Long-term epigenetic alterations in a rat model of Gulf War Illness

Pierce, Lisa; Kurata, Wendy E.; Matsumoto, Karen W.; Clark, Margaret E.; Farmer, Douglas M.

doi:10.1016/j.neuro.2016.05.007

Cited by 27 publications

(19 citation statements)

References 87 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The overall objective of this study was to examine genome-wide epigenetic transcriptional modifications in the brain using an established mouse model of GWI [ 4 , 12 , 15 , 16 ]. Our previous research demonstrates that effects on neuroinflammatory pathways occur shortly after initial exposures.…”

Section: Introductionmentioning

confidence: 99%

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

Ashbrook

Hing

Michalovicz

et al. 2018

J Neuroinflammation

View full text Add to dashboard Cite

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.

show abstract

Section: Introductionmentioning

confidence: 99%

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

Ashbrook

Hing

Michalovicz

et al. 2018

J Neuroinflammation

View full text Add to dashboard Cite

show abstract

“…Second, we considered the possibility that the individuals who contracted GWI might be genetically or epigenetically predisposed to contracting the illness from the neurotoxicant exposures, and hence that there may be something to be learned from comparing cells from equally exposed veterans who either did or did not get sick. 13 By no means did we think that cells from any human being would be unresponsive to the relevant toxicants, but perhaps the sensitivity would be greater in one group compared to the other, or perhaps the reaction would be qualitatively different. For example, neurons derived from the veterans who contracted the illness might react to the toxicants by hyperphosphorylating tau, a microtubule-related protein that becomes aberrantly phosphorylated in a number of neurodegenerative conditions, 36 but the same would not be true of the neurons from the veterans who did not contract the illness.…”

Section: Recruitment Process and Informedmentioning

confidence: 99%

“…Such a scenario might be due, for example, to chromosomal or epigenetic damage that affects cells from multiple systems (i.e., hepatic cells, muscle cells, neurons). 13 More likely, the newly differentiated neurons will represent the status of the veteran prior to exposure Schematic flow chart for planned experimental regimen Group A, Gulf War (GW) veterans without GW illness (GWI); group B, GW veterans with GWI. The types of assessments that will be done on the cells depend on the hypothesis being pursued.…”

Section: Recruitment Process and Informedmentioning

confidence: 99%

“…Should differences be observed, we will further probe for the possibility of genetic pre-deposition or epigenetic variations in the 2 groups. 13 However, should no differences be obtained, the toxicants, such as DFP or PB, will be added into the neuronal cultures from the 2 groups followed by the experimental analyses. A challenge worth mentioning is the difficulty of reproducing the levels or complexity of toxicant exposures in the culture dish to match those experienced by soldiers in the battlefield.…”

Section: Recruitment Process and Informedmentioning

confidence: 99%

“…12 In fact, recent animal models have shown miRNA and other epigenetic changes in GWI-exposed animal models. 13 Despite progress, there has been concern about the continued use of animal models in GWI research by the National Academy of Sciences Institute of Medicine. 14 This is because human diseases often involve proteins and pathways that are not well-reflected in rodents, and because animal work cannot appropriately take into account myriad genetic and epigenetic factors relevant to human disease.…”

mentioning

confidence: 99%

See 2 more Smart Citations

Reprogramming cells from Gulf War veterans into neurons to study Gulf War illness

et al. 2017

View full text Add to dashboard Cite

Gulf War illness (GWI), which afflicts at least 25% of veterans who served in the 1990-1991 war in the Persian Gulf, is thought to be caused by deployment exposures to various neurotoxicants, including pesticides, anti-nerve gas pills, and low-level nerve agents including sarin/cyclosarin. GWI is a multisymptom disorder characterized by fatigue, joint pain, cognitive problems, and gastrointestinal complaints. The most prominent symptoms of GWI (memory problems, poor attention/concentration, chronic headaches, mood alterations, and impaired sleep) suggest that the disease primarily affects the CNS. Development of urgently needed treatments depends on experimental models appropriate for testing mechanistic hypotheses and for screening therapeutic compounds. Rodent models have been useful thus far, but are limited by their inability to assess the contribution of genetic or epigenetic background to the disease, and because disease-vulnerable proteins and pathways may be different in humans relative to rodents. As of yet, no postmortem tissue from the veterans has become available for research. We are moving forward with a paradigm shift in the study of GWI, which utilizes contemporary stem cell technology to convert somatic cells from Gulf War veterans into pluripotent cell lines that can be differentiated into various cell types, including neurons, glia, muscle, or other relevant cell types. Such cell lines are immortal and will be a resource for GWI researchers to pursue mechanistic hypotheses and therapeutics.

show abstract