Lipidomic profiling of phosphocholine-containing brain lipids in mice with sensorimotor deficits and anxiety-like features after exposure to Gulf War agents.
The central nervous system (CNS)-based symptoms of Gulf War Illness (GWI) include motor dysfunction, anxiety, and cognitive impairment. Gulf War (GW) agents, such as pyridostigmine bromide (PB), permethrin (PER), N,N-diethyl-meta-toluamide (DEET), and stress, are among the contributory factors to the pathobiology of GWI. This study characterizes disturbances in phosphocholine-containing lipids that accompany neurobehavioral and neuropathological features associated with GW agent exposure. Exposed mice received PB orally, dermal application of PER and DEET and restraint stress daily for 28 days, while controls received vehicle during this period. Neurobehavioral studies included the rotarod, open field, and Morris water maze tests. Histopathological assessments included glial fibrillary acid protein, CD45, and Nissl staining. Liquid chromatography/mass spectrometry with source collision-induced dissociation in negative and positive ionization scanning modes was performed to characterize brain phosphatidylcholine (PC) and sphingomyelin (SM). A significant increase in ether containing PC (ePC34:0, ePC36:2, and ePC36:1) or long-chain fatty acid-containing PC (38:1, 40:4, 40:2) was observed in exposed mice compared with controls. Among differentially expressed PCs, levels of those with monounsaturated fatty acids were more affected than those with saturated and polyunsaturated fatty acids. Sensorimotor deficits and anxiety, together with an increase in astrocytosis, were observed in exposed mice compared with controls. These lipid changes suggest that alterations in peroxisomal pathways and stearoyl-CoA desaturase activity accompany neurobehavioral and neuropathological changes after GW agent exposure and represent possible treatment targets for the CNS symptoms of GWI.
Roskamp Institute, Sarasota, FL 34243, USA. labdullah@rfdn.org
Laila
L
Abdullah
James E
JE
Evans
Alex
A
Bishop
Jon M
JM
Reed
Gogce
G
Crynen
John
J
Phillips
Robert
R
Pelot
Myles A
MA
Mullan
Austin
A
Ferro
Christopher M
CM
Mullan
Michael J
MJ
Mullan
Ghania
G
Ait-Ghezala
Fiona C
FC
Crawford
D000818:Animals; D001007:Anxiety / Q000139:chemically induced* / Q000378:metabolism / Q000473:pathology; D001259:Ataxia / Q000139:chemically induced* / Q000378:metabolism / Q000473:pathology; D001923:Brain Chemistry / Q000187:drug effects*; D002540:Cerebral Cortex / Q000737:chemistry* / Q000473:pathology; D003671:DEET / Q000633:toxicity*; D018891:Dentate Gyrus / Q000737:chemistry* / Q000473:pathology; D004195:Disease Models, Animal; D005106:Exploratory Behavior / Q000187:drug effects; D005227:Fatty Acids / Q000378:metabolism; D005260:Female; D005911:Gliosis / Q000139:chemically induced / Q000378:metabolism; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D009419:Nerve Tissue Proteins / Q000378:metabolism; D026023:Permethrin / Q000633:toxicity*; D020675:Peroxisomes / Q000378:metabolism; D018923:Persian Gulf Syndrome / Q000378:metabolism*; D010713:Phosphatidylcholines / Q000378:metabolism*; D011597:Psychomotor Performance / Q000187:drug effects; D011729:Pyridostigmine Bromide / Q000633:toxicity*; D011897:Random Allocation; D045442:Rotarod Performance Test; D012678:Sensation Disorders / Q000139:chemically induced* / Q000378:metabolism / Q000473:pathology; D013109:Sphingomyelins / Q000378:metabolism*; D013230:Stearoyl-CoA Desaturase / Q000378:metabolism
D005227:Fatty Acids; D009419:Nerve Tissue Proteins; D010713:Phosphatidylcholines; D013109:Sphingomyelins; D003671:DEET; D026023:Permethrin; D013230:Stearoyl-CoA Desaturase; D011729:Pyridostigmine Bromide