Verdoodt Dorien, Eens Sander, Van Dam Debby, De Deyn Peter Paul, Vanderveken Olivier M, Szewczyk Krystyna, Saldien Vera, Ponsaerts Peter, Van Rompaey Vincent
Department of Translational Neurosciences, Faculty of Medicine and Health Sciences, University of Antwerp, Antwerp, Belgium.
Laboratory of Experimental Hematology, Faculty of Medicine and Health Sciences, Vaccine and Infectious Disease Institute (Vaxinfectio), University of Antwerp, Antwerp, Belgium.
Front Toxicol. 2021 Feb 25;3:641569. doi: 10.3389/ftox.2021.641569. eCollection 2021.
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. Fourteen Coch+/- CBACa mice were randomly allocated into an allylnitrile ( = 8) and a control group ( = 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. 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. 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.
烯丙腈是一种存在于十字花科蔬菜中的化合物，与其他腈类具有相同的致死性和毒性作用。2013年，建立了一种可行的烯丙腈耳毒性小鼠模型。通过用反式-1,2-二氯乙烯（TDCE）抑制CYP2E1来限制烯丙腈的毒性。烯丙腈中毒模型已在129S1小鼠品系中针对前庭功能进行了广泛测试，结果显示前庭器官中的毛细胞显著损失，并伴有严重的行为异常。然而，烯丙腈对听觉功能的影响仍有待评估。进行听力测量常用的麻醉剂是异氟烷和氯胺酮/赛拉嗪麻醉，但这些麻醉剂对听力评估的影响仍不清楚。在本研究中，我们将评估口服烯丙腈对小鼠耳前庭的影响。此外，我们将比较异氟烷和氯胺酮/赛拉嗪麻醉对听力阈值的影响。14只Coch+/- CBACa小鼠被随机分为烯丙腈组（n = 8）和对照组（n = 6）。基线测量在异氟烷麻醉下进行，1周后在氯胺酮/赛拉嗪麻醉下进行。在基线听前庭测量后，小鼠同时给予单剂量的烯丙腈，并为降低全身毒性给予3次腹腔注射TDCE [。通过记录听觉脑干反应（ABR）和畸变产物耳声发射（DPOAE）来评估听力损失。使用特定的前庭功能行为测试组合来评估前庭功能的改变。与氯胺酮/赛拉嗪麻醉相比，在所有ABR频率和DPOAE的中高频使用异氟烷麻醉时，听力阈值显著升高。经烯丙腈处理的小鼠在每个测试频率均未检测到ABR阈值，而DPOAE阈值在耳蜗低频区域显著升高，在中高频区域完全缺失。烯丙腈给药未影响前庭功能。异氟烷麻醉对小鼠听力阈值的测量有负面混杂效应。单次口服烯丙腈可导致小鼠听力丧失，但未显著改变其前庭功能。这是第一项表明给予烯丙腈可导致小鼠听力功能完全丧失的研究。
