HAIR CELL DEGENERATION RESULTING FROM 3,3'-IMINODIPROPIONITRILE TOXICITY IN THE RAT VESTIBULAR EPITHELIA

The present work was aimed at characterizing, using both scanning- and transmission-electron microscopy, the morphological changes occurring in the vestibular sensory epithelia of rats exposed to the synthetic nitrile 3,3'-iminodipropionitrile (IDPN), that belongs to a new class of vestibulotoxic compounds. Male Long-Evans rats were administered 0, 200, 400, 600, 800 or 1000 mg/kg of IDPN (i.p., in 2 ml/kg saline), a nd sacrificed at 1 day to 34 weeks post-dosing. IDPN induced a selecti ve hair cell (HC) loss. Little evidence of HC degeneration was found a fter 200 mg/kg, but loss of HC was evident after 400 mg/kg. The HC deg eneration was almost complete after 600 mg/kg, and complete after 1000 mg/kg of IDPN. Both intra-epitherial (central regions of the receptor s > peripheral regions) and inter-epithelial (crista > utricle > saccu le) differences in sensitivity were found. Type I HC were found to be more sensitive to the toxic effects of IDPN than type II HC. The degen eration process was characterized by cytoplasm vacuolization. The vacu oles likely originated from the endoplasmic reticulum. Alterations in the cell nucleus, mitochondria, and ciliary structures appeared to occ ur later in the degeneration process. The membrane of the degenerating HC was found to detach from the innervating terminals, and disappeara nce of the pre-, post-, and synaptic-cleft densities was observed. A s triking preservation of both afferent and efferent terminals was obser ved to occur. Nerve terminals remained in place during the acute perio d of the IDPN toxicity and after HC loss, degenerating only after long times of deafferentation. The HC degeneration induced by IDPN occurre d mostly within 8 days post-dosing, and was finished by 3 weeks post-d osing. No evidence for further degeneration nor for regeneration of th e HC was found at 6, 10, or 34 weeks post-dosing. The only changes in the morphology of the vestibular receptors after 3 weeks of survival w as the placement of the otoconia from the utriculi of the high-dose an imals below a thin layer of cells, and a slow degeneration of the deaf ferented nerve endings. The present work demonstrates that IDPN has a specific toxic effect on the vestibular HC.