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

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

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.

Conflict of interest statement

Competing Interests: The authors have declared that no competing interests exist.

Figures

Fig 1. Changes in total plasma phospholipid…
Fig 1. Changes in total plasma phospholipid levels in GWI subjects and controls, represented in mean ± SEM in percentage of control.
Individual molecular species for each PL class identified by LC/MS were summed to calculate total PL levels within each class. *p post hoc analysis. Total LPC was significantly increased in GWI subjects (brick bars) compared to GV controls (solid bars).
Fig 2. Degree of unsaturation of PL…
Fig 2. Degree of unsaturation of PL classes in plasma of GWI patients compared to controls, represented in mean ± SEM in percentage of control.
For PC, SFA containing PC species were decreased in GWI patients, whereas for LPC and LPE, PUFA containing species were elevated compared to control subjects. No differences in the degree of unsaturation were observed for LPC and PE. For PI, no SFA containing species were identified (SFA: solid bars, MUFA: stripped bars, PUFA: brick bars). *ppost hoc analysis.
Fig 3. Ether lipid changes in plasma…
Fig 3. Ether lipid changes in plasma of GWI patients and compared to controls, represented in mean ± SEM in percentage of control.
Levels of eLPE were significantly elevated in GWI patients (brick bars) compared to healthy GW controls (solid bars). No differences were observed for ePC, eLPC and ePE. *ppost hoc analysis.
Fig 4. AA containing phospholipid species in…
Fig 4. AA containing phospholipid species in plasma of GWI patients compared to controls, represented in mean ± SEM in percentage of control.
Within GWI patients (brick bars), AA containing LPC and LPE species were significantly elevated compared to controls. No differences were observed within PC, PE and PI. *ppost hoc analysis.
Fig 5. DHA containing phospholipid species in…
Fig 5. DHA containing phospholipid species in plasma of GWI patients compared to controls, represented in mean ± SEM in percentage of control.
Within GWI patients (brick bars), DHA containing PC, LPC and LPE species were significantly elevated compared to controls (solid bars). No differences were observed within DHA containing PE and PI species. *ppost hoc analysis.
Fig 6. Individual molecular species of PC…
Fig 6. Individual molecular species of PC are elevated in plasma from veterans with GWI, rodent model and mouse model of GWI.
A. (blue) Percentage of control ± SEM (n = 11 controls, 22 GWI) showing elevated PC species in GWI subjects compared to controls. (green) Percentage of control ± SEM (n = 4 per group) for the PB+PER model showing that most of these species were also elevated in exposed mice but did not reach statistical significance. (red) Percentage of control ± SEM (n = 6 sham, n = 5 exposed rats) showing elevated PC species in GW agent exposed rats compared to control rats. B. P values for all significant PL species in GW veterans and rodent models. *ppost hoc analysis.
Fig 7. Individual molecular species of LPC…
Fig 7. Individual molecular species of LPC are elevated in plasma from veterans with GWI, rodent model and mouse model of GWI.
A. (blue) Percentage of control ± SEM (n = 11 controls, 22 GWI) showing elevated LPC species in GWI subjects compared to controls. (green) Percentage of control ± SEM (n = 4 per group) for the PB+PER model showing that most of these species were also elevated in exposed mice. (red) Percentage of control ± SEM (n = 6 sham, n = 5 exposed rats) showing elevated LPC species in GW agent exposed rats compared to control rats. B. P values for all significant PL species in GW veterans and rodent models.*ppost hoc analysis.
Fig 8. Individual molecular species of PE…
Fig 8. Individual molecular species of PE are elevated in plasma from veterans with GWI, rodent model and mouse model of GWI.
A. (blue) Percentage of control ± SEM (n = 11 controls, 22 GWI) showing elevated PE species in GWI subjects compared to controls. (green) Percentage of control ± SEM (n = 4 per group) for the PB+PER model showing that most of these species were also elevated in exposed mice but did not reach statistical significance. (red) Percentage of control ± SEM (n = 6 sham, n = 5 exposed rats) showing elevated LPC species in GW agent exposed rats compared to control rats. B. P values for all significant PL species in GW veterans and rodent models.*ppost hoc analysis.
Fig 9. Individual molecular species of LPE…
Fig 9. Individual molecular species of LPE are elevated in plasma from veterans with GWI, rodent model and mouse model of GWI.
A. (blue) Percentage of control ± SEM (n = 11 controls, 22 GWI) showing elevated LPE species in GWI subjects compared to controls. (green) Percentage of control ± SEM (n = 4 per group) for the PB+PER model showing that two out of three species were also elevated in exposed mice. (c) Percentage of control ± SEM (n = 6 sham, n = 5 exposed rats) showing elevated LPE species in GW agent exposed rats compared to control rats. B. P values for all significant PL species in GW veterans and rodent models. *ppost hoc analysis.
Fig 10. Individual molecular species of PI…
Fig 10. Individual molecular species of PI are elevated in plasma from veterans, rodent model and mouse model of GWI.
A. (blue) Percentage of control ± SEM (n = 11 controls, 22 GWI) showing levels PI species in GWI subjects compared to controls. No significance was achieved for any of these species. (green) Percentage of control ± SEM (n = 4 per group) for the PB+PER model showing that 2 out of 5 species were elevated in exposed mice. (red) Percentage of control ± SEM (n = 6 sham, n = 5 exposed rats) showing elevated PI species in GW agent exposed rats compared to control rats. B. P values for all significant PL species in GW veterans and rodent models.*ppost hoc analysis.

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