Early-Ethanol Exposure Induced Region-Specific Changes in Metabolic Proteins in the Rat Brain: A Proteomics Study

Abstract

In utero exposure to alcohol has been shown to cause a spectrum of cognitive and behavioral deficits. This study aimed to explore the long-term effects of early-ethanol exposure on proteins in the brain. Male Sprague-Dawley rat pups were exposed to 12% ethanol (4 g/kg/day i.p.) or volume-controlled saline during the third human trimester equivalent (P4-P9). At P31, prefrontal cortex (PFC) and dorsal hippocampus (DH) proteins were analyzed by isobaric tags for relative and absolute quantitation (iTRAQ) and liquid chromatography mass spectrometry (LC-MS). Early-ethanol exposure increased the capacity for metabolism of NADH and oxidative phosphorylation, as shown by an upregulation of NADH dehydrogenase (ubiquinone, 1 alpha subcomplex 9) while simultaneously decreasing the capacity to protect against oxidative stress in the PFC. Early-ethanol exposure decreased the capacity for ATP synthesis (> 2-fold down regulation of ATP synthase) and increased glycogen synthesis in the DH (> 2-fold decrease in glycogen synthase kinase-3β). The effects of early-ethanol exposure on glucose metabolism and ATP production appeared to be region specific. In addition, early-ethanol exposure decreased structural proteins in both the PFC and DH. A greater number of proteins were altered in the DH than in the PFC, indicating that the DH may be more susceptible to the effects of early-ethanol exposure. These proteomic profiles provide valuable insight into the long-term molecular changes in the brain induced by early-ethanol exposure.

Keywords: Dorsal hippocampus; Energy metabolism, prefrontal cortex; Ethanol; FASD; Proteomics.