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.Electronic supplementary materialThe online version of this article (10.1186/s13293-018-0171-0) contains supplementary material, which is available to authorized users.

Highlights d A cell-type-specific transcriptomic map of the cochlear response to noise d Noise-resilient type 1A auditory neurons upregulate the ATF3/4 pathway d Monocytes significantly alter their gene expression in response to noise exposure d STAT3/IRF7 are probable regulators of a general cochlear transcriptomic response to noise

Studies of developmental and functional biology largely rely on conditional expression of genes in a cell type-specific manner. Therefore, the importance of specificity and lack of inherent phenotypes for Cre-driver animals cannot be overemphasized. The Gfi1Cre mouse is commonly used for conditional hair cell-specific gene deletion/reporter gene activation in the inner ear. Here, using immunofluorescence and flow cytometry, we show that the Gfi1Cre mice produce a pattern of recombination that is not strictly limited to hair cells within the inner ear. We observe a broad expression of Cre recombinase in the Gfi1Cre mouse neonatal inner ear, primarily in inner ear resident macrophages, which outnumber the hair cells. We further show that heterozygous Gfi1Cre mice exhibit an early onset progressive hearing loss as compared with their wild-type littermates. Importantly, vestibular function remains intact in heterozygotes up to 10 months, the latest time point tested. Finally, we detect minor, but statistically significant, changes in expression of hair cell-enriched transcripts in the Gfi1Cre heterozygous mice cochleae compared with their wild-type littermate controls. Given the broad use of the Gfi1Cre mice, both for gene deletion and reporter gene activation, these data are significant and necessary for proper planning and interpretation of experiments.

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