Prenatal Alcohol Exposure Is Associated With Adverse Cognitive Effects and Distinct Whole-Genome DNA Methylation Patterns in Primary School Children.

Stefan Frey,Johannes Kornhuber,Tamme W Goecke,Matthias W Beckmann,Yulia Golub,Hartmut Heinrich,Sabina Gallati,Gunther H Moll,Anna Eichler,Simone Wahl,Jennifer Kriebel,Peter A Fasching,Valeska Stonawski,Oliver Kratz

doi:10.3389/fnbeh.2018.00125

Abstract

Prenatal alcohol exposure (PAE) is known to elicit a broad range of systemic effects, including neurophysiological alterations that result in adverse behavioral and cognitive outcomes. However, molecular pathways underlying these long-term intrauterine effects remain to be investigated. Here, we tested a hypothesis that PAE may lead to epigenetic alterations to the DNA resulting in attentional and cognitive alterations of the children. We report the results of the study that included 156 primary school children of the Franconian Cognition and Emotion Studies (FRANCES) cohort which were tested for an objective marker of PAE, ethyl glucuronide (EtG) in meconium at birth. Thirty-two newborns were found to be exposed to alcohol with EtG values above 30 ng/g (EtG+). Previously we described PAE being associated with lower IQ and smaller amplitude of the event-related potential component P3 in go trials (Go-P3), which indicates a reduced capacity of attentional resources. Whole-genome methylation analysis of the buccal cell DNA revealed 193 differentially methylated genes in children with positive meconium EtG, that were clustered into groups involved in epigenetic modifications, neurodegeneration, neurodevelopment, axon guidance and neuronal excitability. Furthermore, we detected mediation effects of the methylation changes in DPP10 and SLC16A9 genes on the EtG related cognitive and attention-related deficits. Our results suggest that system-wide epigenetic changes are involved in long-term effects of PAE. In particular, we show an epigenetic mediation of PAE effects on cognition and attention-related processes.

Highlights

Adverse prenatal conditions have a potential to induce permanent changes in the developmental trajectories of the fetal brain
As a part of our Franconian Cognition and Emotion Studies (FRANCES) (Hein et al, 2014; Schneider et al, 2014; Eichler et al, 2016), we have studied attention and cognitive development of the 6- to 9-year-old children who were positive for ethyl glucuronide (EtG) in meconium at birth, a child-related biomarker of intrauterine alcohol exposure (Eichler et al, 2018)
We present a comprehensive genome-wide analysis of DNA methylation in buccal cells of children of the same FRANCES cohort both positive and negative for meconium EtG

Summary

Introduction

Adverse prenatal conditions have a potential to induce permanent changes in the developmental trajectories of the fetal brain. PAE is one of the most common in utero insults leading to a broad spectrum of structural, neurophysiological, cognitive and behavioral abnormalities (Hoyme et al, 2016). Whereas a clinical picture of FAS including pre- and postnatal growth retardation, facial dysmorphology, central nervous system alterations and intellectual impairment is well described, less is known about the impact of PAE that does not lead to the development of classic FAS. Cognitive and behavioral impairments and in particular attention deficits (Burden et al, 2005; Burger et al, 2011) in combination with hyperactivity, impulsivity (Mattson and Riley, 2000) and reduced inhibitory control have been described in children prenatally exposed to alcohol (Kingdon et al, 2016)

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Results

Conclusion