Degeneration and gliosis in rat retina and central nervous system following 3,3′-iminodipropionitrile exposure

3,3'-Iminodipropionitrile (IDPN) exposure causes a neurofilamentous axonopathy and olfactory, audiovestibular and visual toxicity. Many events relevant to these effects and the neurotoxic properties of nitriles as a class remain to be elucidated. We characterized the gliosis associated with the IDPN-induced retinal degeneration in comparison to other effects on the visual and central nervous systems. Gliosis was quantified using an ELISA for the intermediate filament protein, glial fibrillary acidic protein (GFAP). IDPN (0-400 mg kg(-1) day(-1) x 3 days, i.p.) caused corneal opacity and dose- and time-dependent increases in retinal GFAP, up to 26-28 fold of control values at 4 weeks post-exposure; a second peak occurred at 16 weeks. In contrast, GFAP peaked at 1 week in olfactory bulbs (OB), cingulate cortex and hippocampus. Cerebellum and striatum showed no gliosis. Retinal dopamine decreased within 2 weeks. Delayed GFAP increases occurred in superior and inferior colliculi. Retina and superior colliculi also showed increased [H-3]PK-11195 binding. Histological analysis demonstrated progressive degeneration and gliosis in retina and colliculi. Taken together, the data indicate that primary and secondary degenerative events occur in the retina, and that this retinal degeneration induces GFAP increases in retina and superior colliculus. In addition, GFAP assays demonstrated that the retinal toxicity of IDPN is enhanced by CCl4 hepatotoxicity and blocked by methimazole inhibition of flavin-mono-oxygenases, similarly to its ototoxicity. GFAP assays also indicated that neither vestibulotoxic doses of crotononitrile nor olfatotoxic doses of dichlobenil damage the retina. The data support the use of GFAP assays for assessing the retinal toxicity of IDPN and other nitriles. (C) 1999 Elsevier Science B.V. All rights reserved.