Noise-induced hearing loss in mice treated with antiretroviral drugs

Abstract

The results reported here for CBA/CaJ mice describe the effects of regular dosing with a common antiretroviral drug combination on outer hair cell (OHC) function using measures of 2f1-f2 distortion product otoacoustic emissions (DPOAEs) and auditory brainstem responses (ABRs). Specifically, experimental mice were treated daily over a 3-mo period with the nucleoside reverse transcriptase inhibitors (NRTIs), zidovudine (ZDV) and lamivudine (3TC), dissolved in their drinking water, while their control counterparts received untreated water. DPOAE levels and ABR detection thresholds prior to and after 12 wk of NRTI treatment did not differ between experimental and control groups. To assess whether NRTI treatment potentiates the adverse effects of noise over-exposure on OHC function, both experimental and control mice were exposed 1 wk later, while still on the drug regimen, to a 10-kHz octave-band noise (OBN) at 105-dB SPL for 1h. A major outcome of the sound over-exposure episode was that the NRTI-pretreated mice showed significantly greater permanent OBN-induced reductions in DPOAE levels at 2 wk postexposure than were observed for the untreated control animals. These findings support the notion that a synergistic relationship exists between certain NRTIs and intense sounds in that such preexposure drug treatments produced greater noise-induced decreases in DPOAE activity than did noise exposure alone. This drug/noise interaction is consistent with the known harmful effects of NRTIs on cellular mitochondrial activity.

Figure 1

Mean DP-grams (±1 SD) collected at three primary-tone levels before (A–C) and after (D–F) 12 wk of NRTI treatment for untreated control (solid circles) and drug-treated (open circles) mice. From inspection of these plots, it is clear that the two groups of mice exhibited similar pre-treatment (left panels) DPOAE levels, and that these measures were basically unchanged at the end of the drug-treatment period (right panels). Dotted lines at the bottom of each plot indicate the related NFs of the measurement system.

Figure 2

Mean ABR thresholds (±1 SD) obtained at six test frequencies before and following 12 wk of administering NRTIs to the experimental group. Mean ABR thresholds for the untreated control group some 12 wk later (diagnonal striped bars) showed no change from their baseline values (solid bars). Similarly, baseline ABR thresholds for the NRTI-treated mice (gray bars) exhibited no apparent changes at any of the test frequencies following the 12-wk treatment period (open bars), nor any differences from the untreated controls (open bars versus diagonal-striped bars)

Figure 3

Mean difference DP-grams (±1 SD) computed by subtracting baseline DPOAE levels from their corresponding postexposure values. DPOAEs were elicited at three primary-tone levels and were obtained immediately (A–C), at 2 d (D–E), and at 2 wk (G–I) postexposure to a 1-h, 105-dB SPL, 10-kHz OBN for the control (solid circles) and NRTI-treated (open circles) mouse groups. Immediately postexposure, DPOAEs for both groups were reduced to the system’s NF. Two days later, both groups showed substantial recovery at all test levels. However, at 2 wk postexposure, the NRTI mice showed permanent DPOAE losses in the high-frequency test region thus suggesting an interaction of NRTIs with noise that enhanced the detrimental effects of the noise over-exposure. Dashed line at ‘0’ on the ordinate indicates no change from preexposure baseline values; heavy dotted lines without symbols designate the maximum possible DPOAE loss; stippled bar centered at 10 kHz indicates the frequency extent of the OBN exposure.