Third Trimester-Equivalent Ethanol Exposure Is Characterized by an Acute Cellular Stress Response and an Ontogenetic Disruption of Genes Critical for Synaptic Establishment and Function in Mice

The developing brain is remarkably sensitive to alcohol exposure, resulting in the wide range of cognitive and neurobehavioral characteristics categorized under the term fetal alcohol spectrum disorders (FASD). The brain is particularly susceptible to alcohol during synaptogenesis, a process that occurs heavily during the third trimester and is characterized by the establishment and pruning of neural circuitry; however, the molecular response of the brain to ethanol during synaptogenesis has not been documented. To model a binge-like exposure during the third-trimester neurodevelopmental equivalent, neonate mice were given a high (5 g/kg over 2 h) dose of ethanol at postnatal day 7. Acute transcript changes within the brain were assessed using expression arrays and analyzed for associations with gene ontology functional categories, canonical pathways, and gene network interactions. The short-term effect of ethanol was characterized by an acute stress response and a downregulation of energetically costly cellular processes. Further, alterations to a number of genes with roles in synaptic transmission and hormonal signaling, particularly those associated with the neuroendocrine development and function, were evident. Ethanol exposure during synaptogenesis was also associated with altered histone deacetylase and microRNA transcript levels, suggesting that abnormal epigenetic patterning may maintain some of the persistent molecular consequences of developmental ethanol exposure. The results shed insight into the sensitivity of the brain to ethanol during the third-trimester equivalent and outline how ethanol-induced alterations to genes associated with neural connectivity may contribute to FASD phenotypes. (C) 2014 S. Karger AG, Basel