The influence of prenatal alcohol exposure and maternal diet on offspring DNA methylation: a cross-species study

Alcohol consumption in pregnancy can affect genome regulation in the developing offspring but results have been contradictory. We employed a physiologically relevant murine model of short-term moderate prenatal alcohol exposure (PAE) resembling common patterns of alcohol consumption in pregnancy. Moderate early PAE was sufficient to affect site-specific DNA methylation in new-born pups without altering behavioural outcomes in adult littermates. Whole genome-bisulphite sequencing of neonatal brain and liver revealed stochastic influence on DNA methylation that was mostly tissue-specific, with some perturbations likely originating as early as gastrulation. Methylation changes were enriched in non-coding genomic regions with regulatory potential indicative of broad effects of alcohol on genome regulation. Replication studies in human cohorts with fetal alcohol spectrum disorder suggested some effects were metastable at genes linked to disease-relevant traits including facial morphology, intelligence, educational attainment, autism, and schizophrenia. A maternal diet high in folate and choline protected against some of the damaging effects of PAE on DNA methylation. Our studies demonstrate that moderate early exposure is sufficient to affect fetal genome regulation even in the absence of overt phenotypic changes and highlight a role for preventative maternal dietary interventions.