Relationship between insult intensity and mode of hair cell loss in the vestibular system of rats exposed to 3,3 '-iminodipropionitrile

A variety of stimuli cause sensory hair cell loss in the mammalian inner ea r. This loss occurs by several differing processes, the significance of whi ch remains undetermined. This study examines the relationship between the i ntensity of the damaging stimulus and the mode of hair cell loss found in t he vestibular sensory epithelia of the rat. The ototoxin 3,3'-iminodipropio nitrile (IDPN) was administered to rats at three different intoxication rat es: acute exposure to high doses, repeated exposure to intermediate doses, and subchronic exposure to low doses. The morphology of the vestibular epit helia was examined by light microscopy and by scanning and transmission ele ctron microscopy (SEM and TEM). In addition, DNA fragmentation in the epith elia was assessed by terminal deoxynucleotidyl transferase (tdt)-dUTP-nick- end-label (TUNEL). One day after acute IDPN, necrosis of hair cells was obs erved. However, at day 4 with this dose, and 1 and 4 days after repeated ex posure, apoptotic figures and positive TUNEL labeling predominated. Subchro nic IDPN resulted in a slowly evolving extrusion of basically intact hair c ells in the crista and utricle. The data demonstrate that extrusion is a ma jor mechanism of hair cell demise in mammals, that necrosis, apoptosis, and extrusion form a continuum of modes of hair cell loss, and that the intens ity of the damaging stimulus determines the prevalence of each mode: Necros is was most evident when the intensity was at its highest, whereas extrusio n predominated when the intensity was at the lowest end of the scale. (C) 2 001 Wiley-Liss, Inc.