STP: Ototoxicity Related to Cisplatin: Does Gender Matter?

Cyrille Sage, Aurore Marie, Randolph Abutin, Rami Tzafriri. Ototoxicity Related to Cisplatin: Does Gender Matter?

Summary: Cisplatin is a first-line treatment of several cancers. Adverse effects include nephrotoxicity, neurotoxicity, and ototoxicity with no preventative treatment for the latter. Cisplatin treatment often results in a bilateral elevation of hearing threshold resulting in irreversible hearing loss. In the literature, animal models evaluating treatments to prevent cisplatin-induced hearing loss utilize male rats; however gender differences have not been previously investigated.

In this study, Wistar rats (200 to 300 g) were infused with 10 mg/kg or 13 mg/kg cisplatin (8 males and 8 females per dose). Ototoxicity was measured pre/post infusion using Auditory Brainstem Response (ABR). To approximate human treatment, cisplatin was infused intraperitoneally (IP) at 10 mg/kg or 13 mg/kg cisplatin over 30 minutes. ABR was recorded at 5 different frequencies (4, 8, 16, 32 and 44.8 kHz) along the tonotopy of the cochlea.

Results show the ABR thresholds in females ranged from 5 to 27 dB and 28-35 dB with 10 and 13 mg/kg cisplatin, respectively for all 5 frequencies tested. The ABR threshold for males was only 18 dB at 44.8 kHz (no changes in other frequencies) with 10 mg/kg cisplatin and 11 to 35 dB at all 5 frequencies tested with 13 mg/kg cisplatin. Statistical analysis confirmed cisplatin sensitivity related to gender (p<0.001) for 4, 8, 32 and 44.8kHz in females, and only for 44.8kHz in males. Analysis of cochlea hair cell loss (cochleogram) to correlate the ABR findings is ongoing.

Conclusion: Female rats appear more sensitive to cisplatin-induced ototoxicity than males.  Potential gender differences should be evaluated when testing preventive treatments for cisplatin-induced ototoxicity.

Presented at the STP 38th Annual Symposium, June 23-27, 2019, in Raleigh, North Carolina.