CHARACTERIZATION OF THE EFFECTS OF N-HYDROXY-IDPN ON THE AUDITORY, VESTIBULAR, AND OLFACTORY SYSTEMS IN RATS

The mechanism of neurotoxicity of 3,3'-iminodipropionitrile (IDPN) has been widely debated, with either the parent compound or putative meta bolites implicated in various studies. The N-hydroxylated form of IDPN (HO-IDPN) has been reported to cause the excitation with choreiform a nd circling (ECC) syndrome in rats at doses approximately one-eighth o f that required to cause comparable signs in rats treated with IDPN. B ecause of the similarity of symptoms induced by HO-IDPN and IDPN, we i nvestigated the effect of HO-IDPN on other aspects of the nervous syst em affected by IDPN, specifically the auditory, vestibular, and olfact ory systems. In addition, ECC symptoms were quantified to replicate th e previous findings. HO-IDPN was administered ip in saline for 3 conse cutive days to two different cohorts of young adult male Sprague-Dawle y rats. The first cohort (60, 80, 100, and 120 mg/kg; n = 2/group, exc ept for the 120 mg/kg group, where n = 1) was used in a dose range-fin ding study. After making the neurobehavioral assessments, animals were sacrificed for olfactory mucosal histopathology. Based on the outcome of the first study, the second cohort (n = 10/group) received saline or HO-IDPN at 100 mg/kg/day for 3 consecutive days. Two animals from e ach of these groups were sacrificed for olfactory mucosal histopatholo gy; the remaining animals were tested for neurobehavioral effects 3 we eks after the last dose. Animals in the second cohort lost approximate ly 8% of their pretreatment body weight. All rats receiving the 100 mg /kg/day dose of HO-IDPN (and the rat receiving 120 mg/kg/day) develope d the ECC syndrome and signs of vestibular dysfunction within 4 days a fter the last dose. HO-IDPN caused a large decrease in the acoustic st artle response and markedly elevated auditory thresholds at all freque ncies tested. The threshold for the ECC syndrome and olfactory mucosal damage was 100 mg/kg. These studies extend previous findings on the n eurotoxicity of HO-IDPN and point to the need for determining whether HO-IDPN is an in vivo metabolite of IDPN.