Chronic elevation of phosphocholine containing lipids in mice exposed to Gulf War agents pyridostigmine bromide and permethrin

Laila Abdullah, James E. Evans, Hannah Montague, Jon M. Reed, Ann B. Moser, Gogce Crynen, Ariel Gonzalez, Zuchra Zakirova, Ivan Ross, Chris Mullan, Michael Mullan, Ghania Ait-Ghezala, Fiona Crawford

Research output: Contribution to journalArticle

Abstract

For two decades, 25% of the veterans who served in the 1991 Gulf War (GW) have been living with Gulf War Illness (GWI), a chronic multisymptom illness. Evidence suggests that brain structures involved in cognitive function may be affected in GWI. Gulf War agents such as the acetylcholinesterase (AChE) inhibitor pyridostigmine bromide (PB) and the pesticide permethrin (PER) are considered key etiogenic factors in GWI. We therefore developed a mouse model of GW agent exposure by co-administering PB and PER and showed that this model exhibits cognitive impairment and anxiety, and increased astrogliosis at chronic post-exposure time-points. Since GW agents inhibit AChE, we hypothesized that PB. +. PER exposure will modulate phosphatidylcholine (PC) and sphingomyelin (SM), which are reservoirs of phosphocholine required for endogenous ACh synthesis. Lipidomic analyses showed that PC and SM were elevated in the brains of exposed compared to control mice. Brain ether PC (ePC) species were increased but lyso-platelet activating factors (lyso-PAF) that are products of ePC were decreased in exposed animals compared to controls. Catalase expression (a marker for peroxisomes) was increased in GW agent exposed mice compared to controls. Ether PC and lyso-PAF modulation was also evident in the plasma of GW agent exposed mice compared to controls. These studies suggest peroxisomal and lysosomal dysfunction in the brain at a chronic post-exposure timepoint following GW agent exposure. Our studies provide a new direction for GWI research, which will be useful for developing suitable therapies for treating GWI.

Original languageEnglish (US)
Pages (from-to)74-84
Number of pages11
JournalNeurotoxicology and Teratology
Volume40
DOIs
StatePublished - Nov 2013

Fingerprint

Gulf War
Pyridostigmine Bromide
Permethrin
Phosphorylcholine
Phosphatidylcholines
Lipids
Brain
Ether
Sphingomyelins
Cholinesterase Inhibitors
Acetylcholinesterase
Pesticides
Catalase
Animals
Modulation
Plasmas
Peroxisomes
Veterans
Cognition

Keywords

  • Gulf War Illness
  • Lipidomics
  • Lyso-platelet activating factor
  • Peroxisome
  • Phosphatidylcholine
  • Sphingomyelin

ASJC Scopus subject areas

  • Developmental Neuroscience
  • Cellular and Molecular Neuroscience
  • Toxicology

Cite this

Chronic elevation of phosphocholine containing lipids in mice exposed to Gulf War agents pyridostigmine bromide and permethrin. / Abdullah, Laila; Evans, James E.; Montague, Hannah; Reed, Jon M.; Moser, Ann B.; Crynen, Gogce; Gonzalez, Ariel; Zakirova, Zuchra; Ross, Ivan; Mullan, Chris; Mullan, Michael; Ait-Ghezala, Ghania; Crawford, Fiona.

In: Neurotoxicology and Teratology, Vol. 40, 11.2013, p. 74-84.

Research output: Contribution to journalArticle

Abdullah, L, Evans, JE, Montague, H, Reed, JM, Moser, AB, Crynen, G, Gonzalez, A, Zakirova, Z, Ross, I, Mullan, C, Mullan, M, Ait-Ghezala, G & Crawford, F 2013, 'Chronic elevation of phosphocholine containing lipids in mice exposed to Gulf War agents pyridostigmine bromide and permethrin', Neurotoxicology and Teratology, vol. 40, pp. 74-84. https://doi.org/10.1016/j.ntt.2013.10.002
Abdullah, Laila ; Evans, James E. ; Montague, Hannah ; Reed, Jon M. ; Moser, Ann B. ; Crynen, Gogce ; Gonzalez, Ariel ; Zakirova, Zuchra ; Ross, Ivan ; Mullan, Chris ; Mullan, Michael ; Ait-Ghezala, Ghania ; Crawford, Fiona. / Chronic elevation of phosphocholine containing lipids in mice exposed to Gulf War agents pyridostigmine bromide and permethrin. In: Neurotoxicology and Teratology. 2013 ; Vol. 40. pp. 74-84.
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abstract = "For two decades, 25{\%} of the veterans who served in the 1991 Gulf War (GW) have been living with Gulf War Illness (GWI), a chronic multisymptom illness. Evidence suggests that brain structures involved in cognitive function may be affected in GWI. Gulf War agents such as the acetylcholinesterase (AChE) inhibitor pyridostigmine bromide (PB) and the pesticide permethrin (PER) are considered key etiogenic factors in GWI. We therefore developed a mouse model of GW agent exposure by co-administering PB and PER and showed that this model exhibits cognitive impairment and anxiety, and increased astrogliosis at chronic post-exposure time-points. Since GW agents inhibit AChE, we hypothesized that PB. +. PER exposure will modulate phosphatidylcholine (PC) and sphingomyelin (SM), which are reservoirs of phosphocholine required for endogenous ACh synthesis. Lipidomic analyses showed that PC and SM were elevated in the brains of exposed compared to control mice. Brain ether PC (ePC) species were increased but lyso-platelet activating factors (lyso-PAF) that are products of ePC were decreased in exposed animals compared to controls. Catalase expression (a marker for peroxisomes) was increased in GW agent exposed mice compared to controls. Ether PC and lyso-PAF modulation was also evident in the plasma of GW agent exposed mice compared to controls. These studies suggest peroxisomal and lysosomal dysfunction in the brain at a chronic post-exposure timepoint following GW agent exposure. Our studies provide a new direction for GWI research, which will be useful for developing suitable therapies for treating GWI.",
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AU - Moser, Ann B.

AU - Crynen, Gogce

AU - Gonzalez, Ariel

AU - Zakirova, Zuchra

AU - Ross, Ivan

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AU - Ait-Ghezala, Ghania

AU - Crawford, Fiona

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