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Étude de la vestibulotoxicité périphérique des solvants aromatiques par une approche in vitro

Abstract : Aromatic solvents (AS) are chemicals widely used in many industrial sectors. Some solvents can cause balance disturbances, which could be the cause of falls and occupational accidents. It is now well established that AS can damage cochlear cells, but their effects on the vestibular receptor, which shares structural homology with the cochlea, remain unknown. The objective of this thesis is to evaluate the toxicity of various AS on the vestibular receptor using an in vitro model. For this, utricles and ampullas are harvested from newborn rats and cultured in a gelatinous matrix. In this environment, the explants close themselves, inflate and ultimately form a sphere filled with a high-potassium endolymph-like fluid. These 3D cultures conserve all the cells involved in the K+ cycle, the role of which is critical in vestibular physiology. The K+ concentration is measured using a microelectrode filled with an ion-exchange membrane before performing histological analyses. The functionality of different cell types was validated using pharmacological agents capable of inhibiting potassium transporters involved in the K+ cycle such as ouabain, bumetanide, gentamicin and gadolinium. The utricle and ampulla cultures were exposed to a range of styrene concentrations for either 2 h or 72 h. These two types of exposure led to a decrease in the K+ concentration and histological damage in the sensory and secretory epithelia. Changes in K+ concentration seem to be a more sensitive marker of toxicity than histological damage. Then the vestibulotoxic potentials of ethylbenzene, toluene or each of the three xylene isomers were assessed by exposing the utricle cultures to 0.75 mM for 2 h or 72 h. Among the tested solvents, only ethylbenzene and o-xylene caused a decrease in K+ concentration following prolonged exposure, but only o-xylene caused histological damage. Immunohistological analyzes and ATP assays both indicate that AS trigger a necrotic process, rather than an apoptotic sequence. These results show that the chemical structure would be a fundamental parameter in the toxicity of solvents on this model. In conclusion, we suggest that utricle and ampulla cultures could be used to screen many potentially vestibulotoxic molecules rapidly, while using few animals given the eight epithelia available in each newborn rat. This model also facilitates the study of toxic mechanisms on the vestibular receptor.
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Submitted on : Thursday, September 9, 2021 - 9:48:26 AM
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Valentin Tallandier. Étude de la vestibulotoxicité périphérique des solvants aromatiques par une approche in vitro. Toxicologie. Université de Lorraine, 2021. Français. ⟨NNT : 2021LORR0060⟩. ⟨tel-03338831⟩



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