title: Toxicogenomic studies of the rat brain at an early time point following acute sarin exposure.
abstract: We have studied sarin-induced global gene expression patterns at an early time point (2 h: 0.5 x LD50) using Affymetrix Rat Neurobiology U34 chips and male Sprague-Dawley rats. A total of 46 genes showed statistically significant alterations from control levels. Three gene categories contained more of the altered genes than any other groups: ion channel (8 genes) and calcium channel and binding proteins (6 genes). Alterations were also found in the following gene groups: ATPases and ATP-based transporters (4), growth factors (4), G-protein-coupled receptor pathway-related molecules (3), neurotransmission and neurotransmitter transporters (3), cytoskeletal and cell adhesion molecules (2), hormones (2), mitochondria-associated proteins (2), myelin proteins (2), stress-activated molecules (2), cytokine (1), caspase (1), GABAnergic (1), glutamergic (1), immediate early gene (1), prostaglandin (1), transcription factor (1), and tyrosine phosphorylation molecule (1). Persistent alteration of the following genes also were noted: Arrb1, CaMKIIa, CaMKIId, Clcn5, IL-10, c-Kit, and Plp1, suggesting altered GPCR, kinase, channel, and cytokine pathways. Selected genes from the microarray data were further validated using relative RT-PCR. Some of those genes (GFAP, NF-H, CaMKIIa, Calm, and MBP) have been shown by other laboratories and ours, to be involved in the pathogenesis of sarin-induced pathology and organophosphate-induced delayed neurotoxicity (OPIDN). Induction of both proapoptotic (Bcl2l11, Casp6) and antiapoptotic (Bcl-X) genes, besides suppression of p21, suggest complex cell death/protection-related mechanisms operating early on. Principal component analysis (PCA) of the expression data confirmed that the changes in gene expression are a function of sarin exposure, since the control and treatment groups separated clearly. Our model (based on current and previous studies) indicates that both degenerative and regenerative pathways are activated early and contribute to the level of neurodegeneration at a later time, leading to neuro-pathological alterations.
authors.affiliation: Department of Pharmacology and Cancer Biology, Duke University Medical Center, P.O. Box 3813, Durham, NC, 27710, USA. damolambopranav@hotmail.com
authors.forename: Tirupapuliyur V
authors.initials: TV
authors.lastname: Damodaran
authors.forename: Stephen T
authors.initials: ST
authors.lastname: Greenfield
authors.forename: Anand G
authors.initials: AG
authors.lastname: Patel
authors.forename: Holly K
authors.initials: HK
authors.lastname: Dressman
authors.forename: Siomon K
authors.initials: SK
authors.lastname: Lin
authors.forename: Mohamed B
authors.initials: MB
authors.lastname: Abou-Donia
mesh_terms: D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D002619:Chemical Warfare Agents / Q000633:toxicity*; D020869:Gene Expression Profiling; D008297:Male; D020411:Oligonucleotide Array Sequence Analysis; D025341:Principal Component Analysis; D051381:Rats; D017207:Rats, Sprague-Dawley; D012524:Sarin / Q000633:toxicity*; D023382:Toxicity Tests, Acute
chemical_list: D002619:Chemical Warfare Agents; D012524:Sarin