Noise-induced hearing loss (NIHL) affects about 40 million adults in the U.S aged 20-69 (1). As the name suggests, it is a loss of hearing due to loud noise exposure. The louder the noise and the more often a person is exposed to it, the more it harms their hearing. Although it is the second most likely reason of hearing loss (the first being age), there is currently no cure, and we don’t fully understand how loud noises biologically cause NIHL.
Several mechanisms have been discovered including: mechanical injury to the inner ear, metabolic damage from oxidative stress and calcium overload, inflammatory harm, and genetic factors (2). However, even combined, these factors don’t account for the extent of NIHL that people suffer from.
Epigenetics coming into play has been researched by several experimenters over past years, although their methods have been very different. Veruscka Leso and a team of researchers at the University of Naples Federico II, Italy, carried out a review of all relevant literature to see if they could come to any conclusions about the epigenetic effects of NIHL. Their results, published in Noise and Health, are both intriguing and promising; three epigenetic mechanisms have been identified that affect NIHL (3).
Difference in DNA Methylation
One study found that U.S army workers, who experienced over 40 blasts, had ten regions of DNA with higher methylation than workers who had not heard that many. One of these areas was the promoter of the Pax8 gene, which lead to a loss of Pax8 gene expression. This gene is a transcription factor involved in thyroid cell function and control, so reducing its levels may suggest that noise can epigenetically affect people in areas other than hearing.
Another study compared DNA methylation in rats who heard moderately loud noise for either a low or high number of days. The researchers examined the methylation levels of LINE-1 untranslated regions and the expression of five genes in five different areas of the brain. After long-term exposure the gene Comt methylation was increased in the inferior colliculus, LINE-1 methylation was increased in the medulla oblongata and the gene Mc2R methylation was decreased in the hippocampus. Why the epigenetics of these specific regions differ in these specific ways is still unknown, and an area for further research!
Are Histone Modifying Enzymes Causing NIHL?
Histone acetyltransferases (HATs) are enzymes that catalyze the addition of an acetyl group onto histone proteins, aiding gene expression. Histone deacetylases (HDACs) have the opposite job, and catalyze the removal of acetyl groups from histones, repressing gene expression. Studies on animal models such as mice and guinea pigs revealed that HDACs may be involved in hearing loss, since their expression is higher after hearing a traumatic noise.
In fact, inhibiting HDACs before the noise exposure prevented after-effects that cause hearing loss, such as death of outer hair cells. Although we don’t understand what exactly is molecularly occurring by inhibiting these HDACs, it is exciting to think of them as a potential target to help cure NIHL.
Methylating histones is another histone-modifying epigenetic mechanism implicated in hearing damage. This process also regulates gene expression by preventing transcription. After a traumatic noise, the enzyme histone lysine methyltransferase is activated, transferring methyl groups onto Histone 3. Blocking its action (by adding BIX 01294 or G9a siRNA) prevented death of outer hair cells and reduced the level of NIHL. This too could be a promising target for drugs to prevent NIHL.
Micro RNAs – Post-transcriptional Control
Micro RNAs (miRNAs) are able to prevent mRNA transcripts from being translated, and thus play an important role in epigenetically controlling gene expression. One case-control study compared the miRNA plasma profiles of people with NIHL, noise-exposed people without NIHL, and a control group of people who were unexposed with normal hearing. They found 73 mRNAs differently expressed in the noise-exposed people without NIHL compared to NIHL patients, and 4 of these are involved in oxidative stress responses. Extreme noise may induce lots of reactive oxygen species to be produced in the cochlea, which would explain the differential expression of miRNAs involved in the oxidative stress response.
Another interesting clue uncovered in a couple of experiments researching miRNAs is the repression of the mitogen-activated protein kinase (MAPK) signaling pathway in NIHL. Research on rats showed that Taok1 mRNA, a target of miRNA-183, was upregulated after loud noise exposure. Since Taok1 I is involved in apoptosis it may have a role in regulating the damage after a traumatic noise exposure.
In fact, Leso et al. suggest that this pathway may be what decreases susceptibility of animals to NIHL. The opposite happens in humans, where the level of miR-1229-5p is raised in people with occupational NIHL. One of the things miR-1229-5p does is post-transcriptionally repress expression of MAPK1, lowering our ability to protect ourselves against noise exposure.
Although Leso et al. discuss all that we understand about the epigenetic mechanisms of NIHL, they simultaneously highlight how much more we don’t understand. Carrying out further research is crucial to enable prevention and treatment of this life-altering condition.
References:
1. CDC Newsroom Non-occupational Noise-induced Hearing Loss CDC. 28 January 2020.
2. Ding T, et. al. (2019) ‘What is noise-induced hearing loss?’ British Journal of Hospital Medicine, 80(9), pp. 525–529.
3. Leso V, et. al. (2020) “Noise induced epigenetic effects: A systematic review.” Noise Health. 22(107):77-89.
