Alterations in Global DNA Methylation/Hydroxymethylation and MicroRNA Expression in a Rat Model of Gulf War Illness

Abstract

Gulf War Illness (GWI) is a chronic, multisymptom illness that affects 25% of the 700,000 US veterans deployed to the Persian Gulf during the 1990-1991 Gulf War. Central nervous system impairments are among the most common symptoms reported, including memory dysfunction and depression. Epidemiological studies have consistently identified neurotoxic chemical exposures during deployment as the strongest risk factors for the persistent symptoms affecting GW veterans, but after nearly 25 years, treatments are lacking and underlying cellular and molecular mechanisms involved in its pathobiology remain poorly understood. Epigenetic changes including DNA methylation and altered microRNA (miRNA) expression play an important role in in learning, memory, and emotion regulation and have been implicated in various neurological disorders. The aim of this study was to determine in a rat model of GWI whether chronic alterations in global DNA methylation/hydroxymethylation and miRNA expression are mechanisms involved in the pathobiology of GWI. One year after a 28-day exposure regimen of GW chemicals and stress, 5-methylcytosine (5mC) and 5-hydroxymethylcytosine (5hmC) content and expression of 84 mature miRNAs were analyzed in the brains of GWI rats and vehicle controls by ELISA and PCR array, respectively. In GWI rats, hippocampal 5mC content increased 46%, while 5hmC content increased 29% in the cerebellum and decreased 45% in the cortex (p<0.01 for all). Ten miRNAs known to be involved in synaptic plasticity and memory function, DNA methylation, or adult neurogenesis were differentially expressed (>1.5 fold change, p<0.01) in the hippocampus. Results from this study implicate a role for epigenetic alterations in GWI.