Abstract
BackgroundNoise-induced hearing loss (NIHL) is the most prevalent form of acquired hearing loss and affects about 40 million US adults. Among the suggested therapeutics tested in rodents, suberoylanilide hydroxamic acid (SAHA) has been shown to be otoprotective from NIHL; however, these results were limited to male mice.MethodsHere we tested the effect of SAHA on the hearing of 10-week-old B6CBAF1/J mice of both sexes, which were exposed to 2 h of octave-band noise (101 dB SPL centered at 11.3 kHz). Hearing was assessed by measuring auditory brainstem responses (ABR) at 8, 16, 24, and 32 kHz, 1 week before, as well as at 24 h and 15–21 days following exposure (baseline, compound threshold shift (CTS) and permanent threshold shift (PTS), respectively), followed by histologic analyses.ResultsWe found significant differences in the CTS and PTS of the control (vehicle injected) mice to noise, where females had a significantly smaller CTS at 16 and 24 kHz (p < 0.0001) and PTS at 16, 24, and 32 kHz (16 and 24 kHz p < 0.001, 32 kHz p < 0.01). This sexual dimorphic effect could not be explained by a differential loss of sensory cells or synapses but was reflected in the amplitude and amplitude progression of wave I of the ABR, which correlates with outer hair cell (OHC) function. Finally, the frequency of the protective effect of SAHA differed significantly between males (PTS, 24 kHz, p = 0.002) and females (PTS, 16 kHz, p = 0.003), and the magnitude of the protection was smaller in females than in males. Importantly, the magnitude of the protection by SAHA was smaller than the effect of sex as a biological factor in the vehicle-injected mice.ConclusionsThese results indicate that female mice are significantly protected from NIHL in comparison to males and that therapeutics for NIHL may have a different effect in males and females. The data highlight the importance of analyzing NIHL experiments from males and females, separately. Finally, these data also raise the possibility of effectors in the estrogen signaling pathway as novel therapeutics for NIHL.
Highlights
Noise-induced hearing loss (NIHL) is the most prevalent form of acquired hearing loss and affects about 40 million US adults
Sex differences have been described in agerelated hearing loss as well as in NIHL, where pre-menopausal women are protected in comparison to age-matched men [21, 22]
We use B6CBAF1/J mice, which are F1 progeny of a cross between C57BL/6J and CBA/J (CBA) for most of our experiments for NIHL. We choose this combination of strains because, while the C57BL/6 mice are used extensively to generate transgenic animals for auditory research owing to availability of its complete genome information [23], long life span and resistance to sound induced seizures [24, 25]; C57BL/6 mice suffer from early onset age-related hearing loss (ARHL) due to recessively inherited mutation in the Cdh23 gene [26] underlying the Ahl locus [27]
Summary
Noise-induced hearing loss (NIHL) is the most prevalent form of acquired hearing loss and affects about 40 million US adults. About the differential responses of male and female mice to noise and its potential therapeutics as historically most studies of acquired hearing loss using animal model were performed exclusively on males [14,15,16,17,18,19]. This is in part because the fluctuating hormone levels during an estrous cycle could introduce a confounding variable in the response to trauma or treatment [20]. Sex differences have been described in agerelated hearing loss (presbycusis) as well as in NIHL, where pre-menopausal women are protected in comparison to age-matched men [21, 22]
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