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

Department

Research

Document Type

Article

Publication Title

Journal Of Neuroinflammation

Abstract

BACKGROUND: Gulf 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. METHODS: C57BL/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. RESULTS: We 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. CONCLUSIONS: Our 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.

First Page

86

DOI

10.1186/s12974-018-1113-9

Volume

15

Issue

1

Publication Date

3-17-2018

Medical Subject Headings

Animals; Anti-Inflammatory Agents (toxicity); Brain (drug effects, metabolism, pathology); Cholinesterase Inhibitors (pharmacology); Chromatin Immunoprecipitation; Corticosterone (toxicity); Cytokines (metabolism); DNA Methylation (drug effects); Disease Models, Animal; Epigenesis, Genetic (drug effects, physiology); Histones (metabolism); Male; Mice; Mice, Inbred C57BL; Persian Gulf Syndrome (drug therapy, pathology); Phosphoric Triester Hydrolases (pharmacology); Stress, Psychological (metabolism); Time Factors

PubMed ID

29549885

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