title: Chronic elevation of phosphocholine containing lipids in mice exposed to Gulf War agents pyridostigmine bromide and permethrin.
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.
authors.affiliation: Roskamp Institute, 2040 Whitfield Ave, Sarasota, FL 34243, United States. Electronic address: labdullah@rfdn.org.
authors.forename: Laila
authors.initials: L
authors.lastname: Abdullah
authors.forename: James E
authors.initials: JE
authors.lastname: Evans
authors.forename: Hannah
authors.initials: H
authors.lastname: Montague
authors.forename: Jon M
authors.initials: JM
authors.lastname: Reed
authors.forename: Ann
authors.initials: A
authors.lastname: Moser
authors.forename: Gogce
authors.initials: G
authors.lastname: Crynen
authors.forename: Ariel
authors.initials: A
authors.lastname: Gonzalez
authors.forename: Zuchra
authors.initials: Z
authors.lastname: Zakirova
authors.forename: Ivan
authors.initials: I
authors.lastname: Ross
authors.forename: Chris
authors.initials: C
authors.lastname: Mullan
authors.forename: Michael
authors.initials: M
authors.lastname: Mullan
authors.forename: Ghania
authors.initials: G
authors.lastname: Ait-Ghezala
authors.forename: Fiona
authors.initials: F
authors.lastname: Crawford
mesh_terms: D000818:Animals; D001923:Brain Chemistry / Q000187:drug effects*; D002800:Cholinesterase Inhibitors / Q000633:toxicity*; D004195:Disease Models, Animal; D007306:Insecticides / Q000633:toxicity*; D008055:Lipids / Q000737:chemistry; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D026023:Permethrin / Q000633:toxicity*; D018923:Persian Gulf Syndrome / Q000139:chemically induced* / Q000378:metabolism; D010713:Phosphatidylcholines / Q000032:analysis*; D010767:Phosphorylcholine / Q000032:analysis; D011729:Pyridostigmine Bromide / Q000633:toxicity*; D013109:Sphingomyelins / Q000032:analysis
chemical_list: D002800:Cholinesterase Inhibitors; D007306:Insecticides; D008055:Lipids; D010713:Phosphatidylcholines; D013109:Sphingomyelins; D010767:Phosphorylcholine; D026023:Permethrin; D011729:Pyridostigmine Bromide
keywords: Gulf War Illness; Lipidomics; Lyso-platelet activating factor; Peroxisome; Phosphatidylcholine; Sphingomyelin