Fetal stress-mediated hypomethylation increases the brain susceptibility to hypoxic-ischemic injury in neonatal rats

Authors

Yong Li, Center for Perinatal Biology, Division of Pharmacology, Department of Basic Sciences, Loma Linda University School of Medicine, Loma Linda, CA 92350, USA.Follow
Qingyi Ma, Center for Perinatal Biology, Division of Pharmacology, Department of Basic Sciences, Loma Linda University School of Medicine, Loma Linda, CA 92350, USA.Follow
Shina Halavi, Department of Psychology, Loma Linda University, Loma Linda, CA 92354, USA.
Katherine Concepcion, Center for Perinatal Biology, Division of Pharmacology, Department of Basic Sciences, Loma Linda University School of Medicine, Loma Linda, CA 92350, USA.Follow
Richard E. Hartman, Department of Psychology, Loma Linda University, Loma Linda, CA 92354, USA.Follow
Andre Obenaus, 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.Follow
Daliao Xiao, Center for Perinatal Biology, Division of Pharmacology, Department of Basic Sciences, Loma Linda University School of Medicine, Loma Linda, CA 92350, USA.Follow
Lubo Zhang, Center for Perinatal Biology, Division of Pharmacology, Department of Basic Sciences, Loma Linda University School of Medicine, Loma Linda, CA 92350, USA.Follow

Document Type

Article

Publication Date

1-1-2016

Publication Title

Experimental neurology

E-ISSN

1090-2430

Abstract

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.

Volume

275 Pt 1

First Page

1

Last Page

10

DOI

10.1016/j.expneurol.2015.10.007

PubMed ID

26597542

Recommended Citation

Li, Yong; Ma, Qingyi; Halavi, Shina; Concepcion, Katherine; Hartman, Richard E.; Obenaus, Andre; Xiao, Daliao; and Zhang, Lubo, "Fetal stress-mediated hypomethylation increases the brain susceptibility to hypoxic-ischemic injury in neonatal rats" (2016). Loma Linda University Faculty Publications. 341.
https://scholarsrepository.llu.edu/fac_pubs/341