Anyone who has been to a loud concert might know that feeling of ringing ears. And some people may experience temporary or permanent hearing loss, or drastic changes in their perception of sound after the loud noises stop. A research team at Pittsburgh Hearing Research Center, University of Pittsburgh School of Medicine, has now discovered a molecular mechanism that is associated with noise-induced hearing loss (NIHL) and showed how it can be mitigated using medication.

Their study, headed by the unit’s director Thanos Tzounopoulos, PhD, found that noise-induced hearing loss stems from cellular damage in the inner ear that is associated with excess free-floating zinc—a mineral that is essential for proper cellular function and hearing. Experiments in mice then demonstrated how a zinc chelator—a compound that acts like molecular sponge to trap the excess zinc—can help to restore lost hearing or, if administered before an expected loud sound exposure, can protect against hearing loss.

A potential treatment is now in development for testing in preclinical safety studies, with a view to one day being able to offer a simple, over-the-counter option that individuals can take to protect against hearing loss. Tzounopoulos and Pitt colleagues, including first author Brandon Bizup, PhD, reported on their discoveries in Science Advances, in a paper titled, “Cochlear zinc signaling dysregulation is associated with noise-induced hearing loss, and zinc chelation enhances cochlear recovery.” In their paper the team reported, “These data reveal that noise-induced zinc dysregulation is associated with cochlear dysfunction and recovery after NIHL, and point to zinc chelation as a potential treatment for mitigating NIHL.”

Exposure to loud noise (NE) induces noise-induced hearing loss primarily due to cochlear damage and degeneration, the authors wrote, citing figures that suggest an estimated 17% of adults in the United States may have NIHL. While some people experience noise-induced hearing loss as a result of an acute traumatic injury to the ear, others notice a sudden hearing impairment after being continuously exposed to loud noise, for example in a battlefield or at a construction site. Others notice their hearing deteriorating after attending a loud music show.

Researchers say such noise-induced hearing loss can be debilitating. Some people start hearing sounds that aren’t there, developing a condition called tinnitus, which severely affects a person’s quality of life. “Hearing loss creates substantial deficits in the ability to communicate with the outside world resulting in higher rates of social stress, depression, and injury,” the team added. However, they pointed out, “Despite the high prevalence and the social and economic burden of NIHL, the precise signaling molecules and pathways that can be targeted to prevent, mitigate, or reverse NIHL remain unknown.” There are “few and insufficient” treatment strategies to protect and restore hearing, the team continued. “As such, identification and mechanistic understanding of the signaling pathways involved in NIHL are required.”

“Noise-induced hearing loss impairs millions of lives but, because the biology of hearing loss is not fully understood, preventing hearing loss has been an ongoing challenge,” added Tzounopoulos, endowed professor and vice-chair of research of otolaryngology at Pitt. Tzounopoulos has focused his scientific career on investigating how hearing works, and on developing ways to treat tinnitus and hearing loss. Tzounopoulos has strived to determine mechanistic underpinnings of hearing loss as groundwork for the development of effective and minimally invasive therapeutic approaches.

Thanos Tzounopoulos, PhD [Joshua Franzos]
Thanos Tzounopoulos, PhD [Joshua Franzos]
Zinc is essential for life, and while about 90% is protein bound and has critical enzymatic and structural roles, about 10% of zinc remains in an unbound (labile) state, and performs crucial signaling roles, the investigators explained. “Labile zinc is mostly found in vesicles in secretory tissues, where it is released and plays a critical signaling role,” the team explained. “In the brain, labile zinc fine-tunes neurotransmission and sensory processing.” Labile zinc is loaded into vesicles by a zinc transported, ZnT3, which is encoded by the Slc30a3 gene. Previous work has implicated dysregulation of labile (ZnT3-dependent) zinc signaling in multiple models neurodegeneration, including ischemic stroke and optic nerve injury.

The newly reported study, involving work in isolated cells of the inner ear, and in engineered mice, demonstrated that hours after mice are exposed to loud noise, their inner ear zinc level spiked. Loud sound exposure caused a robust release of zinc into the extra and intracellular space which, ultimately, led to cellular damage and disruption to normal cell to cell communication.

This discovery, the team showed, may also point to a possible solution. Further experiments demonstrated that disrupting zinc signaling either genetically, or by using a slow-releasing compound that trapped excess free zinc, rendered mice less prone to hearing loss, and protected against noise-induced damage. “Importantly, when we disrupted zinc signaling genetically and pharmacologically, and examined the effects of these manipulations on auditory function, we observed a significant reducing effect on the severity of NIHL,” the scientists stated. In summary, they wrote, “… we demonstrated that labile zinc and ZnT3 are localized to specific subsets of cochlear cells; noise trauma induces dysregulation of cochlear zinc signaling; and disruption of zinc signaling mitigates NIHL … These results highlight zinc signaling as a potential target for preventing and mitigating NIHL.”

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