Damodaran, TV; Greenfield, ST; Patel, AG; Abou-Donia, MB
Sarin induced global gene expression patterns for an early time point (2 hrs: 0.5 X LD50 ) and late time point (3-months:1 X LD50) were studied using affymetrix : Rat Neurobiology U34 chips in Dawley-Sprague rats. A total of 46 and 38 genes were identified, showing statistically significant alteration from control levels at 2 hrs and 3-months respectively. At 2 hrs, genes that are classified as ion channels (8), calcium channels and binding proteins (6) were more in number than any other groups. Other genes that showed changes included: 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), mitochondrial associated proteins (2), myelin proteins (2), stress activated molecules (2), cytokines (1), capsases (1), GABAnergic (1), glutamergic (1), immediate early gene (1), prostaglandins (1), transcription factors(1), and tyrosine phosphorylation molecules(1). At threemonth, genes that are classified as calcium channels and binding proteins, cytoskeletal and cell adhesion molecules, GABAnergic signaling molecules were more in number than any other group. The microarray data showed persistent altered expression in 8 genes at all time points. Selected genes from each of these time points were further validated using RT-PCR. Principal component analysis (PCA) of the expression data of the time points was used for comparative analysis of the gene expression, which indicated that the changes in gene expression is a function of dose, time of euthanasia after the treatment and age of the animal. Our model also predicts that both degenerative and regenerative pathways activated early, contribute to the level of neurodegeneration at later time, leading to neuropathological alterations.