Susceptibility to cisplatin-induced hearing loss in CHOP knockout mice
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Date
2016-05
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The Ohio State University
Abstract
Cisplatin is a chemotherapeutic drug that causes hearing loss, and the mechanisms of its ototoxicity have been under study for several years. A key mechanism of cisplatin ototoxicity is apoptosis of the sensory hair cells. The cellular signals that trigger cisplatin-induced apoptosis in the cochlea are still unclear. The current experiment tested the hypothesis that endoplasmic reticulum stress and the unfolded protein response (UPR) are triggers for cochlear apoptosis. C/EBP homologous protein (CHOP) is a key signaling molecule in UPR-mediated apoptosis. Therefore, we tested susceptibility to cisplatin-induced hearing loss in CHOP knockout mice. Removing the CHOP gene was hypothesized to prevent cisplatin-induced cellular apoptosis and subsequent hearing loss. Electrophysiological hearing thresholds obtained through auditory brainstem response tests were used to assess hearing in CHOP knockout mice and C57Bl6/J controls. The mice were then exposed to cisplatin at four doses (8, 10, 14, 16 mg/kg) administered through intra-peritoneal injections. Post-exposure thresholds were obtained on Day 3 and Day 7 after cisplatin. An initial discovery in the study was that the CHOP knockout mice did not have equivalent hearing sensitivity to the controls. They had higher baseline thresholds, indicating initial hearing loss likely due to developmental damage/malformation of the cells in the cochlea. The finding implies that the UPR is crucial for the normal development of the auditory system. The major finding from the study was less cisplatin-induced hearing loss in the CHOP knockout mice. At each drug dosage, the mean threshold shift after cisplatin was higher in the control group than in the CHOP knockout group. This supports the hypothesis that CHOP is a potential triggering molecule for cisplatin-induced apoptosis in the cochlea. The finding could lead to new methods for preventing cisplatin ototoxicity, and future studies will attempt to modulate the UPR as one of these methods.
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Keywords
cisplatin, hearing loss, unfolded protein response, CHOP, ototoxicity