Association of prenatal alcohol exposure with offspring DNA methylation in mammals: a systematic review of the evidence

Abstract

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).

Prenatal alcohol exposure results in brain region- and sex-specific changes in circHomer1 expression in adult mouse brain

“…Expression of circHomer1 was intermediate in adult occipital cortex and hippocampus, with the lowest levels detected in adult SAC cerebellum (Figure 2A). Previous studies have shown H19 is a prenatal stage-enriched lncRNA important for embryogenesis (Poirier et al, 1991;Gabory et al, 2009;Li et al, 2019) and previously implicated in FASD (Marjonen et al, 2017(Marjonen et al, , 2018Bestry et al, 2022). However, its expression was still detectable in the adult brain in our control SAC brain samples, with higher levels in the cerebellum and lower expression in the adult frontal cortex (Figure 2B), which is the opposite of what was observed for circHomer1.…”

“…Interestingly, H19 has been reported to have sex-specific expression and to be differentially affected by estrogen and androgen treatment (Sun et al, 2015;Basak et al, 2018;Ozgur and Gezer, 2020;Li T. et al, 2021). Moreover, H19 has been previously linked with changes in head circumference in FASD and reported to be epigenetically altered in various tissues (Marjonen et al, 2017(Marjonen et al, , 2018Bestry et al, 2022). Taken together, this allows us to hypothesize that PAE could induce epigenetic changes in the H19 locus in a sex-specific manner, which could result in opposing changes in circHomer1 expression.…”

“…This in turn could result in relatively higher levels of H19, which can in turn down-regulate circHomer1 expression in adult animals following PAE. However, additional research will be needed to further explore such a potential mechanism, especially given the many reported mechanisms of action for H19 (Bestry et al, 2022). Moreover, the modest increases in H19 and reductions in Eif4a3 mRNA observed in adult male hippocampus as a result of PAE were not significant, thus allowing for other potential mechanisms to explain the observed changes in circHomer1 in this brain region.…”

“…Focusing on factors that can control circHomer1 biogenesis, we have reported that the RNA-binding protein (RBP) eukaryotic initiation factor 4A-III (EIF4A3), a member of the exon junction complex important for brain development and synaptic function (Giorgi et al, 2007;Mao et al, 2016), is able to positively regulate circHomer1 expression. A previous study suggested that EIF4A3 activity can be inhibited via its binding to H19 (Han et al, 2016), an imprinted embryonic brain-enriched lncRNA previously shown to be epigenetically altered following PAE and linked to FASD-associated changes in head circumference (Marjonen et al, 2017(Marjonen et al, , 2018Zhong et al, 2021;Bestry et al, 2022).…”

DNA methylation in diabetic retinopathy: pathogenetic role and potential therapeutic targets

“…Folic acid (FA) is a dietary methyl donor for DNA methylation [133], while vitamin B12 is a cofactor involved in the process of transferring the methyl group from FA to DNA [134]. FA has been widely used in the clinic for DR treatment, while studies suggest that low FA levels can result in both hypomethylation and hypermethylation, leading to misregulation of DNA methylation [27,135].…”