title: Potentiation of organophosphorus compound-induced delayed neurotoxicity (OPIDN) in the central and peripheral nervous system of the adult hen: distribution of axonal lesions.
abstract: Clinical manifestations of mild organophosphorus compound-induced delayed neurotoxicity (OPIDN) produced by diisopropylphosphorofluoridate (DFP) in adult hens are potentiated by posttreatment with phenylmethanesulfonyl fluoride (PMSF). The purpose of this study was to assess whether potentiation of mild OPIDN produces a pattern of axonal lesions in the central and peripheral nervous system similar to that seen in severe OPIDN. Groups of 6 hens each were given the following priming/challenge doses sc at 0 and 4 h, respectively: 0.20 ml/kg corn oil/0.50 ml/kg glycerol formal (GF) (control); 0.50 mg/kg DFP/GF (low-dose DFP); 0.50 mg/kg DFP/60 mg/kg PMSF (potentiated DFP); 60 mg/kg PMSF/GF (PMSF alone); 60 mg/kg PMSF/1.5 mg/kg DFP (protected DFP); and 1.5 mg/kg DFP/GF (high-dose DFP). Two hens from each group were used to assay brain neurotoxic esterase (NTE) 24 h after the challenge dose, and the remaining hens were scored for deficits in walking, standing, and perching ability on d 18. Three hens from each group were perfusion-fixed on d 22 and neural tissues were prepared for histologic evaluation. DFP and/or PMSF caused > 88% brain NTE inhibition in all treated groups, compared to control. Protected DFP yielded no clinical deficits and a distribution and frequency of axonal lesions similar to control. PMSF alone produced a small increase in the frequency of lesions in the cervical spinal cord and peripheral nerves compared to control. Low-dose DFP caused minimal ataxia and increased frequency of axonal lesions in dorsal and lateral cervical spinal cord, ventral lumbar spinal cord, and inferior cerebellar peduncles (ICP) compared to control. Potentiated DFP and high-dose DFP produced maximal ataxia and essentially identical increases in the frequency of lesions in dorsal and ventral thoracic spinal cord, lateral lumbar spinal cord, and peripheral nerves compared to low-dose DFP. The results indicate that PMSF potentiation of mild OPIDN induced in adult hens by low-dose DFP results in an overall pattern of axonal degeneration like that produced by a threefold higher dose of DFP alone, and support the hypothesis that potentiation causes an increase in the frequency of axonal lesions in central and peripheral loci normally affected by OPIDN.
authors.affiliation: Department of Environmental and Industrial Health, School of Public Health, University of Michigan, Ann Arbor 48109-2029, USA.
authors.forename: J C
authors.initials: JC
authors.lastname: Randall
authors.forename: B L
authors.initials: BL
authors.lastname: Yano
authors.forename: R J
authors.initials: RJ
authors.lastname: Richardson
mesh_terms: D000818:Animals; D001259:Ataxia / Q000139:chemically induced / Q000503:physiopathology; D001369:Axons / Q000187:drug effects* / Q000473:pathology; D015415:Biomarkers; D001921:Brain / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D001927:Brain Diseases / Q000139:chemically induced* / Q000473:pathology; D002265:Carboxylic Ester Hydrolases / Q000378:metabolism; D002645:Chickens; D004357:Drug Synergism; D004791:Enzyme Inhibitors / Q000633:toxicity*; D005260:Female; D007531:Isoflurophate / Q000633:toxicity*; D017933:Peripheral Nervous System / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D010664:Phenylmethylsulfonyl Fluoride / Q000633:toxicity*; D013116:Spinal Cord / Q000187:drug effects / Q000473:pathology; D013979:Tibial Nerve / Q000187:drug effects / Q000473:pathology
chemical_list: D015415:Biomarkers; D004791:Enzyme Inhibitors; D007531:Isoflurophate; D010664:Phenylmethylsulfonyl Fluoride; D002265:Carboxylic Ester Hydrolases; C021859:neurotoxic esterase