Abstract
The chromogenic and neurotoxic γ-diketone 1,2–diacetylbenzene (1,2-DAB), but not its isomer 1,3-DAB, induces blue discoloration of tissues and urine, clustering of axonal microtubules and proximal neurofilament-filled axonal swellings in rodents. The remarkable chromogenic property of 1,2-DAB, a monocyclic aromatic hydrocarbon, arises from reaction with lysine residues of proteins and formation of dimeric and polymeric derivatives. Tetralin, a dicyclic solvent structurally related to acetyl ethyl tetramethyl tetralin, a chromogenic and neurotoxic agent, reportedly induces excretion of green urine, and causes neurological disturbances in humans. Monocyclic aromatic 1,2,4-triethylbenzene (1,2,4-TEB), but not its isomer 1,3,5-TEB, is also reportedly chromogenic and induces neurophysiological deficits in rodents consistent with axonal neuropathy, but without neuropathological confirmation. We treated 12-week-old C57Bl/6 mice by gavage with 300, 600, or 900 mg/kg/day 1,2,4-TEB, or equivalent doses of 1,3,5-TEB, 3 days/week, for up to 12 weeks, or intraperitoneally with 400 mg/kg/day tetralin, or 50 or 100 mg/kg/day of its α-tetralol analogue, 5 days/week, for up to 5 weeks. Animals treated with 1,2,4-TEB, but not 1,3,5-TEB, tetralin or α-tetralol, developed hind limb weakness, excreted greenish urine, and showed 1,2-DAB-like neuropathology. These findings support the hypothesis that 1,2-spaced ethyl (or acetyl) moieties on a benzene ring of hydrocarbons are required for hydrocarbons to induce chromogenic changes and proximal giant neurofilamentous axonopathy. Key molecular targets of these compounds likely reside in the axon where they serve to maintain normal cytoskeletal organization.
Similar content being viewed by others
References
Al Chalabi A, Miller CC (2003) Neurofilaments and neurological disease. Bioessays 25:346–355
Anthony DC, Boekelheide K, Anderson CW, Graham DG (1983) The effect of 3,4-dimethyl substitution on the neurotoxicity of 2,5-hexanedione. II. Dimethyl substitution accelerates pyrrole formation and protein crosslinking. Toxicol Appl Pharmacol 71:372–382
Anthony DC, Boekelheide K, Graham DG (1983) The effect of 3,4-dimethyl substitution on the neurotoxicity of 2,5-hexanedione. I. Accelerated clinical neuropathy is accompanied by more proximal axonal swellings. Toxicol Appl Pharmacol 71:362–371
Anthony DC, Giangaspero F, Graham DG (1983) The spatio-temporal pattern of the axonopathy associated with the neurotoxicity of 3,4-dimethyl-2,5-hexanedione in the rat. J Neuropathol Exp Neurol 42:548–560
Browning E (1965) Toxicity and metabolism of industrial solvents. American Elsevier, New York
DeCaprio AP (2000) n-Hexane, metabolites, and derivatives. In: Spencer PS, Schaumburg HH (eds) Experimental and clinical neurotoxicology. Oxford University Press, New York pp 633–648
Delisle MB, Carpenter S (1984) Neurofibrillary axonal swellings and amyotrophic lateral sclerosis. J Neurol Sci 63:241–250
Gagnaire F, Ensminger A, Marignac B, De Ceaurriz J (1991) Possible involvement of 1,2-diacetylbenzene in diethylbenzene-induced neuropathy in rats. J Appl Toxicol 11:261–268
Gagnaire F, Marignac B, De Ceaurriz J (1990) Diethylbenzene-induced sensorimotor neuropathy in rats. J Appl Toxicol 10:105–112
Gagnaire F, Marignac B, De Ceaurriz J (1993) Triethylbenzene-induced sensorimotor neuropathy in rats. J Appl Toxicol 13:123–128
Gerarde H (1960) Toxicology and biochemistry of aromatic hydrocarbons. In: Browning E (ed) Elsevier monographs on toxic agents. Elsevier, Amsterdam, p 73
Griffin JW, Parhad I, Gold B, Price DL, Hoffman PN, Fahnestock K (1985) Axonal transport of neurofilament proteins in IDPN neurotoxicity. Neurotoxicology 6:43–53
Hirano A, Donnenfeld H, Sasaki S, Nakano I (1984) Fine structural observations of neurofilamentous changes in amyotrophic lateral sclerosis. J Neuropathol Exp Neurol 43:461–470
Kim MS, Hashemi SB, Spencer PS, Sabri MI (2002) Amino acid and protein targets of 1,2-Diacetylbenzene, a potent aromatic gamma-diketone that induces proximal neurofilamentous axonopathy. Toxicol Appl Pharmacol 183:55–65
Kim MS, Sabri MI, Miller VH, Kayton RJ, Dixon DA, Spencer PS (2001) 1,2-Diacetylbenzene, the neurotoxic metabolite of a chromogenic aromatic solvent, induces proximal axonopathy. Toxicol Appl Pharmacol 177:121–131
Okamoto K, Hirai S, Shoji M, Senoh Y, Yamazaki T (1990) Axonal swellings in the corticospinal tracts in amyotrophic lateral sclerosis. Acta Neuropathol (Berl) 80:222–226
Pinheiro JC, Bates DM (2000) Mixed-effect models in S and S-PLUS. Springer, Berlin Heidelberg New York
R Development Core Team (2004) R: A language and environment for statistical computing. R Foundation for Statistical Computing, Austria
Serve MP, Llewelyn BM, Yu KO, McDonald GM, Olson CT, Hobson DW (1989) Metabolism and nephrotoxicity of tetralin in male Fischer 344 rats. J Toxicol Environ Health 26:267–275
Snyder R (1987) Ethyl Browning’s toxicity and metabolism of industrial solvents. Elsevier, Amsterdam
Spencer PS (2000) Acetyl ethyl tetramethyl tetralin. In: Spencer PS, Schaumburg HH (eds) Experimental and clinical neurotoxicology. Oxford University Press, New York pp 112–115
Spencer PS, Kim MS, Sabri MI (2002) Aromatic as well as aliphatic hydrocarbon solvent axonopathy. Int J Hyg Environ Health 205:131–136
Spencer PS, Schaumburg HH, Sabri MI, Veronesi B (1980) The enlarging view of hexacarbon neurotoxicity. Crit Rev Toxicol 7:279–356
Spencer PS, Sterman AB, Horoupian DS, Foulds MM (1979) Neurotoxic fragrance produces ceroid and myelin disease. Science 204:633–635
Sterman AB, Spencer PS (1981) The pathogenesis of primary internodal demyelination produced by acetyl ethyl tetramethyl tetralin: evidence for preserved Schwann cell somal function. J Neuropathol Exp Neurol 40:112–121
Trimpin S, Mixon AE, Stapels MD, Kim MY, Spencer PS, Deinzer ML (2004) Identification of endogenous phosphorylation sites of bovine medium and low molecular weight neurofilament proteins by tandem mass spectrometry. Biochemistry 43:2091–2105
Tshala-Katumbay DD, Palmer VS, Kayton RJ, Sabri MI, Spencer PS (2005) A new murine model of giant proximal axonopathy. Acta Neuropathol (Berl) 109:405–410
Zagoren JC, Politis MJ, Spencer PS (1983) Rapid reorganization of the axonal cytoskeleton induced by a gamma diketone. Brain Res 270:162–164
Zhan CG, Dixon DA, Sabri MI, Kim MS, Spencer PS (2002) Theoretical determination of chromophores in the chromogenic effects of aromatic neurotoxicants. J Am Chem Soc 124:2744–2752
Acknowledgments
We thank Dan Austin and Juan Muniz for their technical expertise. These studies were supported by PHS grants P42ES10338, U19ES11384, K01NS052183 and the Oregon Worker Benefit Fund.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Tshala-Katumbay, D.D., Palmer, V.S., Lasarev, M.R. et al. Monocyclic and dicyclic hydrocarbons: structural requirements for proximal giant axonopathy. Acta Neuropathol 112, 317–324 (2006). https://doi.org/10.1007/s00401-006-0106-4
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00401-006-0106-4