title: Fetal hypoxia increases vulnerability of hypoxic-ischemic brain injury in neonatal rats: role of glucocorticoid receptors.
abstract: Gestational hypoxia is a common stress to the fetal development and increases the risk of neonatal morbidity. The present study tested the hypothesis that fetal hypoxia results in heightened brain vulnerability to hypoxic-ischemic (HI) injury in neonatal rats via down-regulation of glucocorticoid receptor (GR) in the developing brain. Time-dated pregnant rats were exposed to hypoxia (10.5% O2) from days 15 to 21 of gestation. Brain HI injury was determined in day 10 pups. Maternal hypoxia resulted in asymmetric intrauterine growth restriction in the fetus. The brain HI injury was significantly increased in maternal hypoxia-treated pups as compared with the normoxia control in both males and females. Activation of brain GR by dexamethasone injection into the right lateral ventricle produced a concentration-dependent reduction of HI-induced brain injury in control pups. Maternal hypoxia significantly decreased GR mRNA and protein abundance in the fetal brain and neonatal hippocampus and abolished the dexamethasone-mediated neuroprotective effect in pup brains. This decreased GR expression was resulted from increased DNA methylation, decreased binding of transcription factors Egr-1 and Sp1 to GR gene exon 17 and 111 promoters, and reduced expression of GR exon 17 and 111 mRNA variants. The results demonstrate that gestational hypoxia causes epigenetic repression of GR gene expression in the developing brain resulting in the heightened brain vulnerability to HI injury in neonatal rats.
authors: Center for Perinatal Biology, Division of Pharmacology, Department of Basic Sciences, Loma Linda University School of Medicine, Loma Linda, CA 92350, USA.
authors: Pablo J
authors: PJ
authors: Gonzalez-Rodriguez
authors: Center for Perinatal Biology, Division of Pharmacology, Department of Basic Sciences, Loma Linda University School of Medicine, Loma Linda, CA 92350, USA.
authors: Fuxia
authors: F
authors: Xiong
authors: Center for Perinatal Biology, Division of Pharmacology, Department of Basic Sciences, Loma Linda University School of Medicine, Loma Linda, CA 92350, USA.
authors: Yong
authors: Y
authors: Li
authors: Center for Perinatal Biology, Division of Pharmacology, Department of Basic Sciences, Loma Linda University School of Medicine, Loma Linda, CA 92350, USA.
authors: Jianjun
authors: J
authors: Zhou
authors: 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: Lubo
authors: L
authors: Zhang
mesh_terms: D000367:Age Factors; D000818:Animals; D000831:Animals, Newborn; D001835:Body Weight; D001921:Brain / Q000254:growth & development / Q000378:metabolism; D020520:Brain Infarction / Q000209:etiology / Q000473:pathology; D019175:DNA Methylation; D003907:Dexamethasone / Q000627:therapeutic use; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005260:Female; D005311:Fetal Hypoxia / Q000150:complications* / Q000473:pathology; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects / Q000502:physiology*; D005938:Glucocorticoids / Q000627:therapeutic use; D020925:Hypoxia-Ischemia, Brain / Q000188:drug therapy / Q000209:etiology* / Q000378:metabolism*; D008297:Male; D011247:Pregnancy; D051381:Rats; D017207:Rats, Sprague-Dawley; D011965:Receptors, Glucocorticoid / Q000235:genetics / Q000378:metabolism*; D012737:Sex Factors
chemical_list: D005938:Glucocorticoids; D011965:Receptors, Glucocorticoid; D003907:Dexamethasone
keywords: Glucocorticoids; Hypoxia; Hypoxic–ischemic brain injury; Neonate