Oxaliplatin-chemotherapy induced cochlear synaptopathy

Oxaliplatin is widely used as a first-line and reference anticancer agent for advanced colorectal cancer. However, it frequently causes peripheral neuropathy. It is generally accepted that oxaliplatin is significantly less ototoxic than the other platinum-based antineoplastic drugs, cisplatin and carboplatin. This study aimed to evaluate potential hearing damage induced by oxaliplatin in young male CBA/JRj mice. Mice received intraperitoneal injections of oxaliplatin (3 mg/kg) twice weekly for 3 weeks, for a cumulative dose of 18 mg/kg. Auditory function was assessed using electrophysiological measures, including auditory brainstem responses (ABRs) and compound action potentials (CAPs), distortion product otoacoustic emissions (DPOAEs), and medial olivocochlear (MOC) reflex measurements, followed by histopathological analysis of the organ of Corti and the cochlear auditory pathway. Oxaliplatin did not alter hearing thresholds, as assessed by ABR or DPOAE, and hair cells remained morphologically intact. However, despite preserved hearing sensitivity, significant neural deficits were observed, including reduced suprathreshold CAP amplitudes, early and sustained loss of ribbon synapses, reduced spiral ganglion cell density, and marked attenuation of the MOC reflex associated with loss of efferent fibers. Our findings suggest that oxaliplatin induces a form of hidden neuro-ototoxicity. The structural and functional impairments observed after oxaliplatin treatment are similar to cochlear synaptopathy associated with aging and acute noise exposure. These results challenge the assumption that oxaliplatin is not ototoxic and highlight the need for more sensitive auditory monitoring in patients receiving oxaliplatin treatment. Particular attention should be given to suprathreshold auditory measures, including ABR wave I amplitudes and MOC reflex function, which may reveal early neural deficits despite preserved hearing thresholds. The development of clinical tests specifically targeting these subclinical auditory abnormalities could improve the detection and monitoring of oxaliplatin-induced neuro-ototoxicity.