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Simultaneous study of cochleotoxicity and vestibulotoxicity of 3,3'- iminodipropionitrile in rats through several
M Chalansonnet1, A Thomas1, S Boucard1
1French Research and Safety Institute for the Prevention of Occupational Accidents and Diseases (INRS), Toxicology and Biomonitoring Division, 1 rue Morvan, Vandoeuvre les Nancy F-54519, France.
Abstract:
Many industrial chemicals and clinical compounds are toxic to the inner ear. Some preferentially target the cochlea or vestibular structures, whereas others are harmful to both. The reasons behind these distinct ototoxic profiles remain poorly understood. The lack of a clear structure-toxicity relationship means that the prediction of the ototoxic potential of new drugs or chemical compounds is challenging and that in vivo testing is necessary. Vestibular or cochlear toxicity can be readily assessed independently, but we lack a method to simultaneously evaluate both functional and histological impairments in the same animals. Here, we describe and test such a method using 3,3'-iminodipropionitrile (IDPN), a compound known to induce hair cell loss in both cochlear and vestibular epithelia in the inner ear of rodents. Female Long-Evans rats were treated with IDPN (0, 150, 200, or 300 mg/kg/day for three days, i.p.). Auditory function was assessed using distortion product otoacoustic emissions (DPOAEs), while vestibular function was evaluated by measuring post-rotatory nystagmus (PRN) and anti-gravity reflexes: the tail-lift and air-righting tests. These tests were conducted before, and four weeks after treatment. Inner ears were collected to count hair cells and to examine the cochlea, utricle, saccule, and cristae by scanning electron microscopy (SEM). Auditory and balance deficits, as well as histological damage in all epithelia, were observed from 200 mg/kg/day, with a strong correlation between functional impairments and histological findings. The method described provides a comprehensive and unbiased means to compare vestibular and cochlear toxicity.
Insights
A new method assesses both auditory and balance system damage from inner ear toxins simultaneously. This research used 3,3'-iminodipropionitrile (IDPN) in rats, revealing dose-dependent toxicity and correlating functional deficits with hair cell loss.
Area of Science:
- Ototoxicology
- Neuroscience
- Pharmacology
Background:
- Industrial chemicals and clinical compounds can harm the inner ear, affecting either the cochlea or vestibular system, or both.
- Understanding the distinct ototoxic profiles and predicting potential toxicity of new compounds is challenging due to a lack of clear structure-toxicity relationships.
- Current methods assess vestibular or cochlear toxicity independently, lacking a way to simultaneously evaluate both functional and histological impairments in the same animal.
Purpose of the Study:
- To describe and validate a novel method for simultaneously assessing functional and histological impairments in both cochlear and vestibular systems.
- To evaluate the ototoxic effects of 3,3 -iminodipropionitrile (IDPN) on auditory and balance functions and inner ear histology in rodents.
Main Methods:
- Female Long-Evans rats were treated with varying doses of IDPN (0, 150, 200, 300 mg/kg/day for three days).
- Auditory function was assessed using distortion product otoacoustic emissions (DPOAEs).
- Vestibular function was evaluated via post-rotatory nystagmus (PRN) and anti-gravity reflexes (tail-lift, air-righting tests).
- Inner ears were examined histologically using scanning electron microscopy (SEM) to count hair cells and assess damage in cochlear and vestibular epithelia.
Main Results:
- Dose-dependent auditory and balance deficits, along with histological damage in cochlear and vestibular epithelia, were observed starting at 200 mg/kg/day of IDPN.
- A strong correlation was found between functional impairments and histological findings across all tested epithelia.
- The study demonstrated that IDPN induces hair cell loss in both cochlear and vestibular structures.
Conclusions:
- The developed method provides a comprehensive and unbiased approach for comparing vestibular and cochlear toxicity.
- This integrated assessment method is crucial for understanding the ototoxic potential of various compounds.
- The findings highlight the need for simultaneous evaluation of both auditory and vestibular functions to accurately characterize inner ear toxicity.
