title: Fetal stress-mediated hypomethylation increases the brain susceptibility to hypoxic-ischemic injury in neonatal rats.
abstract: OBJECTIVE
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Center for Perinatal Biology, Division of Pharmacology, Department of Basic Sciences, Loma Linda University School of Medicine, Loma Linda, CA 92350, USA.
authors.forename: Yong
authors.initials: Y
authors.lastname: Li
authors.affiliation: Center for Perinatal Biology, Division of Pharmacology, Department of Basic Sciences, Loma Linda University School of Medicine, Loma Linda, CA 92350, USA.
authors.forename: Qingyi
authors.initials: Q
authors.lastname: Ma
authors.affiliation: Department of Psychology, Loma Linda University, Loma Linda, CA 92354, USA.
authors.forename: Shina
authors.initials: S
authors.lastname: Halavi
authors.affiliation: Center for Perinatal Biology, Division of Pharmacology, Department of Basic Sciences, Loma Linda University School of Medicine, Loma Linda, CA 92350, USA.
authors.forename: Katherine
authors.initials: K
authors.lastname: Concepcion
authors.affiliation: Department of Psychology, Loma Linda University, Loma Linda, CA 92354, USA.
authors.forename: Richard E
authors.initials: RE
authors.lastname: Hartman
authors.affiliation: Department of Pediatrics, Loma Linda University School of Medicine, Loma Linda, CA 92354, USA; Cell, Molecular and Developmental Biology Program, Department of Neuroscience, University of California, Riverside, CA 92521, USA.
authors.forename: Andre
authors.initials: A
authors.lastname: Obenaus
authors.affiliation: Center for Perinatal Biology, Division of Pharmacology, Department of Basic Sciences, Loma Linda University School of Medicine, Loma Linda, CA 92350, USA.
authors.forename: Daliao
authors.initials: D
authors.lastname: Xiao
authors.affiliation: Center for Perinatal Biology, Division of Pharmacology, Department of Basic Sciences, Loma Linda University School of Medicine, Loma Linda, CA 92350, USA. Electronic address: lzhang@llu.edu.
authors.forename: Lubo
authors.initials: L
authors.lastname: Zhang
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001921:Brain / Q000378:metabolism* / Q000473:pathology; D019175:DNA Methylation; D004198:Disease Susceptibility; D005260:Female; D005311:Fetal Hypoxia / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D020925:Hypoxia-Ischemia, Brain / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D011247:Pregnancy; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9
keywords: 5-aza-2′-deoxycytidine; DNA methylation; Fetal hypoxia; Hypoxia-inducible factor 1α; Hypoxic–ischemic brain injury