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

Abstract

Recent studies have identified sex-differences in auditory physiology and in the susceptibility to noise-induced hearing loss (NIHL). We hypothesize that 17β-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.

Conditional Ablation of Glucocorticoid and Mineralocorticoid Receptors from Cochlear Supporting Cells Reveals Their Differential Roles for Hearing Sensitivity and Dynamics of Recovery from Noise-Induced Hearing Loss

“…For control (no tamoxifen) GR male mice, credible intervals suggest near complete recovery of P1 amplitudes (BF 10 = 0.4, 95% CrI = −0.71 to 0.1). GR-related male noise vulnerability is consistent with reports of male susceptibility to sensory and neural hearing losses compared to noise susceptibility of females [ 53 , 54 , 55 ].…”

“…Our observations of differential sensitivity to damage between male and female mice is consistent with a meta-analysis in which male rodents experienced greater hair cell loss and threshold shift compared to female rodents [ 102 ]. Studies have also found male vulnerability to mild noise exposure and P1 amplitude reduction [ 54 , 103 ], though see [ 53 ]. Recent investigation suggests that estrogen may directly modulate spiral ganglion neurons [ 54 ].…”

“…Studies have also found male vulnerability to mild noise exposure and P1 amplitude reduction [ 54 , 103 ], though see [ 53 ]. Recent investigation suggests that estrogen may directly modulate spiral ganglion neurons [ 54 ]. Our current study suggests that a GR-related pathologic mechanism was in part blunted by estrogen signaling.…”

Sex differences in glutamate AMPA receptor subunits mRNA with fast gating kinetics in the mouse cochlea

“…ABR wave I is a measure of the response of multiple afferent fibers in the auditory nerve to sound, so larger ABR wave I amplitude suggests that females have greater synchrony of spiral ganglion neuron (SGN) afferent fibers or recruitment of more SGNs of a specific population at higher sound levels (Young et al, 2021). While sex hormones including estradiol and testosterone modulate auditory afferent synchrony in fish (Sisneros et al, 2004) and mice (Shuster et al, 2021), the underlying molecular mechanism of the sex difference in peripheral auditory processing in healthy inner ears of female and male mammals remains almost entirely unexplored. Understanding how healthy peripheral auditory systems differ between males and females is essential for tailoring specific hearing loss treatments and maintaining optimal auditory processing in both biological sexes.…”

Local Long-Term Inner Ear Drug Delivery in Normal Hearing Guinea Pig—An Animal Model to Develop Preventive Treatment for Noise-Induced Hearing Loss

“…NIHL is a complex disease and many factors have to be considered when establishing a new animal model. For example, both the melatonin of pigmented animals [ 75 ] and the estradiol of females [ 76 ] show a protective effect, so the selection of the animals is an important factor. Moreover, the circadian rhythm should be considered when planning the experimental setup [ 77 ].…”