Gene expression profiles of the rat brain both immediately and 3 months following acute sarin exposure.
We have studied sarin-induced global gene expression patterns at an early time point (15 min; 0.5xLD50) and a later time point (3 months; 1xLD50) using Affymetrix: Rat Neurobiology U34 chips in male, Sprague-Dawley rats and have identified a total of 65 (early) and 38 (late) genes showing statistically significant alterations from control levels at 15 min and 3 months, respectively. At the early time point, those that are classified as ion channel, cytoskeletal and cell adhesion molecules, in addition to neuropeptides and their receptors predominated over all other groups. The other groups included: cholinergic signaling, calcium channel and binding proteins, transporters, chemokines, GABAnergic, glutamatergic, aspartate, catecholaminergic, nitric oxide synthase, purinergic, and serotonergic signaling molecules. At the late time point, genes that are classified as calcium channel and binding proteins, cytoskeletal and cell adhesion molecules and GABAnergic signaling molecules were most prominent. Seven molecules (Ania-9, Arrb-1, CX-3C, Gabab-1d, Nos-2a, Nrxn-1b, PDE2) were identified that showed altered persistent expression in both time points. Selected genes from each of these time points were further validated using semi quantitative RT-PCR approaches. Some of the genes that were identified in the present study have been shown to be involved in organophosphate-induced neurotoxicity by both other groups as well as ours. Principal component analysis (PCA) of the expression data from both time points was used for comparative analysis of the gene expression, which indicated that the changes in gene expression were a function of dose and time of euthanasia after the treatment. Our model also predicts that besides dose and duration of post-treatment period, age and possibly other factors may be playing important roles in the regulation of pathways, leading to the neurotoxicity.
Damodaran
Tirupapuliyur V
TV
Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC 27710, USA.
Patel
Anand G
AG
Greenfield
Stephen T
ST
Dressman
Holly K
HK
Lin
Simon M
SM
Abou-Donia
Mohamed B
MB
D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D015220:Calcium Channels / Q000235:genetics; D002619:Chemical Warfare Agents / Q000633:toxicity; D002800:Cholinesterase Inhibitors / Q000633:toxicity; D016000:Cluster Analysis; D020869:Gene Expression Profiling / Q000379:methods*; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D007273:Injections, Intramuscular; D008297:Male; D019001:Nitric Oxide Synthase / Q000235:genetics; D020411:Oligonucleotide Array Sequence Analysis / Q000379:methods; D051381:Rats; D017207:Rats, Sprague-Dawley; D018079:Receptors, GABA / Q000235:genetics; D016194:Receptors, N-Methyl-D-Aspartate / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012524:Sarin / Q000633:toxicity*; D013997:Time Factors
D015220:Calcium Channels; D002619:Chemical Warfare Agents; D002800:Cholinesterase Inhibitors; D018079:Receptors, GABA; D016194:Receptors, N-Methyl-D-Aspartate; D012524:Sarin; D019001:Nitric Oxide Synthase