Epigenetic impacts of stress priming of the neuroinflammatory response to sarin surrogate in mice: a model of Gulf War illness

Abstract

BackgroundGulf War illness (GWI) is an archetypal, medically unexplained, chronic condition characterised by persistent sickness behaviour and neuroimmune and neuroinflammatory components. An estimated 25–32% of the over 900,000 veterans of the 1991 Gulf War fulfil the requirements of a GWI diagnosis. It has been hypothesised that the high physical and psychological stress of combat may have increased vulnerability to irreversible acetylcholinesterase (AChE) inhibitors leading to a priming of the neuroimmune system. A number of studies have linked high levels of psychophysiological stress and toxicant exposures to epigenetic modifications that regulate gene expression. Recent research in a mouse model of GWI has shown that pre-exposure with the stress hormone corticosterone (CORT) causes an increase in expression of specific chemokines and cytokines in response to diisopropyl fluorophosphate (DFP), a sarin surrogate and irreversible AChE inhibitor.MethodsC57BL/6J mice were exposed to CORT for 4 days, and exposed to DFP on day 5, before sacrifice 6 h later. The transcriptome was examined using RNA-seq, and the epigenome was examined using reduced representation bisulfite sequencing and H3K27ac ChIP-seq.ResultsWe show transcriptional, histone modification (H3K27ac) and DNA methylation changes in genes related to the immune and neuronal system, potentially relevant to neuroinflammatory and cognitive symptoms of GWI. Further evidence suggests altered proportions of myelinating oligodendrocytes in the frontal cortex, perhaps connected to white matter deficits seen in GWI sufferers.ConclusionsOur findings may reflect the early changes which occurred in GWI veterans, and we observe alterations in several pathways altered in GWI sufferers. These close links to changes seen in veterans with GWI indicates that this model reflects the environmental exposures related to GWI and may provide a model for biomarker development and testing future treatments.Electronic supplementary materialThe online version of this article (10.1186/s12974-018-1113-9) contains supplementary material, which is available to authorized users.

Oligodendrocyte involvement in Gulf War Illness

“…The results of the quantitative histological analysis of oligodendroglia in the PFC of the GWI rat model is consistent with RNA‐seq data in mice showing that combined Cort and DFP treatment decreases the fraction of mRNA transcripts associated with mature oligodendrocytes in the PFC (Ashbrook et al, ), but our results are not consistent with this gene profiling study in other respects. Cort treatment alone did not alter the number of mature oligodendrocytes in the PFC, but mRNA transcripts associated with oligodendrocytes are reportedly reduced in this condition (Ashbrook et al, ). Also, the frequency of mature oligodendrocytes in the PFC decreased in response to DFP treatment, but mRNA transcripts associated with mature oligodendrocytes remained unchanged under this condition (Ashbrook et al, ).…”

“…The results of the quantitative histological analysis of oligodendroglia in the PFC of the GWI rat model is consistent with RNA-seq data in mice showing that combined Cort and DFP treatment decreases the fraction of mRNA transcripts associated with mature oligodendrocytes in the PFC (Ashbrook et al, 2018), but our results are not consistent with this gene profiling study in other respects.…”

“…Cort treatment alone did not alter the number of mature oligodendrocytes in the PFC, but mRNA transcripts associated with oligodendrocytes are reportedly reduced in this condition (Ashbrook et al, 2018).…”

“…Also, the frequency of mature oligodendrocytes in the PFC decreased in response to DFP treatment, but mRNA transcripts associated with mature oligodendrocytes remained unchanged under this condition (Ashbrook et al, 2018). These discrepancies may be explained by the fact that gene and protein abundance are indirect indicators of cell numbers, and gene expression and protein levels are influenced by physiological conditions.…”

Modeling the Genetic Basis of Individual Differences in Susceptibility to Gulf War Illness

“…Indeed, Trevedi and colleagues [17] showed DNA methylation changes in monocytes from GWI affected veterans in genes related to immune function, thus supporting the hypothesis of neuroimmune sequelae of GWI. In mice, Ashbrook et al [18] showed genome-wide histone modification and DNA methylation in the frontal cortex. Many of the genes so modified are related to myelin production in oligodendrocytes and thus may be related to the observation of reduced white matter in frontal cortex of GWI veterans.…”