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), and sacrificed at 1 day to 34 weeks post-dosing. IDPN induced a selective hair cell (HC) loss. Little evidence of HC degeneration was found after 200 mg/kg, but loss of HC was evident after 400 mg/kg. The HC degeneration was almost complete after 600 mg/kg, and complete after 1000 mg/kg of IDPN. Both intra-epitherial (central regions of the receptors > peripheral regions) and inter-epithelial (crista > utricle > saccule) 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 degeneration process was characterized by cytoplasm vacuolization. The vacuoles likely originated from the endoplasmic reticulum. Alterations in the cell nucleus, mitochondria, and ciliary structures appeared to occur later in the degeneration process. The membrane of the degenerating HC was found to detach from the innervating terminals, and disappearance of the pre-, post-, and synaptic-cleft densities was observed. A striking preservation of both afferent and efferent terminals was observed to occur. Nerve terminals remained in place during the acute period of the IDPN toxicity and after HC loss, degenerating only after long times of deafferentation. The HC degeneration induced by IDPN occurred mostly within 8 days post-dosing, and was finished by 3 weeks post-dosing. No evidence for further degeneration nor for regeneration of the 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 was the placement of the otoconia from the utriculi of the high-dose animals below a thin layer of cells, and a slow degeneration of the deafferented nerve endings. The present work demonstrates that IDPN has a specific toxic effect on the vestibular HC.