Abstract
BackgroundMaternal consumption of alcohol during pregnancy is associated with a range of physical, cognitive and behavioural outcomes in the offspring which are collectively called foetal alcohol spectrum disorders. We and others have proposed that epigenetic modifications, such as DNA methylation and post-translational histone modifications, mediate the effects of prenatal alcohol exposure on gene expression and, ultimately, phenotype. Here we use an inbred C57BL/6J mouse model of early gestational ethanol exposure equivalent, developmentally, to the first 3–4 weeks of pregnancy in humans to examine the long-term effects on gene expression and epigenetic state in the hippocampus.ResultsGene expression analysis in the hippocampus revealed sex- and age-specific up-regulation of solute carrier family 17 member 6 (Slc17a6), which encodes vesicular glutamate transporter 2 (VGLUT2). Transcriptional up-regulation correlated with decreased DNA methylation and enrichment of histone H3 lysine 4 trimethylation, an active chromatin mark, at the Slc17a6 promoter. In contrast to Slc17a6 mRNA levels, hippocampal VGLUT2 protein levels were significantly decreased in adult ethanol-exposed offspring, suggesting an additional level of post-transcriptional control. MicroRNA expression profiling in the hippocampus identified four ethanol-sensitive microRNAs, of which miR-467b-5p was predicted to target Slc17a6. In vitro reporter assays showed that miR-467b-5p specifically interacted with the 3′UTR of Slc17a6, suggesting that it contributes to the reduction of hippocampal VGLUT2 in vivo. A significant correlation between microRNA expression in the hippocampus and serum of ethanol-exposed offspring was also observed.ConclusionsPrenatal ethanol exposure has complex transcriptional and post-transcriptional effects on Slc17a6 (VGLUT2) expression in the mouse hippocampus. These effects are observed following a relatively moderate exposure that is restricted to early pregnancy, modelling human consumption of alcohol before pregnancy is confirmed, and are only apparent in male offspring in adulthood. Our findings are consistent with the idea that altered epigenetic and/or microRNA-mediated regulation of glutamate neurotransmission in the hippocampus contributes to the cognitive and behavioural phenotypes observed in foetal alcohol spectrum disorders. Although further work is needed in both mice and humans, the results also suggest that circulating microRNAs could be used as biomarkers of early gestational ethanol exposure and hippocampal dysfunction.Electronic supplementary materialThe online version of this article (doi:10.1186/s13072-015-0032-6) contains supplementary material, which is available to authorized users.
Highlights
Maternal consumption of alcohol during pregnancy is associated with a range of physical, cognitive and behavioural outcomes in the offspring which are collectively called foetal alcohol spectrum disorders
Zhang et al Epigenetics & Chromatin (2015) 8:40 in both mice and humans, the results suggest that circulating microRNAs could be used as biomarkers of early gestational ethanol exposure and hippocampal dysfunction
Prenatal ethanol exposure disrupts the developmental silencing of solute carrier family 17 member 6 (Slc17a6) in the male hippocampus The average daily consumption of 10 % (v/v) ethanol by pregnant C57BL/6J females was 3.3 ± 0.7 ml, which was not significantly different to the volume of water consumed by control mice (Additional file 1: Figure S1A)
Summary
Maternal consumption of alcohol during pregnancy is associated with a range of physical, cognitive and behavioural outcomes in the offspring which are collectively called foetal alcohol spectrum disorders. Alcohol-associated reductions in hippocampal volume have been reported in humans exposed in utero, and combined imaging and behavioural studies have linked altered hippocampal volume with memory deficits [3, 4]. Animal studies have documented ethanolinduced reductions in hippocampal volume [5, 6] and impaired hippocampal-dependent learning and memory [7, 8]. They have revealed that prenatal ethanol exposure results in altered electrophysiological properties [9, 10], as well as cell loss [6] and compromised neurogenesis [11, 12] in the hippocampus. Dysregulation of a number of genes involved in glutamatergic signalling and synaptic plasticity, including vesicular glutamate transporter 1, complexin 1, excitatory amino acid transporters 1 and 3, and some N-methyl-d-aspartate (NMDA) receptor subunits, has been reported in rats [7, 13, 14] but the mechanisms underlying these ethanol-induced expression changes in the hippocampus are not known
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