title: Translational potential of long-term decreases in mitochondrial lipids in a mouse model of Gulf War Illness.
abstract: Gulf War Illness (GWI) affects 25% of veterans from the 1990-1991 Gulf War (GW) and is accompanied by damage to the brain regions involved in memory processing. After twenty-five years, the chronic pathobiology of GWI is still unexplained. To address this problem, we examined the long-term consequences of GW exposures in an established GWI mouse model to identify biological processes that are relevant to the chronic symptoms of GWI. Three-month old male C57BL6 mice were exposed for 10days to GW agents (pyridostigmine bromide and permethrin). Barnes Maze testing conducted at 15- and 16-months post-exposure revealed learning and memory impairment. Immunohistochemical analyses showed astroglia and microglia activation in the hippocampi of exposed mice. Proteomic studies identified perturbation of mitochondria function and metabolomics data showed decreases in the Krebs cycle compounds, lactate, β-hydroxybutyrate and glycerol-3 phosphate in the brains of exposed mice. Lipidomics data showed decreases in fatty acids, acylcarnitines and phospholipids, including cardiolipins in the brains of exposed mice. Pilot biomarker studies showed that plasma from exposed mice and veterans with GWI had increases in odd-chain, and decreases in long-chain, acylcarnitines compared to their respective controls. Very long-chain acylcarnitines were decreased in veterans with GWI compared to controls. These studies suggest that mitochondrial lipid disturbances might be associated with GWI and that further investigation is required to determine its role in the pathophysiology of this illness. Targeting mitochondrial function may provide effective therapies for GWI, and that lipid abnormalities could serve as biomarkers of GWI.
authors.affiliation: Roskamp Institute, Sarasota, FL, USA; James A. Haley VA Hospital, Tampa, FL, USA; Open University, Milton Keynes, UK. Electronic address: labdullah@rfdn.org.
authors.forename: Laila
authors.initials: L
authors.lastname: Abdullah
authors.affiliation: Roskamp Institute, Sarasota, FL, USA; James A. Haley VA Hospital, Tampa, FL, USA.
authors.forename: James E
authors.initials: JE
authors.lastname: Evans
authors.affiliation: Roskamp Institute, Sarasota, FL, USA; Open University, Milton Keynes, UK.
authors.forename: Utsav
authors.initials: U
authors.lastname: Joshi
authors.affiliation: Roskamp Institute, Sarasota, FL, USA; James A. Haley VA Hospital, Tampa, FL, USA; Open University, Milton Keynes, UK.
authors.forename: Gogce
authors.initials: G
authors.lastname: Crynen
authors.affiliation: Roskamp Institute, Sarasota, FL, USA; James A. Haley VA Hospital, Tampa, FL, USA.
authors.forename: Jon
authors.initials: J
authors.lastname: Reed
authors.affiliation: Roskamp Institute, Sarasota, FL, USA; James A. Haley VA Hospital, Tampa, FL, USA; Open University, Milton Keynes, UK.
authors.forename: Benoit
authors.initials: B
authors.lastname: Mouzon
authors.affiliation: Agilent Technologies, Santa Clara, CA, USA.
authors.forename: Stephan
authors.initials: S
authors.lastname: Baumann
authors.affiliation: University College London, London, UK.
authors.forename: Hannah
authors.initials: H
authors.lastname: Montague
authors.affiliation: Icahn School of Medicine at Mount Sinai, NY, USA.
authors.forename: Zuchra
authors.initials: Z
authors.lastname: Zakirova
authors.affiliation: Roskamp Institute, Sarasota, FL, USA; James A. Haley VA Hospital, Tampa, FL, USA; Open University, Milton Keynes, UK.
authors.forename: Tanja
authors.initials: T
authors.lastname: Emmerich
authors.affiliation: Roskamp Institute, Sarasota, FL, USA; Open University, Milton Keynes, UK.
authors.forename: Corbin
authors.initials: C
authors.lastname: Bachmeier
authors.affiliation: NOVA Southeastern University, Ft. Lauderdale, FL, USA; Miami VAMC, Miami FL, USA.
authors.forename: Nancy
authors.initials: N
authors.lastname: Klimas
authors.affiliation: Boston University School of Public Health, Boston, MA, USA.
authors.forename: Kimberly
authors.initials: K
authors.lastname: Sullivan
authors.affiliation: Roskamp Institute, Sarasota, FL, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Mullan
authors.affiliation: Roskamp Institute, Sarasota, FL, USA; James A. Haley VA Hospital, Tampa, FL, USA; Open University, Milton Keynes, UK.
authors.forename: Ghania
authors.initials: G
authors.lastname: Ait-Ghezala
authors.affiliation: Roskamp Institute, Sarasota, FL, USA; James A. Haley VA Hospital, Tampa, FL, USA; Open University, Milton Keynes, UK.
authors.forename: Fiona
authors.initials: F
authors.lastname: Crawford
mesh_terms: D000328:Adult; D000818:Animals; D015415:Biomarkers / Q000097:blood; D001923:Brain Chemistry / Q000187:drug effects; D004195:Disease Models, Animal; D006801:Humans; D007150:Immunohistochemistry; D050356:Lipid Metabolism / Q000187:drug effects*; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D008569:Memory Disorders / Q000139:chemically induced / Q000523:psychology; D051379:Mice; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000378:metabolism*; D020258:Neurotoxicity Syndromes / Q000523:psychology; D018923:Persian Gulf Syndrome / Q000097:blood / Q000378:metabolism*
chemical_list: D015415:Biomarkers
keywords: Acylcarnitine; Cardiolipin; Gulf War Illness; Mitochondria; Pesticides; Pyridostigmine bromide