Metformin Protects Against Noise-Induced Hearing Loss in Male Mice.

HYPOTHESIS: Metformin treatment will protect mice from noise-induced hearing loss (NIHL). BACKGROUND: We recently identified metformin as the top-ranking, Food and Drug Administration-approved drug to counter inner ear molecular changes induced by permanent threshold shift-inducing noise. This study is designed to functionally test metformin as a potential otoprotective drug against NIHL. METHODS: Male and female B6CBAF1/J mice were obtained at 7 to 8 weeks of age. A cohort of the females underwent ovariectomy to simulate menopause and eliminate the effect of ovarian-derived estrogens. At 10 weeks of age, mice underwent a permanent threshold shift-inducing noise exposure (102.5 or 105 dB SPL, 8-16 kHz, 2 h). Auditory brainstem response (ABR) thresholds were obtained at baseline, 24 h after noise exposure, and 1 week after noise exposure. Mice were administered metformin (200 mg/kg/d) or a saline control in their drinking water after the baseline ABR and for the remainder of the study. After the 1-week ABR, mice were euthanized and cochlear tissue was analyzed. RESULTS: Metformin treatment reduced the 1-week ABR threshold shift at 16 kHz ( p < 0.01; d = 1.20) and 24 kHz ( p < 0.01; d = 1.15) as well as outer hair cell loss in the 32-45.5 kHz range ( p < 0.0001; d = 2.37) in male mice. In contrast, metformin treatment did not prevent hearing loss or outer hair cell loss in the intact or ovariectomized female mice. CONCLUSIONS: Metformin exhibits sex-dependent efficacy as a therapeutic for NIHL. These data compel continued investigation into metformin's protective effects and demonstrate the importance of evaluating the therapeutic efficacy of drugs in subjects of both sexes.

Sex-Linked Biology and Gender-Related Research Is Essential to Advancing Hearing Health.

There is robust evidence that sex (biological) and gender (behavioral/social) differences influence hearing loss risk and outcomes. These differences are noted for animals and humans-in the occurrence of hearing loss, hearing loss progression, and response to interventions. Nevertheless, many studies have not reported or disaggregated data by sex or gender. This article describes the influence of sex-linked biology (specifically sex-linked hormones) and gender on hearing and hearing interventions, including the role of sex-linked biology and gender in modifying the association between risk factors and hearing loss, and the effects of hearing loss on quality of life and functioning. Most prevalence studies indicate that hearing loss begins earlier and is more common and severe among men than women. Intrinsic sex-linked biological differences in the auditory system may account, in part, for the predominance of hearing loss in males. Sex- and gender-related differences in the effects of noise exposure or cardiovascular disease on the auditory system may help explain some of these differences in the prevalence of hearing loss. Further still, differences in hearing aid use and uptake, and the effects of hearing loss on health may also vary by sex and gender. Recognizing that sex-linked biology and gender are key determinants of hearing health, the present review concludes by emphasizing the importance of a well-developed research platform that proactively measures and assesses sex- and gender-related differences in hearing, including in understudied populations. Such research focus is necessary to advance the field of hearing science and benefit all members of society.

Estradiol Protects against Noise-Induced Hearing Loss and Modulates Auditory Physiology in Female Mice.

Recent studies have identified sex-differences in auditory physiology and in the susceptibility to noise-induced hearing loss (NIHL). We hypothesize that 17ß-estradiol (E2), a known modulator of auditory physiology, may underpin sex-differences in the response to noise trauma. Here, we gonadectomized B6CBAF1/J mice and used a combination of electrophysiological and histological techniques to study the effects of estrogen replacement on peripheral auditory physiology in the absence of noise exposure and on protection from NIHL. Functional analysis of auditory physiology in gonadectomized female mice revealed that E2-treatment modulated the peripheral response to sound in the absence of changes to the endocochlear potential compared to vehicle-treatment. E2-replacement in gonadectomized female mice protected against hearing loss following permanent threshold shift (PTS)- and temporary threshold shift (TTS)-inducing noise exposures. Histological analysis of the cochlear tissue revealed that E2-replacement mitigated outer hair cell loss and cochlear synaptopathy following noise exposure compared to vehicle-treatment. Lastly, using fluorescent in situ hybridization, we demonstrate co-localization of estrogen receptor-2 with type-1C, high threshold spiral ganglion neurons, suggesting that the observed protection from cochlear synaptopathy may occur through E2-mediated preservation of these neurons. Taken together, these data indicate the estrogen signaling pathways may be harnessed for the prevention and treatment of NIHL.

A cell-type-specific atlas of the inner ear transcriptional response to acoustic trauma.

Noise-induced hearing loss (NIHL) results from a complex interplay of damage to the sensory cells of the inner ear, dysfunction of its lateral wall, axonal retraction of type 1C spiral ganglion neurons, and activation of the immune response. We use RiboTag and single-cell RNA sequencing to survey the cell-type-specific molecular landscape of the mouse inner ear before and after noise trauma. We identify induction of the transcription factors STAT3 and IRF7 and immune-related genes across all cell-types. Yet, cell-type-specific transcriptomic changes dominate the response. The ATF3/ATF4 stress-response pathway is robustly induced in the type 1A noise-resilient neurons, potassium transport genes are downregulated in the lateral wall, mRNA metabolism genes are downregulated in outer hair cells, and deafness-associated genes are downregulated in most cell types. This transcriptomic resource is available via the Gene Expression Analysis Resource (gEAR; https://umgear.org/NIHL) and provides a blueprint for the rational development of drugs to prevent and treat NIHL.

Music level preference and perceived exercise intensity in group spin classes.

CONTEXT: Sound levels in fitness classes often exceed safe levels despite studies that show many participants find high sound levels stressful. AIMS: The objective is to determine if lower sound levels in spinning classes significantly impact exercise intensity and to determine if class participants prefer the music played at lower levels. SETTINGS AND DESIGN: Observational study of 1-hour group spin classes. METHODS AND MATERIALS: Sound levels were measured in 18 spin classes over two weeks. No adjustments were made in week-1 and sound levels were decreased by 3 dB in week-2. Participant preferences and data on post-class hearing changes were collected via post-class questionnaires (n = 213) and divided into three terciles based on the total sound exposure of corresponding classes. STATISTICAL ANALYSIS USED: Unweighted survey generalized linear models are used to sort the causal relationships between different variables simultaneously and participant responses. The Chi-square test is used to reveal statistically significant relationships between two or more categorical variables. RESULTS: When mean sound levels exceeded 98.4 dBC, respondents were 23 times more likely to report the music as too loud than too quiet (P < 0.05), and four times more likely to prefer a decrease, rather than an increase, in sound level (P < 0.05). There was no significant difference in respondents reporting high exercise intensity between the middle (95.7-98.1 dBC) and upper (98.4-101.0 dBC) terciles, 67.1% and 71.8%, respectively (P = 0.53). Overall, 25.9% of respondents reported auditory symptoms following classes. Analysis in the context of dBA and dBC produced congruent conclusions and interpretations. CONCLUSIONS: Sound levels in many fitness classes remain dangerously high. However, music level can be lowered without a significant impact on perceived exercise intensity and many participants prefer lower sound levels than current levels.

Sex differences in hearing: Probing the role of estrogen signaling.

Hearing loss is the most common form of sensory impairment in humans, with an anticipated rise in incidence as the result of recreational noise exposures. Hearing loss is also the second most common health issue afflicting military veterans. Currently, there are no approved therapeutics to treat sensorineural hearing loss in humans. While hearing loss affects both men and women, sexual dimorphism is documented with respect to peripheral and central auditory physiology, as well as susceptibility to age-related and noise-induced hearing loss. Physiological differences between the sexes are often hormone-driven, and an increasing body of literature demonstrates that the hormone estrogen and its related signaling pathways may in part, modulate the aforementioned differences in hearing. From a mechanistic perspective, understanding the underpinnings of the hormonal modulation of hearing may lead to the development of therapeutics for age related and noise induced hearing loss. Here the authors review a number of studies that range from human populations to animal models, which have begun to provide a framework for understanding the functional role of estrogen signaling in hearing, particularly in normal and aberrant peripheral auditory physiology.