Monocyclic and dicyclic hydrocarbons: structural requirements for proximal giant axonopathy.
The chromogenic and neurotoxic gamma-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 alpha-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 alpha-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.
Tshala-Katumbay
Desire D
DD
Center for Research on Occupational and Environmental Toxicology, Oregon Health & Science University, 3181 S.W. Jackson Park Road, Portland, OR 97239, USA. tshalad@ohsu.edu
Palmer
Valerie S
VS
Lasarev
Michael R
MR
Kayton
Robert J
RJ
Sabri
Mohammad I
MI
Spencer
Peter S
PS
D000818:Animals; D001369:Axons / Q000473:pathology*; D001522:Behavior, Animal / Q000187:drug effects; D001555:Benzene Derivatives / Q000633:toxicity; D001835:Body Weight; D006841:Hydrocarbons, Aromatic / Q000737:chemistry* / Q000633:toxicity*; D007536:Isomerism; D008124:Locomotion / Q000187:drug effects; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008854:Microscopy, Electron; D009043:Motor Activity / Q000187:drug effects; D020258:Neurotoxicity Syndromes / Q000473:pathology* / Q000523:psychology; D011083:Polycyclic Compounds / Q000737:chemistry* / Q000633:toxicity*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012584:Sciatic Nerve / Q000473:pathology; D013045:Species Specificity; D013116:Spinal Cord / Q000473:pathology; D013329:Structure-Activity Relationship; D013764:Tetrahydronaphthalenes / Q000633:toxicity; D044024:Tetralones / Q000633:toxicity
D001555:Benzene Derivatives; D006841:Hydrocarbons, Aromatic; D011083:Polycyclic Compounds; D013764:Tetrahydronaphthalenes; D044024:Tetralones; C019106:tetralol; C081028:1,2,4-triethylbenzene; C095210:tetralin