Comparison of cis- and trans-crotononitrile effects in the rat reveals specificity in the neurotoxic properties of nitrile isomers.

The neurotoxic compound crotononitrile has two isomeric forms, cis and trans. We compared the effects of these two isomers isolated by distillation from the commercially available mixture. Adult male Long-Evans rats were administered vehicle control, cis-crotononitrile (80, 100, and 120 mg/kg/day), or trans-crotononitrile (250 mg/kg/day) for 3 days and the changes in corneal transparency and vestibular function were assessed. Surface preparations of the vestibular sensory epithelia and the organ of Corti were examined for hair cell loss by scanning electron microscopy. Concentrations in retina and brain regions of glial fibrillary acidic protein, a marker for reactive gliosis, were also determined in rats exposed to cis-crotononitrile. In a dose-dependent manner, cis-crotononitrile induced vestibular dysfunction, corneal opacity, and hair cell loss in both vestibular epithelia and organ of Corti, and gliosis in retina, olfactory bulb, superior colliculus, inferior colliculus, hypothalamus, hippocampus, and cingulate cortex, but not in cerebellum or striatum. This neurotoxic pattern is similar to that caused by 3,3'-iminodipropionitrile and allylnitrile. In contrast, trans-crotononitrile triggered rearing deficits but not vestibular dysfunction, hair cell loss, or corneal opacity. The isomeric specificity of crotononitrile isomers shows that the neurotoxic effects of nitriles depend on strict structural requirements, suggesting that they act through interaction with specific molecular targets.