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
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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