Maternal consumption of alcohol during pregnancy is associated with structural and functional abnormalities of the central nervous system in the offspring however the underlying mechanisms are not fully understood. We used an inbred C57BL/6J mouse model of early gestational ethanol exposure that is equivalent, developmentally, to the first 3-4 weeks of pregnancy in humans to examine the long-term consequences on gene expression and epigenetic state in the hippocampus.
Solute carrier family 17 member 6 (Slc17a6), which encodes vesicular glutamate transporter 2 (VGLUT2), was significantly up-regulated in the hippocampi of adult ethanol-exposed male offspring. Transcriptional activation was associated with changes in both promoter DNA methylation and histone H3 lysine 4 trimethylation, a mark of active chromatin. Several ethanol-sensitive microRNAs were also identified in the hippocampus, one of which was shown to specifically interact with Slc17a6, revealing an additional level of post-transcriptional control. A significant correlation between microRNA expression in the hippocampus and serum of ethanol-exposed offspring was also observed.
Prenatal ethanol exposure has complex transcriptional and post-transcriptional effects on Slc17a6 (VGLUT2) expression in the mouse hippocampus. Altered epigenetic and microRNA-mediated regulation of glutamate neurotransmission in the hippocampus could contribute to the cognitive and behavioural phenotypes observed in fetal alcohol spectrum disorders. Our results also support the idea that circulating microRNAs could be used as biomarkers of early gestational ethanol exposure and/or hippocampal dysfunction.