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Genetic Susceptibility to Hearing Loss from Noise Exposure

White, Patricia M. PhD

doi: 10.1097/01.HJ.0000602896.08600.65
Genetics and Hearing Loss
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Dr. White is an associate professor at the Ernest J. Del Monte Institute for Neuroscience at the University of Rochester in Rochester, NY. Her research is focused on the genetic mechanisms of noise damage and hearing restoration in mouse models.

Between 10 million and 40 million adults in the United States are estimated to have some signs of noise-induced hearing loss (NIHL).1 NIHL can result from transient exposure to very loud sound bursts, such as gunfires, or chronic exposure to noisy environments. Excessive noise in occupational or recreational settings can be hazardous. Similar levels of noise exposure can affect individuals in different ways; some people are more susceptible while others are more resistant. Though lifestyle differences such as smoking2 are known to confer susceptibility to NIHL, recent evidence suggests that genetics also play a role. This review summarizes the effects of noise on cochlear structures and the animal models being used to understand the genetics of NIHL.

Figure 1.

Figure 1.

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IMPACT ON INNER EAR STRUCTURES

NIHL can present with different symptoms. In some cases, loud noise exposure can lead to temporary reduction in auditory thresholds. Chronic or dramatically loud noises, including jet engine sounds, can lead to permanent auditory threshold shifts. Individuals with a history of noise exposure but have normal auditory thresholds are at risk for difficulties understanding speech in noisy environments,3 although recent studies have questioned this correlation.4 Tinnitus is a common sequela of noise exposure that may be sporadic or constant.5

The symptoms of NIHL can be correlated with injury to specific structures within the ear. Acoustic waves impact the tympanic membrane and cause the ossicles to vibrate, thereby transferring acoustic waves to the inner ear. Blast damage can rupture or destroy these structures, interrupting this transfer and causing permanent hearing loss.6 In the inner ear, acoustic waves travel along the length of the cochlear spiral. When they encounter the cochlear region that corresponds to their frequency, their energy is amplified by the outer hair cells, which in turn contract and expand rapidly to enhance detection of the acoustic vibrations by inner hair cells. This energy-intensive process is fueled by a potassium ion gradient in the cochlear endolymph. The gradient is generated by the lateral structures of the cochlea, the stria vascularis and spiral ligament, as well as the supporting cells surrounding the hair cells. Excessive noise can damage or kill outer hair cells,7 or drive inflammation of the lateral structures.8 Like damage to the tympanic membrane and ossicles, these cellular injuries also cause threshold shifts.

Upon detecting acoustic vibrations, inner hair cells encode information by signaling to innervating spiral ganglion neurons. Each inner hair cell is contacted by 10 to 20 neurons depending on frequency; each neuron only receives input from a single inner hair cell synapse. Inner hair cell synapses are characterized by pre-synaptic protein structures called ribbons, which are required in synchronous auditory signaling.9 The accurate timing of synaptic encoding is key to disambiguating different sources of sounds.10 Importantly, spiral ganglion neuron activity is regulated by the central nervous system through cortical efferent feedback, crucial for promoting certain auditory signals, like speech, in noisy environments. They also protect the cochlea from noise damage and enable the enormous dynamic range of human hearing.11 Injury to inner hair cell innervation and changes in cortical efferents are potential causes of difficulties in understanding speech in noise. Such injuries may also underlie forms of tinnitus.

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INFLUENCE OF GENETICS

How could genetics be used to better understand a complicated process that involves so many structures? It is instructive to compare the search for NIHL variants to the search for those that cause familial non-syndromic hearing loss called Deafness or DFN variants. Over 140 gene variants have been proposed to cause hearing loss in the absence of other symptoms.12 The proteins encoded by these genes play distinct roles in the cochlea. Some are required for hair cell mechanotransduction, while others may be required for the generation of the potassium-rich endolymph. Many have functions that are not yet characterized. Nonetheless, the studies on DFN variants have greatly enriched our understanding of cochlear function and hearing loss.

In contrast, 34 genes have been identified, for which variants are associated with human NIHL in at least one study (see Table 1 online: bit.ly/WhiteTable1). NIHL variants can be identified in populations subjected to occupational noise, such as workers in a large and noisy factory.13 About 38 percent of NIHL variants are in genes with variants previously associated with familial hearing loss (Fig. 1, red). Thus, DFN variants that are not sufficiently deleterious to cause hearing loss can still confer stress sensitivity. These genes include proteins involved in stereociliary function and maintenance of the endolymph potassium gradient. About 18 percent of NIHL variants are in genes that regulate other genes (Fig. 1, purple), and 15 percent are involved in cell-to-cell communication (Fig. 1, green).

Auditory function is an energy-intensive activity that requires active mitochondria, which may become compromised by oxidative stress. Notably, 23 percent of NIHL variants are in oxidative stress response genes (Fig. 1, blue).14 These genes encode proteins that neutralize radical peroxide byproducts produced from the mitochondrial electron transport chain. Considerable cellular energy is needed to counteract noise exposure and repair its subsequent damage. Genetic variants that reduce a cell's ability to react to mitochondrial stress can cause NIHL.15 Strikingly, some variants in the mitochondrial genome itself are associated with late-onset hearing loss.16 Taken together, these suggest that the study of NIHL variants can reveal the cellular basis for noise susceptibility.

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INSIGHTS FROM ANIMAL MODELS

NIHL is difficult to study in humans due to different lifestyles, health histories, and genetic backgrounds. Animal models employing noise exposure enable the control of these potentially confounding variables. For example, age-matched congenic mice with and without mutations in candidate NIHL genes can be exposed to controlled amounts of noise energy, and changes in their hearing thresholds can be monitored at different times. It is also possible to assess sites and degrees of cellular injury in animal models.

For example, we have studied the consequences of noise exposure for mice with a gene mutation called FOXO3, which regulates the expression of other genes and is a key player in oxidative stress response.17 Certain human variants of FOXO3 are significantly more frequent in nonagenarians, suggesting a role in longevity.18-21 Specific human variants of FOXO3 are also overrepresented in occupational NIHL, linking this gene to hearing loss.22 We found that mice with no functional copies of FOXO3 are strikingly susceptible to NIHL. They have greater threshold shifts, poorer recovery, and more outer hair cell death compared with their wild-type littermates.23 Identifying the mechanism of FOXO3’s actions, including the additional genes it regulates as a transcription factor, will help us understand why its absence primes outer hair cells for death.

Animal models for the study of tinnitus or perception of speech in noise are less straightforward. Tinnitus often follows noise exposure and presages hearing loss. It can be assessed in animals using prepulse inhibition. In this assay, tinnitus can mask a gap signal called the prepulse that warns an animal of a startling noise impulse.24 However, tinnitus is often sporadic, intermittent, and affected by stress, thereby requiring larger numbers of animals for accurate studies. No known gene variant is associated with tinnitus in humans or animals. Similarly, perceptions of speech in noise or vocalizations in noise are also difficult to study in animal models. No known gene variants are associated with this form of auditory dysfunction. These disorders may be multifactorial or dependent on many genes at once. Alternatively, they could be less influenced by genetics compared with auditory thresholds.

In conclusion, individuals may have differential susceptibility to NIHL, and some of these differences are likely due to variants in specific genes. NIHL may manifest differently, including difficulty perceiving sounds in noise, tinnitus, or the raised auditory thresholds that characterize hearing loss. These manifestations could reflect the cochlear cellular injuries that follow from noise exposure. Variants in 34 genes have been associated with a susceptibility to raised auditory thresholds from NIHL in individuals with occupational noise exposure. Animal models have proven useful in characterizing genetic variants for NIHL. However, investigations of noise-induced tinnitus and speech perception in noise have not revealed any genetic variants for these auditory dysfunctions. Further work on the genetic and cellular bases of NIHL could enable the characterization of individual susceptibilities and help prevent this widespread disease.

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