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 day 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.

IUGR increases chromatin-remodeling factor Brg1 expression and binding to GR exon 1.7 promoter in newborn male rat hippocampus

“…In our study, we found that UPI-induced IUGR increased Sp1 binding to GR exon 1.7 promoter concurrently with Brg1 binding and increased GR exon 1.7 expression. In contrast, IUGR induced by maternal hypoxia in neonatal rats led to decreased hippocampal Sp1 binding to GR exon 1.7 promoter in association with decreased GR and exon 1.7 mRNA variant expressions (14). Taken together, these data suggest that Sp1 binding to GR exon 1.7 promoter is necessary for GR exon 1.7 transcription.…”

“…The expression of the exon 1.7 variant is highly abundant in the hippocampus, but it is absent in other tissues (48). Exon 1.7 plays an important role in regulating hippocampus GR expression and programming the HPA axis sensitivity (14,48,50,77). Interestingly, UPI-induced IUGR specifically increases GR exon 1.7 mRNA variant expression in male rat pup hippocampus (34).…”

“…GR promoters contain many GCrich motifs that are the consensus sequences for Sp1 binding. Sp1 regulates GR gene expression through binding to the Sp binding site on GR promoters in the developing brain (14,68). Sp1 is generally a transcriptional activator (16,70) and enhances transcription by RNA pol II (56,61).…”

Gestational hypoxia and epigenetic programming of brain development disorders

“…Accumulating evidence from both human and animal studies indicates that epigenetic modifications serve as a memory of early life events and can induce long-term changes in gene expression profiles, which potentially result in disease in later life [8,13,14] (Figure 1). For example, in a recent study, epigenetic programming of the glucocorticoid receptor ( GR ) gene after maternal hypoxia was found to be related to the enhanced susceptibility of neonate hypoxic-ischemic encephalopathy (HIE) brain injury [15]. …”

“…Maternal hypoxia also delays neuronal migration and alters neurotransmitters expression during embryogenesis [18], subsequently compromising neuronal circuits and affecting neural organization in the brain tissue [19]. As a result, maternal hypoxia leads to increased susceptibility to seizures, epilepsy [20], and cerebral insults in affected offspring [15,19]. However, the molecular mechanisms of gestational hypoxia in the programming of brain disorders in postnatal life remain largely elusive.…”