title: Characterization of the effects of N-hydroxy-IDPN on the auditory, vestibular, and olfactory systems in rats.
abstract: The mechanism of neurotoxicity of 3,3'-iminodipropionitrile (IDPN) has been widely debated, with either the parent compound or putative metabolites implicated in various studies. The N-hydroxylated form of IDPN (HO-IDPN) has been reported to cause the excitation with choreiform and circling (ECC) syndrome in rats at doses approximately one-eighth of that required to cause comparable signs in rats treated with IDPN. Because of the similarity of symptoms induced by HO-IDPN and IDPN, we investigated the effect of HO-IDPN on other aspects of the nervous system affected by IDPN, specifically the auditory, vestibular, and olfactory systems. In addition, ECC symptoms were quantified to replicate the previous findings. HO-IDPN was administered ip in saline for 3 consecutive days to two different cohorts of young adult male Sprague-Dawley rats. The first cohort (60, 80, 100, and 120 mg/kg; n = 2/group, except for the 120 mg/kg group, where n = 1) was used in a dose range-finding 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 each of these groups were sacrificed for olfactory mucosal histopathology; the remaining animals were tested for neurobehavioral effects 3 weeks after the last dose. Animals in the second cohort lost approximately 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) developed the ECC syndrome and signs of vestibular dysfunction within 4 days after the last dose. HO-IDPN caused a large decrease in the acoustic startle response and markedly elevated auditory thresholds at all frequencies tested. The threshold for the ECC syndrome and olfactory mucosal damage was 100 mg/kg. These studies extend previous findings on the neurotoxicity of HO-IDPN and point to the need for determining whether HO-IDPN is an in vivo metabolite of IDPN.
authors.affiliation: Neurotoxicology Division, NHEERL, U.S. Environmental Protection Agency, Research Triangle Park, NC 27711, USA.
authors.forename: K M
authors.initials: KM
authors.lastname: Crofton
authors.forename: X
authors.initials: X
authors.lastname: Zhao
authors.forename: L M
authors.initials: LM
authors.lastname: Sayre
authors.forename: M B
authors.initials: MB
authors.lastname: Genter
mesh_terms: D000818:Animals; D001309:Auditory Threshold / Q000187:drug effects*; D001522:Behavior, Animal / Q000187:drug effects*; D008297:Male; D009498:Neurotoxins / Q000633:toxicity*; D009570:Nitriles / Q000633:toxicity*; D009831:Olfactory Mucosa / Q000187:drug effects* / Q000473:pathology; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D009498:Neurotoxins; D009570:Nitriles; C101867:N-hydroxy-3,3'-iminodipropionitrile