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Neuropathological Studies of Rats Following Multiple Exposure to Tri-Ortho-Tolyl Phosphate, Chlorpyrifos and StressLaboratory for Neurotoxicity Studies, Virginia-Maryland Regional College of Veterinary Medicine, Virginia Tech, Blacksburg, Virginia 24061-0442, USA Correspondence: Address correspondence to: Bernard S. Jortner, VMD, Laboratory for Neurotoxicity Studies, Virginia-Maryland Regional College of Veterinary Medicine, Virginia Tech, Blacksburg, Virginia 24061-0442, USA, e-mail:bjortner{at}vt.edu Adult male Long-Evans rats were exposed to 2 neurotoxic organophosphates in a setting of chronic stress, over a 63-day period. The organophosphates were tri-ortho-tolyl phosphate (TOTP) administered in 14 gavage doses of 75, 150 or 300 mg/kg, and chlorpyrifos, given in two 60 mg/kg subcutaneous exposures. Corticosterone was added to the drinking water at 400 µg/ml, to model aspects of chronic stress. These compounds/dosages were administered individually and in combination, with appropriate controls, giving rise to 16 experimental groups. The major neuropathologic change was the presence of axonal degeneration progressing to myelinated fiber degeneration, mainly in distal regions of selected fiber tracts and peripheral nerve, seen in animals sacrificed on experimental day 63. The cervical spinal cord and medullary levels of the sensory gracile fasciculus were most prominently affected. This axonopathy/fiber degeneration was TOTP dose-related at the 300 and 150 mg/kg levels. There was association of this lesion with inhibition of the enzyme neurotoxic esterase in hippocampal tissue from TOTP-treated rats. Such an association categorizes this disease process as organophosphate ester-induced delayed neuropathy. Neither chlorpyrifos nor corticosterone appeared to contribute to the neuropathic events or the enzyme inhibition. A cohort of rats was maintained on the corticosterone dosing, but without additional exposure to TOTP or chlorpyrifos, for an additional 27 days. When these rats were examined on day 90, the nerve fiber degeneration had progressed in all experimental groups administered the 300 mg/kg dose of TOTP (lower doses were not studied at the 90-day interval), although hippocampal neurotoxic esterase had returned to control values.
Key Words: Organophosphorus ester-induced delayed neuropathy • tri-ortho-tolyl phosphate • chlorpyrifos • corticosterone • stress • rat Abbreviations: CHAT, choline acetyltransferase • FOB, Functional Observational Battery • GFAP, glial fibrillary acidic protein • H&E, hematoxylin and eosin • NTE, neurotoxic esterase • OPIDN, organophosphorus ester-induced delayed neuropathy • TOTP, tri-ortho-tolyl phosphate • TUNEL, terminal deoxynucleotidyl transferase nick-end labeling • USEPA, United States Environmental Protection Agency
Toxicologic Pathology, Vol. 33, No. 3,
378-385 (2005) |
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