Pathology of the rat vestibular sensory epithelia during subchronic 3,3'-iminodipropionitrile exposure: hair cells may not be the primary target of toxicity.

3,3'-Iminodipropionitrile (IDPN) is a neurotoxic compound that causes proximal neurofilamentous axonopathy and loss of the vestibular sensory hair cells. During subchronic exposure, the hair cells are eliminated by extrusion of the virtually intact cell from the sensory epithelia towards the luminal cavity. We describe the alterations of the vestibular epithelia before and during hair cell extrusion. Adult male Long-Evans rats were exposed to 0.2% IDPN in the drinking water for 1, 3, 5, 8 or 14 weeks, or to 0.1% IDPN for 14 weeks. Protrusion and subsequent extrusion of hair cells were observed in the cristae and utricular maculae of rats exposed to 0.2% IDPN for at least 5 weeks. At earlier time points and at lower doses, we observed the following pathological signs: blebbing of hair cells, swelling, retraction and fragmentation of the afferent nerve terminals, detachment of hair cells from the surrounding structures and loss of the pre- and post-synaptic membrane thickenings between hair cells and their afferent terminals. Widespread enlargement of the intercellular spaces also preceded and accompanied the extrusion process. The present data challenge the hypothesis that IDPN specifically affects hair cells.