Accelerating Translation of Estrogen Signaling as a Treatment for Noise-Induced Hidden Hearing Loss in Both Sexes
Abstract
Background: For years, it was believed that noise trauma was harmful only if hearing thresholds became permanently elevated following exposure, as detected by a standard audiogram in the office. We now know that sustained, less-intense noise exposures that produce only transient elevations of hearing thresholds cause damage to the auditory nerve that is often equally detrimental. These types of exposures permanently impair the ability to clearly discern speech in the presence of competing background noise (e.g., a restaurant, aircraft, or battlefield), and threaten the safety and preparedness of men and women in both combat and non-combat roles. This type of hearing loss has been termed Noise-induced Hidden Hearing Loss (NIHHL), because it often escapes clinical detection. Unfortunately, to date, there are no Food and Drug Administration (FDA)-approved biological treatments to reverse or prevent noise-induced hearing loss (NIHL). Thus, there is incredible value in exploring new therapeutic options. While NIHL afflicts both men and women, our laboratory has published data demonstrating that female mice have an inherent protection against NIHL compared to males and that circulating estrogen underpins this protection. To control for estrogen levels we ovariectomized female mice to remove circulating estrogen and either supplemented them with estrogen or oil (control). Our data show that (a) after a severe noise exposure, female mice supplemented with estrogen suffer less permanent hearing loss than those that not supplemented; and that (b) estrogen supplementation also protects against NIHHL and ameliorates damage to the auditory nerve. Published research suggests that the protective effects of estrogen on hearing are mediated specifically via the estrogen receptor 2 (ESR2), a receptor that is not feminizing or carcinogenic and for which there are FDA-approved agonists. These data suggest that estrogen signaling may be harnessed to protect all forms of NIHL, and that ESR2-agonists approved to treat other diseases could potentially be repurposed to treat all forms of hearing loss. Importantly, we show that ESR2 is expressed in the auditory neurons of both male and female inner ears. Additional data generated from a previous project also identified two common medications used to treat high cholesterol and type-II diabetes--statins and metformin, respectively--as potential therapeutics for NIHL. From a translational perspective, the use of statins and metformin as therapeutics for NIHL is particularly promising, because they are FDA-approved for use in both males and females and demonstrate strong safety profiles. Project Objectives/Focus Area: To accelerate translation of biological repair mechanisms following acoustic trauma into therapies that treat auditory system injury and restore auditory function, with a focus on NIHHL. We will investigate whether ESR2-agonists, and the widely used and FDA-approved drugs statins, or metformin, alone or in combination, can prevent/treat NIHHL in both sexes. This will be accomplished through three Specific Aims: Aim 1: To determine if activation of ESR2-mediated signaling can prevent/treat NIHHL in intact female mice. Successful completion of this aim will determine whether ESR2 agonists, in the presence of endogenous hormones (i.e., gonadally intact females), are candidate treatments for NIHHL. Aim 2: To determine if ESR2-agonists, statins, and metformin, alone or in combination, can prevent/treat NIHHL in the presence of endogenous hormones in males and females. Successful completion of this aim will determine the efficacy of three candidate treatments for NIHHL and will set the foundation for clinical trials evaluating the therapeutic potential of statins and metformin in humans. Aim 3: To investigate the protective mechanisms of ESR2-agonists, statins, and metformin using a molecular biology approach. Successful completion of this aim will unravel
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110578
Entities
People
- Ronna Hertzano
Organizations
- United States Army
- University of Maryland, Baltimore