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ToxSci Advance Access published online on November 25, 2008
Toxicological Sciences, doi:10.1093/toxsci/kfn241
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© The Author 2008. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For permissions, please email: journals.permissions@oxfordjournals.org

Probing mechanisms of axonopathy. Part II: Protein targets of 2,5-hexanedione, the neurotoxic metabolite of the aliphatic solvent n-hexane.

Desire Tshala-Katumbay*,{ddagger}, Victor Monterroso{dagger}, Robert Kayton{ddagger}, Michael Lasarev{ddagger}, Mohammad Sabri*,{ddagger} and Peter Spencer*,{ddagger}

* Department of Neurology {dagger} Department of Comparative Medicine, School of Medicine {ddagger} Center for Research on Occupational & Environmental Toxicology, Oregon Health & Science University, 3181 SW Sam Jackson Park Road, Portland, Oregon 97239

Corresponding Author, Desire Tshala-Katumbay, M.D., Ph.D., Center for Research on Occupational and Environmental Toxicology, Oregon Health & Science University, 3181 S.W. Jackson Park Road, mail code L606, Portland, Oregon 97239, Telephone: +1 503 494-0999, Facsimile: +1 503 494-6831, Email: tshalad{at}ohsu.edu

Received October 10, 2008; revision received November 7, 2008; accepted November 11, 2008


  Abstract

Neuroprotein changes in the spinal cord of rodents with aliphatic {gamma}diketone axonopathy induced by 2,5-hexanedione (2,5-HD) are compared with those reported previously in aromatic {gamma}diketone-like axonopathy induced by 1,2-diacetylbenzene (1,2-DAB). Sprague-Dawley rats were treated intraperitoneally with 500 mg/kg/day 2,5-HD, equimolar doses of 2,3-hexanedione (negative control), or an equivalent amount of saline containing 50% DMSO (vehicle), 5 days a week, for 3 weeks. Analysis of the lumbosacral proteome by 2D-DIGE and MALDI-TOF/MS-MS revealed 34 proteins markedly modified by 2,5-HD of which neurofilament triplet L, gelsolin, protein disulfide isomerase, glutathione S-transferase, NADH dehydrogenase 1{alpha}, pyruvate kinase, and fatty acid synthase were also modified by 1,2-DAB. The expression of proteins involved in maintaining the physical integrity of the cytoskeleton or controlling the redox and protein-folding mechanisms was reduced, whereas that of proteins supporting energy metabolism was mainly increased. The similarity of the neuroproteomic patterns of 2,5-HD and 1,2-DAB axonopathy suggests common biomarkers and/or mechanisms of neurotoxicity associated with exposure to their parent chemicals, namely the industrial solvents n-hexane and 1,2-diethylbenzene, respectively.

Key Words: axonopathy; biomarkers; {gamma}-diketones; proteomics; solvent neurotoxicity; neurodegeneration.


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