Phospholipid profiling of plasma from GW veterans and rodent models to identify potential biomarkers of Gulf War Illness

Abstract

Gulf War Illness (GWI), which affects at least one fourth of the 700,000 veterans deployed to the Gulf War (GW), is characterized by persistent and heterogeneous symptoms, including pain, fatigue and cognitive problems. As a consequence, this illness remains difficult to diagnose. Rodent models have been shown to exhibit different symptomatic features of GWI following exposure to particular GW agents (e.g. pyridostigmine bromide, permethrin and DEET) and/or stress. Preclinical analyses have shown the activation of microglia and astroglia as a pathological hallmark in these mouse and rat models. Although much has been learned in recent years from these different rodent models and independent clinical studies, characterization studies to identify overlapping features of GWI in animals and humans have been missing. Thus, we aimed to identify biomarkers that co-occur in the plasma of rodent models of GWI and human GWI patients. We observed increases of multiple phospholipid (PL) species across all studied cohorts. Furthermore, these data suggested dysfunction within ether and docosahexaenoic acid and arachidonic acid containing PL species in relation to GWI. As these PL species play a role in inflammatory processes, these findings suggest a possible role for inflammatory imbalance in GWI. Overall, we show that the peripheral lipid disturbances are present both in human GWI patients and in the preclinical rodent models of GWI, highlighting the importance of lipidomics as a potential platform for further biomarker discovery and supporting the value of GW agent exposed models of GWI.

Oleoylethanolamide treatment reduces neurobehavioral deficits and brain pathology in a mouse model of Gulf War Illness

“…Our exploratory studies showed that lipids which are specially metabolized in peroxisomes, including VLCFA, Pristanic acid, and DHA, were altered in plasma from veterans with GWI. These findings were supported by our previous studies showing that omega-3 DHA and ether-containing PL were disturbed in veterans with GWI 11 . Our preclinical mouse model studies also showed that VLCFA containing PL species were elevated in the brains of GWI compared to control mice 8 , 10 .…”

“…Many of these lipids decline with aging and chronicity of the post-exposure time-points 8 . These lipid changes are also detected in the blood of veterans with GWI 11 . Since metabolism of VLCFA and synthesis of DHA and ether-containing PL is dependent upon normal peroxisomal function 12 , these studies suggest a role of altered peroxisomal function in the chronic pathology of GWI.…”

Effects of a high fat diet on gut microbiome dysbiosis in a mouse model of Gulf War Illness

“…Animal model of GWI. An established mouse model of GWI, as effectively employed by Crawford and colleagues [27][28][29][30] , was used in the present studies. This model has been extensively validated 31 and has been deemed a GWI-relevant animal model in The Gulf War Illness Landscape (https://cdmrp.army.mil/gwirp/pdfs/GWIRP_ Landscape.pdf) published by the DoD GWI Research Program.…”

Acetylcholinesterase inhibitor exposures as an initiating factor in the development of Gulf War Illness, a chronic neuroimmune disorder in deployed veterans

“…During the 1991 Gulf War, soldiers had the potential to be exposed to all three of these categories of AChEIs: the pesticides chlorpyrifos (CPF) and dichlorvos (DDVP) were regularly and pervasively used for pest control, pyridostigmine bromide (PB) was prescribed to be taken every 8 h as a prophylactic against potential nerve agent exposure, and the demolition of ammunition storage facilities released sarin and cyclosarin nerve agents and potentially exposed veterans to these chemical weapons ( Tuovinen et al, 1999 ; Institute of Medicine (US) Committee on Health Effects Associated with Exposures During the Gulf War, 2000 ; Research Advisory Committee on Gulf War Veteran’ Illnesses, 2008 ; White et al, 2016 ). Exposure to AChEIs has been repeatedly implicated as the potential cause of Gulf War Illness (GWI), a chronic multi-symptom disorder affecting nearly one-third of the veterans that returned from the 1991 conflict, by both epidemiological ( Sullivan et al, 2003 ; Research Advisory Committee on Gulf War Veteran’ Illnesses, 2008 ; Steele et al, 2012 ; Kerr, 2015 ; White et al, 2016 ; Sullivan et al, 2018 ) and preclinical studies ( Henderson et al, 2001 ; Amourette et al, 2009 ; Lamproglou et al, 2009 ; Abdullah et al, 2012 ; Abdullah et al, 2013 ; Parihar et al, 2013 ; Hattiangady et al, 2014 ; Ojo et al, 2014 ; Nutter et al, 2015 ; O’Callaghan et al, 2015 ; Zakirova et al, 2015 ; Abdullah et al, 2016 ; Cooper et al, 2016 ; Phillips and Deshpande, 2016 ; Pierce et al, 2016 ; Alhasson et al, 2017 ; Emmerich et al, 2017 ; Flunker et al, 2017 ; Locker et al, 2017 ; Shetty et al, 2017 ; Zakirova et al, 2017 ; Ashbrook et al, 2018 ; Carreras et al, 2018 ; Cooper et al, 2018 ; Koo et al, 2018 ; Macht et al, 2018 ; Miller et al, 2018 ; Phillips and Deshpande, 2018 ; Seth et al, 2018 ; Macht et al, 2019 ; Michalovicz et al, 2019 ). Acute exposure to toxic levels of AChEIs, particularly the organophosphate (OP) compounds like the pesticides and nerve agents, has a number of systemic effects (i.e.…”