Effect of Oral Allylnitrile Administration on Cochlear Functioning in Mice Following Comparison of Different Anesthetics for Hearing Assessment

Dorien Verdoodt; Sander Eens; Debby Van Dam; Peter Paul De Deyn; Olivier M Vanderveken; Krystyna Szewczyk; Vera Saldien; Peter Ponsaerts; Vincent Van Rompaey

doi:10.3389/ftox.2021.641569

Effect of Oral Allylnitrile Administration on Cochlear Functioning in Mice Following Comparison of Different Anesthetics for Hearing Assessment

Front Toxicol. 2021 Feb 25:3:641569. doi: 10.3389/ftox.2021.641569. eCollection 2021.

Authors

Dorien Verdoodt^{1

2}, Sander Eens¹, Debby Van Dam^{3

4}, Peter Paul De Deyn^{3

4

5}, Olivier M Vanderveken^{1

6}, Krystyna Szewczyk¹, Vera Saldien⁷, Peter Ponsaerts², Vincent Van Rompaey^{1

6}

Affiliations

¹ Department of Translational Neurosciences, Faculty of Medicine and Health Sciences, University of Antwerp, Antwerp, Belgium.
² Laboratory of Experimental Hematology, Faculty of Medicine and Health Sciences, Vaccine and Infectious Disease Institute (Vaxinfectio), University of Antwerp, Antwerp, Belgium.
³ Laboratory of Neurochemistry and Behaviour, Faculty of Pharmaceutical, Biomedical and Veterinary Sciences, University of Antwerp, Antwerp, Belgium.
⁴ Department of Neurology and Alzheimer Research Center, University of Groningen and University Medical Center Groningen, Groningen, Netherlands.
⁵ Department of Neurology, Memory Clinic of Hospital Network Antwerp (ZNA) Middelheim and Hoge Beuken, Antwerp, Belgium.
⁶ Department of Otorhinolaryngology and Head and Neck Surgery, Antwerp University Hospital, Edegem, Belgium.
⁷ Department of Anaesthesiology, Antwerp University Hospital, Edegem, Belgium.

Abstract

Background: Allylnitrile is a compound found in cruciferous vegetables and has the same lethality and toxic effects as the other nitriles. In 2013, a viable allylnitrile ototoxicity mouse model was established. The toxicity of allylnitrile was limited through inhibition of CYP2E1 with trans-1,2-dichloroethylene (TDCE). The allylnitrile intoxication model has been extensively tested in the 129S1 mouse strain for vestibular function, which showed significant HC loss in the vestibular organ accompanied by severe behavioral abnormalities. However, the effect of allylnitrile on auditory function remains to be evaluated. Commonly used anesthetics to conduct hearing measurements are isoflurane and ketamine/xylazine anesthesia but the effect of these anesthetics on hearing assessment is still unknown. In this study we will evaluate the otovestibular effects of oral allylnitrile administration in mice. In addition, we will compare the influence of isoflurane and ketamine/xylazine anesthesia on hearing thresholds. Methods and Materials: Fourteen Coch+/- CBACa mice were randomly allocated into an allylnitrile (n = 8) and a control group (n = 6). Baseline measurements were done with isoflurane and 1 week later under ketamine/xylazine anesthesia. After baseline audiovestibular measurements, mice were co-administered with a single dose of allylnitrile and, to reduce systemic toxicity, three intraperitoneal injections of TDCE were given. Hearing loss was evaluated by recordings of auditory brainstem responses (ABR) and distortion product otoacoustic emissions (DPOAE). Specific behavioral test batteries for vestibular function were used to assess alterations in vestibular function. Results: Hearing thresholds were significantly elevated when using isoflurane anesthesia compared to ketamine/xylazine anesthesia for all frequencies of the ABR and the mid-to-high frequencies in DPOAE. Allylnitrile-treated mice lacked detectable ABR thresholds at each frequency tested, while DPOAE thresholds were significantly elevated in the low-frequency region of the cochlea and completely lacking in the mid-to high frequency region. Vestibular function was not affected by allylnitrile administration. Conclusion: Isoflurane anesthesia has a negative confounding effect on the measurement of hearing thresholds in mice. A single oral dose of allylnitrile induced hearing loss but did not significantly alter vestibular function in mice. This is the first study to show that administration of allylnitrile can cause a complete loss of hearing function in mice.

Keywords: DPOAE; allylnitrile; anesthesia; auditory brainstem response; vestibular function.