Quantitative morphometric analysis was used to characterize expression of myelinated axon swelling and atrophy in rat peripheral nerve during 2,5- hexanedione (HD) intoxication. HD was administered by gavage according to different daily dosing regiments (100, 175, 250, or 400 mg/kg/day) and four proximodistal nerve regions (5th lumbar spinal nerve, proximal and distal sciatic nerve, and tibial nerve) were examined morphometrically. Morphometric determinations were made at four behavioral endpoints (unaffected, slight, moderate, and severe toxicity) and were correlated to electrophysiologic measurements of peripheral nerve function. Results show that, for all HD dose rates, onsets of behavioral neurotoxicity and nerve dysfunction were generally related to development of abundant axon atrophy. The proximodistal manifestation of atrophy was dependent upon the dosing rate; i.e., the atrophy response produced by subacute intoxication with higher daily dosing rates (250 and 400 mg/kg/day) was restricted to distal nerve regions whereas subchronic induction with lower dosing rates (100 and 175 mg/kg/day) produced abundant fiber atrophy in all proximodistal areas. In contrast to atrophy, axonal swellings constituted an inconsistent minor morphologic response, the expression of which was dependent upon subchronic dosing rates (100-250 mg/kg/day). Subacute HD administration (400 mg/kg/day) produced significant changes in neurobehavior and nerve electrophysiologic parameters in the absence of peripheral axon swelling. Thus, conditional expression of swellings suggests they are an epiphenomenon related to low-dose induction rates. Fiber atrophy, however, was numerically dominant, correlated with nerve dysfunction, and occurred at all dosing levels. These characteristics suggest atrophy is a neurotoxicologically significant feature of ≥-diketone peripheral neuropathy. (C) 2000 Academic Press.
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