Association of Prenatal Alcohol Exposure with Offspring DNA Methylation in Mammals: a Systematic Review of the Evidence

Background: Prenatal alcohol exposure (PAE) is associated with a range of adverse offspring neurodevelopmental outcomes. Several studies suggest that PAE modifies DNA methylation in offspring cells and tissues, providing evidence for a potential mechanistic link to Fetal Alcohol Spectrum Disorder (FASD). We systematically reviewed existing evidence on the extent to which maternal alcohol use during pregnancy is associated with offspring DNA methylation.

Methods: A systematic literature search was conducted across five online databases according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. PubMed, Web of Science, EMBASE, Google Scholar and CINAHL Databases were searched for articles relating to PAE in placental mammals. Data were extracted from each study and the Risk of Bias in Non-Randomized Studies of Interventions (ROBINS-I) was used to assess the potential for bias in human studies.

Results: Forty-three articles were identified for inclusion. Twenty-six animal studies and 16 human studies measured offspring DNA methylation in various tissues using candidate gene analysis, methylome-wide association studies (MWAS), or total nuclear DNA methylation content. PAE dose and timing varied between studies. Risk of bias was deemed high in nearly all human studies. There was insufficient evidence in human and animal studies to support global disruption of DNA methylation from PAE. Inconclusive evidence was found for hypomethylation at IGF2/H19 regions within somatic tissues. MWAS assessing PAE effects on offspring DNA methylation showed inconsistent evidence. There was some consistency in the relatively small number of MWAS conducted in populations with FASD. Meta-analyses could not be conducted due to significant heterogeneity between studies.

Conclusion: Considering heterogeneity in study design and potential for bias, evidence for an association between PAE and offspring DNA methylation was inconclusive. Some reproducible associations were observed in populations with FASD although the limited number of these studies warrants further research. Trail Registration: This review is registered with PROSPERO (registration number: CRD42020167686).