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Toxicogenomic Studies of the Rat Brain at an Early Time Point Following Acute Sarin Exposure

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Abstract

We have studied sarin-induced global gene expression patterns at an early time point (2 h: 0.5×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.

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Abbreviations

ACh:

Acetylcholine

AChE:

Acetylcholinesterase

ATP:

Adenosine Tri-Phosphate

BBB:

Blood–Brain-Barrier

CREB:

cAMP-Response Element Binding Protein

Calm:

Calmodulin

CaMKII:

Ca2+/Calmodulin-dependent Protein Kinase II

CaRE:

Calcium Response Element

cAMP:

Cyclic AMP

CBP:

CREB-Binding Protein

CNS:

Central Nervous System

CTF:

Constitutional Transcriptional Factors

CRE:

Cyclic-AMP Responsive Element

DEPC:

Diethylpyrocarbonate

DFP:

Diisopropyl Phosphorofluoridate

ERK:

Extra-cellular signal-Regulated Kinase

GFAP:

Glial Fibrillary Acidic Protein

HSP:

Heat Shock Proteins

IEG:

Immediate Early Gene

ITF:

Inducible Transcriptional Factor

JNK:

Jun-C N-terminal Kinase

MSK:

Mitogen and Stress activated Kinase

MAPK:

Mitogen Activated Protein Kinase

MBP:

Myelin Basic Protein

NF:

Neurofilament(s)

NF-H:

Neurofilament High molecular weight protein

OP:

Organophosphates

OPICN:

Organophosphorus ester-Induced Chronic Neurotoxicity

OPIDN:

Organophosphorus ester Induced Delayed Neurotoxicity

p-CREB:

Phospho-CREB

PCA:

Principle Component Analysis

PCD:

Programmed Cell Death

PKA:

Protein Kinase A

RT-PCR:

Reverse Transcriptase Polymerase Chain Reaction

SAPK:

Stress Activated Protein Kinase

SRE:

Serum Response Element

SRF:

Serum Response Factor

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Acknowledgements

This work is supported in part by the U.S Army Medical Research and Materiel Command under contract no: DAMD 17-98-8027. The views, opinions, and/or findings contained in this report are those of the author(s) and should not be construed as official Department of the Army positions, policy, or decisions, unless so designated by other documentation.

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Authors and Affiliations

  1. Department of Pharmacology and Cancer Biology, Duke University Medical Center, P.O. Box 3813, Durham, NC, 27710, USA

    Tirupapuliyur V. Damodaran, Stephen T. Greenfield, Anand G. Patel & Mohamed B. Abou-Donia

  2. Division of Medical Genetics, Department of Pediatrics, Duke University Medical Center, Durham, NC, 27710, USA

    Tirupapuliyur V. Damodaran

  3. Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, NC, USA

    Holly K. Dressman

  4. Department of Biostatistics and Bioinformatics, Duke University Medical Center, Durham, NC, USA

    Siomon K. Lin

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  1. Tirupapuliyur V. Damodaran
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Correspondence to Tirupapuliyur V. Damodaran or Mohamed B. Abou-Donia.

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Note: Explanations for gene symbols used in the text, figures, and flow charts can be found in Table 2, corresponding to the list of genes and their classifications.

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Damodaran, T.V., Greenfield, S.T., Patel, A.G. et al. Toxicogenomic Studies of the Rat Brain at an Early Time Point Following Acute Sarin Exposure. Neurochem Res 31, 367–381 (2006). https://doi.org/10.1007/s11064-005-9023-5

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