Fetal stress-mediated hypomethylation increases the brain susceptibility to hypoxic–ischemic injury in neonatal rats
Autor: | Lubo Zhang, Qingyi Ma, Richard E. Hartman, Andre Obenaus, Yong Li, Shina Halavi, Daliao Xiao, Katherine R. Concepcion |
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Rok vydání: | 2016 |
Předmět: |
Male
0301 basic medicine Pathology Reproductive health and childbirth Matrix metalloproteinase Hypoxia-inducible factor 1 alpha Rats Sprague-Dawley 0302 clinical medicine Pregnancy Infant Mortality 5-aza-2 '-deoxycytidine Psychology Pediatric DNA methylation Brain Stroke Matrix Metalloproteinase 9 Neurology Hypoxia-Ischemia Brain Matrix Metalloproteinase 2 Gestation Female Hypoxia-Inducible Factor 1 Disease Susceptibility medicine.symptom 5-aza-2′-deoxycytidine medicine.medical_specialty Physical Injury - Accidents and Adverse Effects 1.1 Normal biological development and functioning Clinical Sciences Biology alpha Subunit Fetal Hypoxia Article 03 medical and health sciences Developmental Neuroscience Underpinning research In vivo Internal medicine Hypoxia-Ischemia medicine Hypoxia-inducible factor 1α Animals Hypoxic-ischemic brain injury Fetus Neurology & Neurosurgery Prevention Neurosciences Perinatal Period - Conditions Originating in Perinatal Period DNA Methylation Hypoxia (medical) Newborn Hypoxia-Inducible Factor 1 alpha Subunit medicine.disease Brain Disorders Rats 030104 developmental biology Endocrinology Animals Newborn Hypoxic–ischemic brain injury Sprague-Dawley 030217 neurology & neurosurgery DNA hypomethylation |
Zdroj: | Experimental neurology, vol 275 Pt 1, iss 0 1 |
ISSN: | 0014-4886 |
Popis: | Background and purpose Fetal hypoxia increases brain susceptibility to hypoxic–ischemic (HI) injury in neonatal rats. Yet mechanisms remain elusive. The present study tested the hypothesis that DNA hypomethylation plays a role in fetal stress-induced increase in neonatal HI brain injury. Methods Pregnant rats were exposed to hypoxia (10.5% O2) from days 15 to 21 of gestation and DNA methylation was determined in the developing brain. In addition, 5-aza-2′-deoxycytidine (5-Aza) was administered in day 7 pups brains and the HI treatment was conducted in day 10 pups. Brain injury was determined by in vivo MRI 48 h after the HI treatment and neurobehavioral function was evaluated 6 weeks after the HI treatment. Results Fetal hypoxia resulted in DNA hypomethylation in the developing brain, which persisted into 30-day old animals after birth. The treatment of neonatal brains with 5-Aza induced similar hypomethylation patterns. Of importance, the 5-Aza treatment significantly increased HI-induced brain injury and worsened neurobehavioral function recovery six weeks after the HI-treatment. In addition, 5-Aza significantly increased HIF-1α mRNA and protein abundance as well as matrix metalloproteinase (MMP)-2 and MMP-9, but decreased MMP-13 protein abundance in neonatal brains. Consistent with the 5-Aza treatment, hypoxia resulted in significantly increased expression of HIF-1α in both fetal and neonatal brains. Inhibition of HIF-1α blocked 5-Aza-mediated changes in MMPs and abrogated 5-Aza-induced increase in HI-mediated brain injury. Conclusion The results suggest that fetal stress-mediated DNA hypomethylation in the developing brain causes programming of hypoxic–ischemic sensitive phenotype in the brain and increases the susceptibility of neonatal brain to hypoxic–ischemic injury in a HIF-1α-dependent manner. |
Databáze: | OpenAIRE |
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