Boadas-Vaello Pere, Sedó-Cabezón Lara, Verdú Enrique, Llorens Jordi
Grup de Recerca d'Anatomia Clínica, Embriologia i Neurociència (NEOMA), Departament de Ciències Mèdiques, Facultat de Medicina, Universitat de Girona, 17003 Girona, Catalunya, Spain.
Departament de Ciències Fisiològiques and Institut de Neurociències, Universitat de Barcelona, 08907 Hospitalet de Llobregat, Catalunya, Spain.
Toxicol Sci. 2017 Mar 1;156(1):109-122. doi: 10.1093/toxsci/kfw238.
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.
腈类化合物3,3'-亚氨基二丙腈（IDPN）会导致多种哺乳动物和非哺乳动物内耳前庭上皮中的毛细胞损失。作为耳毒性和前庭再生研究中的一种模型化合物，它备受关注，但其对小鼠的影响，包括品系和性别差异对易感性的潜在相关性，尚未得到充分表征。在本研究中，我们在剂量反应研究（口服0、8、12、16和24 mmol/kg IDPN）中比较了IDPN对两种不同小鼠品系（RjOrl:Swiss/CD-1和129S1/SvImJ）的雄性和雌性小鼠的前庭毒性。通过一系列特定的行为测试评估，3,3'-亚氨基二丙腈在所有性别和品系组中均导致前庭功能呈剂量依赖性丧失。然而，记录到全身毒性存在很大差异，与对瑞士小鼠的有限影响相比，129S1品系的雌雄小鼠全身毒性都很高。暴露后，瑞士小鼠的雌雄两性后肢步幅宽度均显著增加。用IDPN处理的瑞士小鼠（而非129S1小鼠）在旷场试验中表现出多动。行为效应的剂量反应关系与通过扫描电子显微镜评估的毛细胞损失程度相匹配。总体而言，数据表明129S1小鼠和瑞士小鼠在IDPN全身毒性方面存在显著的品系依赖性差异，相比之下，品系之间在前庭毒性方面无差异，性别之间差异较小。这些结果支持将暴露于IDPN的瑞士小鼠用作前庭治疗和再生研究的小鼠损伤模型。
