title: Gene expression profiling of rat hippocampus following exposure to the acetylcholinesterase inhibitor soman.
abstract: Soman (O-pinacolyl methylphosphonofluoridate) is a potent neurotoxicant. Acute exposure to soman causes acetylcholinesterase inhibition, resulting in excessive levels of acetylcholine. Excessive acetylcholine levels cause convulsions, seizures, and respiratory distress. The initial cholinergic crisis can be overcome by rapid anticholinergic therapeutic intervention, resulting in increased survival. However, conventional treatments do not protect the brain from seizure-related damage, and thus, neurodegeneration of soman-sensitive brain areas is a potential postexposure outcome. We performed gene expression profiling of the rat hippocampus following soman exposure to gain greater insight into the molecular pathogenesis of soman-induced neurodegeneration. Male Sprague-Dawley rats were pretreated with the oxime HI-6 (l-(((4-aminocarbonyl)pyridinio)methoxyl)methyl)-2-((hydroxyimino)methyl)-pyridinium dichloride; 125 mg/kg, ip) 30 min prior to challenge with soman (180 microg/kg, sc). One minute after soman challenge, animals were treated with atropine methyl nitrate (2.0 mg/kg, im). Hippocampi were harvested 1, 3, 6, 12, 24, 48, 72, 96, and 168 h after soman exposure and RNA extracted to generate microarray probes for gene expression profiling. Principal component analysis of the microarray data revealed a progressive alteration in gene expression profiles beginning 1 h postexposure and continuing through 24 h postexposure. At 48 h to 168 h postexposure, the gene expression profiles clustered nearer to controls but did not completely return to control profiles. On the basis of the principal component analysis, analysis of variance was used to identify the genes most significantly changed as a result of soman at each postexposure time point. To gain insight into the biological relevance of these gene expression changes, genes were rank ordered by p-value and categorized using gene ontology-based algorithms into biological functions, canonical pathways, and gene networks significantly affected by soman. Numerous signaling and inflammatory pathways were identified as perturbed by soman. These data provide important insights into the molecular pathways involved in soman-induced neuropathology and a basis for generating hypotheses about the mechanism of soman-induced neurodegeneration.
authors.affiliation: Cell and Molecular Biology Branch, US Army Medical Research Institute of Chemical Defense, Aberdeen Proving Ground, Maryland 21010-5400, USA. james.dillman@us.army.mil
authors.forename: James F
authors.initials: JF
authors.lastname: Dillman
authors.forename: Christopher S
authors.initials: CS
authors.lastname: Phillips
authors.forename: Denise M
authors.initials: DM
authors.lastname: Kniffin
authors.forename: Christina P
authors.initials: CP
authors.lastname: Tompkins
authors.forename: Tracey A
authors.initials: TA
authors.lastname: Hamilton
authors.forename: Robert K
authors.initials: RK
authors.lastname: Kan
mesh_terms: D000818:Animals; D001286:Atropine Derivatives / Q000008:administration & dosage; D002800:Cholinesterase Inhibitors / Q000008:administration & dosage / Q000633:toxicity*; D020869:Gene Expression Profiling; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism*; D015850:Interleukin-6 / Q000378:metabolism; D008297:Male; D020411:Oligonucleotide Array Sequence Analysis; D025341:Principal Component Analysis; D051381:Rats; D017207:Rats, Sprague-Dawley; D012999:Soman / Q000008:administration & dosage / Q000633:toxicity*; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D001286:Atropine Derivatives; D002800:Cholinesterase Inhibitors; D015850:Interleukin-6; D014409:Tumor Necrosis Factor-alpha; C006649:methylatropine; D012999:Soman