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

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.

The association between prenatal alcohol consumption and preschool child stress system disturbance

“…These findings support previous research (based on maternal self‐report) (Pearson et al., 2015) that intrauterine alcohol exposure is a risk factor for an altered HPA axis development and provide the first evidence that meconium EtG can be used as an effective biomarker for such exposure. Additionally, our results support previous research findings that the EtG biomarker of intrauterine alcohol exposure can be used as a predictor of child development (Eichler et al., 2018; Frey et al., 2018).…”

“…The majority of the meconium (75%) is created during the last 8 weeks of pregnancy. Positive cut‐off for intrauterine alcohol exposure varies from study to study; in most studies, a minimum of 10 ng/g EtG (equivalent to the limit of detection) argues for fetal alcohol exposure during the third trimester (Bakdash et al., 2010; Eichler et al., 2018; Frey et al., 2018; Himes et al., 2015). Himes et al.…”

“…To examine the validity of EtG as a biomarker for intrauterine alcohol exposure, it is essential to check the correspondence with varying child developmental outcomes. Until now, there are only two studies which have found a correspondence between meconium EtG levels and impaired child brain development: meconium EtG levels were associated with adverse cognitive outcomes (Eichler et al., 2018) and distinct whole‐genome DNA methylation patterns in primary school children (Frey et al., 2018). Studies associating the meconium biomarkers with child neurobiological outcomes, that is HPA axis activity, are entirely missing.…”

Alcohol use in pregnancy and its impact on the mother and child

“…Whether epigenetic changes can be transmitted to subsequent generations, even without direct alcohol exposure, is an emerging question. Animal studies demonstrate transmission of epigenetic changes through at least three generations that were reversible through DNA methylation [170] and histone modifying inhibitors [171].…”

Quantitative genetics of gene expression and methylation in the chicken

“…Six of these genes (DPP10, PAPSS2, KLF12, MYLK, NSUN4 and DDX18) have previously been linked DNA methylation regulation (Cámara et al, 2011;Du et al, 2016;Shulha et al, 2012;Wang et al, 2014;Zhang et al, 2010). DPP10 and DDX18 have also been linked to neurological diseases, with DPP10 being associated with DNA methylation and ADHD (Heinrich et al, 2017), and adverse cognitive effects due to prenatal alcohol exposure (Frey et al, 2018), while DDX18 has been linked to opioid susceptibility (Cheng et al, 2020). The link between DNA methylation and cognition is interesting and will require further studies to be disentangled.…”