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.