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Surgical Labyrinthectomy of the Rat to Study the Vestibular System
Published on: May 19, 2018
Three-dimensional cultured ampullae from rats as a screening tool for vestibulotoxicity: Proof of concept using
V Tallandier1, L Merlen2, M Chalansonnet2
1French Research and Safety Institute for the Prevention of Occupational Accidents and Diseases (INRS), Toxicology and Biomonitoring Division, Vandoeuvre les Nancy, France; DevAH EA 3450 - Développement, Adaptation et Handicap. Régulations cardio-respiratoires et de la motricité-Université de Lorraine, F-54500 Vandœuvre, France.
Abstract:
Numerous ototoxic drugs, such as some antibiotics and chemotherapeutics, are both cochleotoxic and vestibulotoxic (causing hearing loss and vestibular disorders). However, the impact of some industrial cochleotoxic compounds on the vestibular receptor, if any, remains unknown. As in vivo studies are long and expensive, there is considerable need for predictive and cost-effective in vitro models to test ototoxicity. Here, we present an organotypic model of cultured ampullae harvested from rat neonates. When cultured in a gelatinous matrix, ampulla explants form an enclosed compartment that progressively fills with a high-potassium (K+) endolymph-like fluid. Morphological analyses confirmed the presence of a number of cell types, sensory epithelium, secretory cells, and canalar cells. Treatments with inhibitors of potassium transporters demonstrated that the potassium homeostasis mechanisms were functional. To assess the potential of this model to reveal the toxic effects of chemicals, explants were exposed for either 2 or 72 h to styrene at a range of concentrations (0.5-1 mM). In the 2-h exposure condition, K+ concentration was significantly reduced, but ATP levels remained stable, and no histological damage was visible. After 72 h exposure, variations in K+ concentration were associated with histological damage and decreased ATP levels. This in vitro 3D neonatal rat ampulla model therefore represents a reliable and rapid means to assess the toxic properties of industrial compounds on this vestibular tissue, and can be used to investigate the specific underlying mechanisms.
Insights
This study introduces a new 3D organotypic model of neonatal rat ampullae for testing chemical toxicity. The model effectively identifies vestibular damage from industrial compounds like styrene, offering a faster, cost-effective alternative to animal studies.
Area of Science:
- Ototoxicity research
- Vestibular system toxicology
- In vitro model development
Background:
- Ototoxic drugs cause hearing and vestibular dysfunction.
- Impact of industrial chemicals on vestibular system is largely unknown.
- Need for cost-effective in vitro models for ototoxicity testing.
Purpose of the Study:
- Develop and validate an organotypic in vitro model of neonatal rat ampullae.
- Assess the utility of this model for evaluating industrial compound ototoxicity.
- Investigate mechanisms of styrene-induced vestibular toxicity.
Main Methods:
- Harvesting and culturing neonatal rat ampullae in a 3D matrix.
- Establishing an endolymph-like fluid environment within cultured ampullae.
- Exposing explants to styrene and analyzing potassium concentration, ATP levels, and histology.
Main Results:
- The model successfully maintained key vestibular cell types and functional potassium homeostasis.
- Short-term (2h) styrene exposure reduced potassium levels without damage.
- Long-term (72h) styrene exposure caused histological damage and decreased ATP levels, correlating with potassium dysregulation.
Conclusions:
- The 3D neonatal rat ampulla model is a reliable and rapid tool for assessing vestibular toxicity of industrial compounds.
- This model can elucidate specific mechanisms of chemical-induced ototoxicity.
- It provides a valuable alternative to expensive and time-consuming in vivo studies.
