Wednesday, February 04, 2009

Neurotoxicity of n-Hexane explored, 1,2-diethylbenzene revealed

Toxicol. Sci. 2009 107: 482-489; doi:10.1093/toxsci/kfn241.
Probing Mechanisms of Axonopathy. Part II: Protein Targets of 2,5-Hexanedione, the Neurotoxic Metabolite of the Aliphatic Solvent n-Hexane
Desire Tshala-Katumbay, Victor Monterroso, Robert Kayton, Michael
Lasarev, Mohammad Sabri, and Peter Spencer
* Department of Neurology Center for Research on Occupational & Environmental Toxicology Department of Comparative Medicine, School of Medicine, Oregon Health & Science University, Portland, Oregon 97239
1 To whom correspondence should be addressed at Center for Research on Occupational and Environmental Toxicology, Oregon Health & Science University, 3181 S.W. Jackson Park Road, mail code L606, Portland, OR 97239. Fax: (503) 494-6831. E-mail:

Neuroprotein changes in the spinal cord of rodents with aliphatic -diketone axonopathy induced by 2,5-hexanedione (2,5-HD) are compared with those reported previously in aromatic -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% dimethyl sulfoxide (vehicle), 5 days a week, for 3 weeks. Analysis of the lumbosacral proteome by 2-dimensional differential in-gel electrophoresis and matrix-assisted laser desorption ionization time-of-flight/tandem mass spectrometry revealed 34 proteins markedly modified by 2,5-HD of which neurofilament triplet L, gelsolin, protein disulfide isomerase, glutathione S-transferase, nicotinamide adenine dinucleotide (reduced) dehydrogenase 1, 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; -diketones; proteomics; solvent neurotoxicity; neurodegeneration.
BrooklynDodger(s) comment: The Dodger(s) fear(s) that this high tech mechanistic work, which is essentially hazard identification, will eventually become another barrier to risk assessment - agents which don't alter these proteins but do cause whole animal effects will be judged irrelevent. Confessing again not to have searched out the whole text, what does "modified" mean? Increased, decreased, absolute concentration or proportion? Does 1,2-DAB have neurotoxic effects in the whole animal - it's a really neat anologue of n-hexane. Potency per mole rather than mg?

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