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

Tanja Emmerich,Zuchra Zakirova,Gogce Crynen,James E Evans,Ashok K Shetty,Ghania Ait-Ghezala,Kimberly Sullivan,Fiona Crawford,Laila Abdullah,Geetha A Shetty,Bharathi Hattiangady,Michael Mullan,Nancy Klimas,Gary S Laco,Alexandra Kavushansky

doi:10.1371/journal.pone.0176634

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.

Highlights

Gulf War Illness (GWI) is a chronic multisymptom illness, which affects approximately one fourth of the 700,000 US veterans, who were deployed to the 1990–91 Persian Gulf War (GW) [1,2,3,4,5,6,7]
These differences were evident within the lysophospholipids. This first attempt at a pilot translational study using two different rodent models and a clinical cohort of veterans with GWI proved successful in suggesting strong potential avenues for further larger studies of phospholipid biomarkers of GWI
Principal component analysis for human samples showing factors and total variance associated with each component, which were significantly associated with exposure based on MLM analyses

Summary

Introduction

Gulf War Illness (GWI) is a chronic multisymptom illness, which affects approximately one fourth of the 700,000 US veterans, who were deployed to the 1990–91 Persian Gulf War (GW) [1,2,3,4,5,6,7]. Veterans with GWI experience chronic health symptoms such as fatigue, muscle and joint pain and gastrointestinal problems [8]. Among the central nervous system (CNS) based symptoms, memory problems are among the most commonly reported complaints [1,2,5,8,9,10,11,12,13]. Twenty-five years later, GW veterans are still struggling with this chronic illness, which remains difficult to diagnose due to a lack of objective diagnostic tests. Clinical diagnosis is most commonly made by self-report of health symptoms using the Fukuda Center for Disease Control (CDC) or the Kansas criteria [2,5,8,18]. Blood based biomarkers of GWI are needed to assist clinicians with providing an objective diagnosis of GWI and for developing targeted treatment strategies

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