expression of nearly 10% of the genome in bronchopulmonary dysplasia patients.


Subject(s)
Bronchopulmonary Dysplasia/metabolism , Gene Expression Regulation, Developmental/genetics , Genome, Human/genetics , Infant, Premature/metabolism , Bronchopulmonary Dysplasia/genetics , Gene Expression Profiling , Humans , Infant, Newborn , Oligonucleotide Array Sequence Analysis , Real-Time Polymerase Chain Reaction
8.
Pediatr Res ; 74(5): 536-44, 2013 Nov.
Article in English | MEDLINE | ID: mdl-23999071

ABSTRACT

BACKGROUND: The use of oxygen in acute treatment of asphyxiated term newborns is associated with increased mortality. It is unclear how hyperoxic reoxygenation after hypoxia affects transcriptional changes in the newborn lung. METHODS: On postnatal day 7, C57BL/6 mice (n = 62) were randomized to 120-min hypoxia (fraction of inspired oxygen (FiO2) 0.08) or normoxia. The hypoxia group was further randomized to reoxygenation for 30 min with FiO2 0.21, 0.40, 0.60, or 1.00, and the normoxia group to FiO2 0.21 or 1.00. Transcriptome profiling was performed on homogenized lung tissue using the Affymetrix 750k expression array, and validation was carried out by real-time polymerase chain reaction and enzyme-linked immunosorbent assay. RESULTS: The hypoxia-reoxygenation model induced hypoxia-inducible factor 1 (HIF-1) targets like Vegfc, Adm, and Aqp1. In total, ~70% of the significantly differentially expressed genes were detected in the two high hyperoxic groups (FiO2 0.60 and 1.00). Reoxygenation with 100% oxygen after hypoxia uniquely upregulated Gadd45g, Dusp1, Peg3, and Tgm2. Pathway analysis identified mammalian target of rapamycin (mTOR) signaling pathway, DNA repair, c-jun N-terminal kinase (JNK)-pathway regulation, and cell cycle after hyperoxic reoxygenation was applied. CONCLUSION: Acute hypoxia induces HIF-1 targets independent of the reoxygenation regime applied. Hyperoxic reoxygenation affects pathways regulating cell growth and survival. DNA-damage-responsive genes are restricted to reoxygenation with 100% oxygen.


Subject(s)
Animals, Newborn/metabolism , Gene Expression Regulation/drug effects , Hypoxia/therapy , Lung/metabolism , Oxygen/adverse effects , Signal Transduction/drug effects , Animals , Animals, Newborn/genetics , Cluster Analysis , DNA Primers/genetics , DNA Repair/drug effects , Enzyme-Linked Immunosorbent Assay , Gene Expression Profiling , Linear Models , MAP Kinase Signaling System/drug effects , MAP Kinase Signaling System/genetics , Mice , Mice, Inbred C57BL , Microarray Analysis , Oxygen/therapeutic use , Real-Time Polymerase Chain Reaction , Signal Transduction/genetics , TOR Serine-Threonine Kinases/metabolism
9.
Pediatr Res ; 73(4 Pt 1): 476-83, 2013 Apr.
Article in English | MEDLINE | ID: mdl-23269122

ABSTRACT

BACKGROUND: Retinopathy of prematurity (ROP) is one of the most common preventable causes of blindness and impaired vision among children in developed countries. The aim of the study was to compare whole-genome expression in the first month of life in groups of infants with and without ROP. METHODS: Blood samples were drawn from 111 newborns with a mean gestational age of 27.8 wk on the 5th, 14th, and 28th day of life (DOL). The mRNA samples were evaluated for gene expression with the use of human whole-genome microarrays. The infants were divided into two groups: no ROP (n = 61) and ROP (n = 50). RESULTS: Overall, 794 genes were differentially expressed on the 5th DOL, 1,077 on the 14th DOL, and 3,223 on the 28th DOL. In each of the three time points during the first month of life, more genes were underexpressed than overexpressed in the ROP group. Fold change (FC), which was used in analysis of gene expression data, ranged between 1.0 and 1.5 in the majority of genes differentially expressed. CONCLUSION: Pathway enrichment analysis revealed that genes in four pathways related to inflammatory response were consistently downregulated due to the following variables: ROP and gestational age.


Subject(s)
Gene Expression Profiling , Infant, Premature , RNA, Messenger/blood , Retinopathy of Prematurity/genetics , Analysis of Variance , Case-Control Studies , Chi-Square Distribution , Female , Gene Expression Profiling/methods , Gene Expression Regulation, Developmental , Genetic Markers , Genetic Predisposition to Disease , Genome-Wide Association Study , Gestational Age , Humans , Infant, Extremely Premature/blood , Infant, Newborn , Infant, Premature/blood , Inflammation/genetics , Intensive Care Units, Neonatal , Linear Models , Male , Oligonucleotide Array Sequence Analysis , Phenotype , Principal Component Analysis , Prospective Studies , Real-Time Polymerase Chain Reaction , Reproducibility of Results , Retinopathy of Prematurity/diagnosis , Risk Factors , Severity of Illness Index
10.
Neonatology ; 101(4): 315-25, 2012.
Article in English | MEDLINE | ID: mdl-22940621

ABSTRACT

In this review oxygenation and hyperoxic injury of newborn infants are described through molecular and genetic levels. Protection and repair mechanisms that may be important for a new understanding of oxidative stress in the newborn are discussed. The research summarized in this article represents a basis for the reduced oxygen supplementation and oxidative load of newborn babies, especially since the turn of the century. The mechanisms discussed may also contribute to an understanding of why hyperoxic resuscitation of the newborn may damage DNA and affect its repair, thus increasing the risk that it may be carcinogenic. Today, term babies should be resuscitated with air rather than 100% oxygen and very and extremely low birth weight infants in need of stabilization or resuscitation at birth should be administered initially 21-30% oxygen and the level should be titrated according to the response, preferably measured by pulse oximetry. In the postnatal period the oxygen saturation should be targeted low <95%; however, saturations between 85 and 89% seem to increase mortality. The optimal oxygen saturation target for these infants postnatally is still unknown.


Subject(s)
Infant, Newborn, Diseases/therapy , Oxygen Inhalation Therapy/adverse effects , Ventilator-Induced Lung Injury/etiology , Ventilator-Induced Lung Injury/genetics , DNA Damage/physiology , DNA Repair/physiology , Genomic Instability/drug effects , Genomic Instability/physiology , Humans , Hyperoxia/complications , Hyperoxia/etiology , Hyperoxia/genetics , Hyperoxia/metabolism , Infant, Newborn , Infant, Newborn, Diseases/genetics , Infant, Newborn, Diseases/metabolism , Models, Biological , Oxygen/pharmacology , Oxygen/toxicity , Oxygen Inhalation Therapy/methods , Ventilator-Induced Lung Injury/metabolism
SELECTION OF CITATIONS
SEARCH DETAIL
...