Altered neurodevelopmental DNA methylation status after fetal growth restriction with brain-sparing

Abstract

It is under debate how preferential perfusion of the brain (brain-sparing) in fetal growth restriction (FGR) relates to long-term neurodevelopmental outcome. Epigenetic modification of neurotrophic genes by altered fetal oxygenation may be involved. To explore this theory, we performed a follow-up study of 21 FGR children, in whom we prospectively measured the prenatal cerebroplacental ratio (CPR) with Doppler sonography. At 4 years of age, we tested their neurodevelopmental outcome using the Wechsler Preschool and Primary Scale of Intelligence, the Child Behavior Checklist, and the Behavior Rating Inventory of Executive Function. In addition, we collected their buccal DNA to determine the methylation status at predefined genetic regions within the genes hypoxia-inducible factor-1 alpha (HIF1A), vascular endothelial growth factor A (VEGFA), erythropoietin (EPO), EPO-receptor (EPOR), brain-derived neurotrophic factor (BDNF), and neurotrophic tyrosine kinase, receptor, type 2 (NTRK2) by pyrosequencing. We found that FGR children with fetal brain-sparing (CPR <1, n = 8) demonstrated a trend (0.05 < p < 0.1) toward hypermethylation of HIF1A and VEGFA at their hypoxia-response element (HRE) compared with FGR children without fetal brain-sparing. Moreover, in cases with fetal brain-sparing, we observed statistically significant hypermethylation at a binding site for cyclic adenosine monophophate response element binding protein (CREB) of BDNF promoter exon 4 and hypomethylation at an HRE located within the NTRK2 promoter (both p <0.05). Hypermethylation of VEGFA was associated with a poorer Performance Intelligence Quotient, while hypermethylation of BDNF was associated with better inhibitory self-control (both p <0.05). These results led us to formulate the hypothesis that early oxygen-dependent epigenetic alterations due to hemodynamic alterations in FGR may be associated with altered neurodevelopmental outcome in later life. We recommend further studies to test this hypothesis.

[Retracted] Helicid Improves Lipopolysaccharide‐Induced Apoptosis of C6 Cells by Regulating SH2D5 DNA Methylation via the CytC/Caspase9/Caspase3 Signaling Pathway

“…It has been confirmed that BDNF is involved in depression-related behavioral phenomena and the therapeutic effect of antidepressants. The higher degree of CpG methylation of the BDNF promoter region is associated with a significant decrease in the synthesis of this factor in neurons [ 38 ]. In addition, it has been confirmed that the methylation levels of the BDNF promoter are elevated in patients with depressive symptoms and those with suicidal ideation.…”

Congenital heart defects in monochorionic twin pregnancy complicated by selective fetal growth restriction

“…It is already known that at 11–13 weeks, intertwin discordance in the crown–rump length can exceed 20%, with a risk of fetal demise of 70% for the small twin 21 . Similarly, low oxygenation, as demonstrated previously in the context of neurodevelopment in singleton pregnancy with fetal growth restriction and brain sparing 22 , could cause epigenetic modification via DNA methylation or expression of microRNAs in early cardiogenesis, thereby altering gene regulation. Epigenetic analysis identified differentially methylated regions in the promoters of genes involved in cardiac development and lateralization in monozygotic twins discordant for CHD 23–25 .…”

Association of amniotic fluid Neurotrophins levels with intrauterine growth restriction

“…Richter et al observed altered methylations in the neurodevelopmental DNA among fetal growth restricted fetuses that were subject to brain-sparing. 19 Specifically, the authors reported significant hypermethylation at a binding site for cyclic adenosine monophophate response element binding protein (CREB) of BDNF promoter exon 4 and hypomethylation at an HRE located within the neurotrophic tyrosine kinase, receptor, type 2 (NTRK2) promoter.…”