title: Strain and Sex Differences in the Vestibular and Systemic Toxicity of 3,3'-Iminodipropionitrile in Mice.
abstract: The nitrile 3,3'-iminodipropionitrile (IDPN) causes a loss of hair cells in the vestibular epithelium of the inner ear in several species of both mammals and nonmammals. It is of interest as a model compound in ototoxicity and vestibular regeneration research, but its effects on the mouse, including the potential relevance of strain and sex differences for susceptibility, have not yet been thoroughly characterized. In this study, we compared the vestibular toxicity of IDPN in dose-response studies (0, 8, 12, 16, and 24 mmol/kg IDPN p.o.) in males and females of 2 different mouse strains (RjOrl:Swiss/CD-1 and 129S1/SvImJ). 3,3'-Iminodipropionitrile caused a dose-dependent loss of vestibular function in all sex and strain groups, as assessed by a specific battery of behavioral tests. However, large differences in systemic toxicity were recorded, with high systemic toxicity in 129S1 mice of both sexes compared to limited effects on the Swiss mice. Both male and female Swiss mice showed a marked increase of hindlimb stride width after exposure. The Swiss, but not the 129S1, mice treated with IDPN showed hyperactivity in the open field. The dose-response relationships in the behavioral effects were matched by the extent of hair cell loss assessed by scanning electron microscopy. Altogether, the data demonstrated prominent strain-dependent differences in the systemic toxicity of IDPN between 129S1 and Swiss mice, in contrast to no differences between the strains and small differences between the sexes in its vestibular toxicity. These results support the use of Swiss mice exposed to IDPN as a mouse lesion model for research in vestibular therapy and regeneration.
authors.affiliation: Grup de Recerca d'Anatomia Clínica, Embriologia i Neurociència (NEOMA), Departament de Ciències Mèdiques, Facultat de Medicina, Universitat de Girona, 17003 Girona, Catalunya, Spain.
authors.forename: Pere
authors.initials: P
authors.lastname: Boadas-Vaello
authors.affiliation: Departament de Ciències Fisiològiques and Institut de Neurociències, Universitat de Barcelona, 08907 Hospitalet de Llobregat, Catalunya, Spain.|Institut d'Investigació Biomèdica de Bellvitge (IDIBELL), 08907 Hospitalet de Llobregat, Catalunya, Spain.
authors.forename: Lara
authors.initials: L
authors.lastname: Sedó-Cabezón
authors.affiliation: Grup de Recerca d'Anatomia Clínica, Embriologia i Neurociència (NEOMA), Departament de Ciències Mèdiques, Facultat de Medicina, Universitat de Girona, 17003 Girona, Catalunya, Spain.
authors.forename: Enrique
authors.initials: E
authors.lastname: Verdú
authors.affiliation: Departament de Ciències Fisiològiques and Institut de Neurociències, Universitat de Barcelona, 08907 Hospitalet de Llobregat, Catalunya, Spain.|Institut d'Investigació Biomèdica de Bellvitge (IDIBELL), 08907 Hospitalet de Llobregat, Catalunya, Spain.
authors.forename: Jordi
authors.initials: J
authors.lastname: Llorens
mesh_terms: D000284:Administration, Oral; D017109:Akathisia, Drug-Induced / Q000473:pathology* / Q000503:physiopathology; D000818:Animals; D021461:Animals, Outbred Strains; D001522:Behavior, Animal / Q000187:drug effects; D000071699:Bilateral Vestibulopathy / Q000139:chemically induced* / Q000473:pathology / Q000503:physiopathology; D004305:Dose-Response Relationship, Drug; D004351:Drug Resistance; D005106:Exploratory Behavior / Q000187:drug effects; D005260:Female; D005684:Gait / Q000187:drug effects; D018069:Hair Cells, Vestibular / Q000187:drug effects* / Q000473:pathology / Q000648:ultrastructure; D008297:Male; D051379:Mice; D057507:Mice, 129 Strain; D008855:Microscopy, Electron, Scanning; D009570:Nitriles / Q000008:administration & dosage / Q000633:toxicity*; D012727:Sex Characteristics; D013045:Species Specificity; D023382:Toxicity Tests, Acute; D015431:Weight Loss / Q000187:drug effects; D015262:Xenobiotics / Q000008:administration & dosage / Q000633:toxicity*
chemical_list: D009570:Nitriles; D015262:Xenobiotics; C008110:3,3'-iminodipropionitrile
keywords: IDPN; hair cell; hyperactivity; mouse.; vestibular function; vestibular toxicity