title: Vestibular toxicity of cis-2-pentenenitrile in the rat.
abstract: cis-2-Pentenenitrile, an intermediate in the synthesis of nylon and other products, causes permanent behavioral deficits in rodents. Other low molecular weight nitriles cause degeneration either of the vestibular sensory hair cells or of selected neuronal populations in the brain. Adult male Long-Evans rats were exposed to cis-2-pentenenitrile (0, 1.25, 1.50, 1.75, or 2.0mmol/kg, oral, in corn oil) and assessed for changes in open field activity and rating scores in a test battery for vestibular dysfunction. Surface preparations of the vestibular sensory epithelia were observed for hair cell loss using scanning electron microscopy. A separate experiment examined the impact of pre-treatment with the universal CYP inhibitor,1-aminobenzotriazole, on the effect of cis-2-pentenenitrile on vestibular rating scores. The occurrence of degenerating neurons in the central nervous system was assessed by Fluoro-Jade C staining. cis-2-Pentenenitrile had a dose-dependent effect on body weight. Rats receiving 1.50mmol/kg or more of cis-2-pentenenitrile displayed reduced rearing activity in the open field and increased rating scores on the vestibular dysfunction test battery. Hair cell loss was observed in the vestibular sensory epithelia and correlated well with the behavioral deficits. Pre-treatment with 1-aminobenzotriazole blocked the behavioral effect. Fluoro-Jade C staining did not reveal significant neuronal degeneration in the central nervous system apart from neurite labeling in the olfactory glomeruli. We conclude that cis-2-pentenenitrile causes vestibular toxicity in a similar way to allylnitrile, cis-crotononitrile and 3,3'-iminodipropionitrile (IDPN), and also shares other targets such as the olfactory system with these other nitriles. The present data also suggest that CYP-mediated bioactivation is involved in cis-2-pentenenitrile toxicity.
authors.affiliation: Departament de Ciències Fisiològiques II, Universitat de Barcelona, Feixa Llarga s/n, 08907 Hospitalet de Llobregat-Catalunya, Spain.
authors.forename: Sandra
authors.initials: S
authors.lastname: Saldaña-Ruíz
authors.forename: Gerard
authors.initials: G
authors.lastname: Hernández-Mir
authors.forename: Lara
authors.initials: L
authors.lastname: Sedó-Cabezón
authors.forename: Blanca
authors.initials: B
authors.lastname: Cutillas
authors.forename: Jordi
authors.initials: J
authors.lastname: Llorens
mesh_terms: D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D002490:Central Nervous System / Q000187:drug effects; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation / Q000187:drug effects; D004848:Epithelium / Q000473:pathology; D005452:Fluoresceins; D005456:Fluorescent Dyes; D006198:Hair Cells, Auditory / Q000473:pathology; D008297:Male; D008855:Microscopy, Electron, Scanning; D009043:Motor Activity / Q000187:drug effects; D009570:Nitriles / Q000633:toxicity*; D051381:Rats; D020318:Rats, Long-Evans; D014230:Triazoles / Q000494:pharmacology; D015837:Vestibular Diseases / Q000139:chemically induced* / Q000473:pathology; D014722:Vestibule, Labyrinth / Q000473:pathology
chemical_list: D005452:Fluoresceins; D005456:Fluorescent Dyes; D009570:Nitriles; D014230:Triazoles; C534582:fluoro-jade C; C062712:2-pentenenitrile; C033020:1-aminobenzotriazole; D003577:Cytochrome P-450 Enzyme System