ToxSci Advance Access published online on May 5, 2009
Toxicological Sciences, doi:10.1093/toxsci/kfp091
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Neurotoxicogenomic Investigations to Assess Mechanisms of Action of the Munitions Constituents RDX and 2,6-DNT in Northern Bobwhite (Colinus virginianus)
* U.S. Army Corps of Engineers, Environmental Laboratory, EP-P, Vicksburg, MS 39180, Phone: 601-634-2366, karl.j.indest{at}erdc.usace.army.mil, Phone: 601-634-2954, joan.clarke{at}usace.army.mil, Phone: 601-634-2872, edward.j.perkins{at}erdc.usace.army.mil
The Johns Hopkins University, School of Medicine, Baltimore, MD 21287, Phone: 410-502-5740, mpirooz1{at}jhmi.edu
¶ U.S. Army Center for Heath Promotion and Preventative Medicine, Edgewood, MD 21010, Phone: 410-436-1064, michael.james.quinn{at}us.army.mil, Phone: 410-436-5081, mark.s.johnson{at}us.army.mil
SpecPro Inc. 3909 Halls Ferry Rd. ERDC-USACE-EL-EP-P Vicksburg, MS 39180, Phone: 601-634-3646, lynn.escalon{at}erdc.usace.army.mil, xin.guan{at}erdc.usace.army.mil, Phone: 601-634-5229, youping.deng{at}erdc.usace.army.mil, Phone: 601-634-3521, ping.gong{at}erdc.usace.army.mil
(Corresponding Author): Phone: 601-634-3593, Fax: 601-634-4002, kurt.a.gust{at}usace.army.mil
Received February 9, 2009; revision received April 17, 2009; accepted April 20, 2009
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Abstract |
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Munitions constituents (MCs) including hexahydro-1,3,5-trinitro-1,3,5-triazine (RDX), 2,4,6-trinitrotoluene (TNT) and TNT derivatives are recognized to elicit aberrant neuromuscular responses in many species. The onset of seizures resulting in death was observed in the avian-model Northern bobwhite after oral dosing with RDX beginning at 8 mg/kg/d in subacute (14d) exposures, whereas affective doses of the TNT derivative, 2,6-dinitrotoluene (2,6-DNT) caused gastrointestinal impacts, lethargy and emaciation in subacute and subchronic (60d) exposures. To assess and contrast the potential neurotoxicogenomic effects of these MCs, a Northern bobwhite microarray was developed consisting of 4119 cDNA features enriched for differentially expressed brain transcripts from exposures to RDX and 2,6-DNT. RDX affected hundreds of genes in brain tissue whereas 2,6-DNT affected few (
17) indicating that 2,6-DNT exposure had relatively little impact on the brain in comparison to RDX. Birds exhibiting RDX-induced seizures accumulated over 20x more RDX in brain tissues in comparison to non-seizing birds even within a common dose. In parallel, expression patterns were unrelated among seizing and non-seizing birds exposed to equivalent RDX doses. In birds experiencing seizures genes related to neuronal electrophysiology and signal transduction were significantly affected. Comparative toxicology revealed strong similarity in acute exposure effects between RDX and the organochlorine insecticide dichlorodiphenyltrichloroethane (DDT) regarding both molecular mechanisms and putative mode of action. In a manner similar to DDT, we hypothesize that RDX elicits seizures by inhibition of neuronal cell repolarization post-action potential leading to heightened neuronal excitability and seizures facilitated by multiple molecular mechanisms.
Key Words: Munitions Constituents; Genomics; Mechanisms of Action; Seizures.