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Reduced Systemic Toxicity and Preserved Vestibular Toxicity Following Co-treatment with Nitriles and CYP2E1 Inhibitors: a Mouse Model for Hair Cell Loss

  • Sandra Saldaña-Ruíz
  • Pere Boadas-Vaello
  • Lara Sedó-Cabezón
  • Jordi LlorensEmail author
Research Article

Abstract

Several nitriles, including allylnitrile and cis-crotononitrile, have been shown to be ototoxic and cause hair cell degeneration in the auditory and vestibular sensory epithelia of mice. However, these nitriles can also be lethal due in large part to the microsomal metabolic release of cyanide, which is mostly dependent on the activity of the 2E1 isoform of the cytochrome P450 (CYP2E1). In this study, we co-administered mice with a nitrile and, to reduce their lethal effects, a selective CYP2E1 inhibitor: diallylsulfide (DAS) or trans-1,2-dichloroethylene (TDCE). Both in female 129S1/SvImJ (129S1) mice co-treated with DAS and cis-crotononitrile and in male RjOrl:Swiss/CD-1 (Swiss) mice co-treated with TDCE and allylnitrile, the nitrile caused a dose-dependent loss of vestibular function, as assessed by a specific behavioral test battery, and of hair cells, as assessed by hair bundle counts using scanning electron microscopy. In the experiments, the CYP2E1 inhibitors provided significant protection against the lethal effects of the nitriles and did not diminish the vestibular toxicity as assessed by behavioral effects in comparison to animals receiving no inhibitor. Additional experiments using a single dose of allylnitrile demonstrated that TDCE does not cause hair cell loss on its own and does not modify the vestibular toxicity of the nitrile in either male or female 129S1 mice. In all the experiments, high vestibular dysfunction scores in the behavioral test battery predicted extensive to complete loss of hair cells in the utricles. This provides a means of selecting animals for subsequent studies of vestibular hair cell regeneration or replacement.

Keywords

ototoxicity vestibular toxicity allylnitrile cis-crotononitrile mouse hair cell ablation 

Notes

Acknowledgments

We thank the student Xavier Farré for his assistance in some of the experiments, and Angel Messeguer (CSIC, Barcelona, Spain) for helping with the distillation of the cis-crotononitrile isomer. This work was supported by the Spanish Ministry of Science and Innovation (grant numbers BFU2009-06945 and BFU2012-31364) and the Generalitat of Catalonia (grant number 2009 SGR 1059). The SEM studies were performed at the Science and Technology Centers of the University of Barcelona.

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Copyright information

© Association for Research in Otolaryngology 2013

Authors and Affiliations

  • Sandra Saldaña-Ruíz
    • 1
    • 2
  • Pere Boadas-Vaello
    • 3
  • Lara Sedó-Cabezón
    • 1
    • 2
  • Jordi Llorens
    • 1
    • 2
    Email author
  1. 1.Departament de Ciències Fisiològiques IIUniversitat de BarcelonaCataloniaSpain
  2. 2.Institut d’Investigació Biomèdica de Bellvitge (IDIBELL)CataloniaSpain
  3. 3.NEOMA Research Group, Departament de Ciències Mèdiques, Facultat de MedicinaUniversitat de GironaCataloniaSpain

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