A new murine model of giant proximal axonopathy.
The aromatic gamma-diketone 1,2-diacetylbenzene (1,2-DAB), the putative active metabolite of the organic solvent 1,2-diethylbenzene, forms blue-colored polymeric protein adducts and induces the formation of amyotrophic lateral sclerosis (ALS)-like giant, intraspinal neurofilamentous axonal swellings in Sprague Dawley rats. The pathogenetic mechanism of this neuropathy has yet to be understood. We assessed whether these pathological changes are also seen in the C57BL/6 mouse, the animal of choice for toxicogenomic studies. Mice were treated intraperitoneally with 30, 35, 50, or 70 mg/kg 1,2-DAB or its inactive isomer 1,3-DAB per day (or on alternate days) for up to 43 days. Animals treated with 30 or 35 mg/kg per day 1,2-DAB, but not with 1,3-DAB, developed muscle spasms and progressive weakness, most prominently in hind limbs. Light microscopy revealed swollen axons in spinal anterior horns and proximal ventral roots, and to a lesser extent in dorsal root ganglia of 1,2-DAB-treated animals. Ultrastructural examination of swollen axons revealed clumps of maloriented 10-nm neurofilaments. Sciatic nerves showed clustering of axonal microtubules and other organelles. These findings are qualitatively comparable to those reported in rats treated with 1,2-DAB and represent a suitable phenotype with which to explore molecular mechanisms of proximal, giant neurofilamentous axonopathy using proteomic and genomic technologies.
Tshala-Katumbay
D D
DD
Center for Research on Occupational and Environmental Toxicology, Oregon Health and Science University, Portland, OR 97239, USA.
Palmer
V S
VS
Kayton
R J
RJ
Sabri
M I
MI
Spencer
P S
PS
D000098:Acetophenones / Q000633:toxicity*; D000690:Amyotrophic Lateral Sclerosis / Q000139:chemically induced* / Q000473:pathology* / Q000503:physiopathology; D000818:Animals; D001369:Axons / Q000187:drug effects* / Q000473:pathology / Q000648:ultrastructure; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D046529:Microscopy, Electron, Transmission / Q000379:methods; D011897:Random Allocation; D013116:Spinal Cord / Q000187:drug effects / Q000473:pathology / Q000648:ultrastructure; D013997:Time Factors
D000098:Acetophenones; C048792:1,2-diacetylbenzene