The complex problem of noise-induced hearing loss (NIHL) can be viewed as the cochlear biochemical response to mechanical movement of the tympanic membrane—a conglomerate of molecular processes isolated by both organelle and plasma membranes but connected by intra- and intercellular signaling to coordinate the organism's reaction to acoustic waves. Several databases, such as DAVID, KEGG, and Reactome, are bioinformatics tools for analysis of pathways, complexes, and interactions, and can serve as an overview of patterns of determinant genes in reaction to insult and repair. Although all these programs have their assets, for this literature review, Reactome was chosen because of ease of use and its data coordination (1,2). This curated database, freely available online at http://reactome.org, divides cellular activity into 23 interconnected pathways within respective organelles, including metabolism, signal transduction, neuronal system, gene expression, DNA replication, cell cycle, etc. A pathway is defined as a group of molecules in a cell that work together to control one or more functions, and includes proteins, complexes, mRNAs, small molecules, genes, and their interactions. Each pathway is then subdivided into individual reactions that include binding, activation, translocation, and degradation, among others. In this review, Reactome is utilized as a tool to organize the abundant laboratory and population data amassed regarding NIHL to attempt to aggregate individual research articles into a meaningful unity, and to create an overview of where these genes and processes fit into areas that may prove fruitful for prevention and treatment.
In regards to human studies, to our knowledge, there are no large population studies that have used genome-wide association studies to examine noise-induced hearing loss. Instead, putative candidate genes and their associated RefSeqs have been chosen based on laboratory findings and studied in specific human populations via polymerase chain reaction (PCR) (3–7). This technique does not allow for discovery of new single-nucleotide polymorphisms (SNPs). Nevertheless, some small population-specific human studies have identified genes associated with noise sensitivity, including oxidative stress genes such as CAT, PON2, and others (5,8–10), heat-shock proteins including HSP70-1, HSP70-2, and HSP70-hom (11), and potassium recycling genes, i.e., KCNE1 and KCNQ4 (12). Other authors have not been able to confirm the population studies, possibly because of the analysis of small homogenous populations. Carlsson et al. (13) found no meaningful antioxidant enzymes in Swedish noise-exposed workers, including GSTM1, GSTT1, CAT, SOD, GPX, GSR, and GSTP1, even though other studies had found positive correlations in at least some of these genes (9,14,15). Subsequent to these negative findings in 2005, the 1,000 Human Genome Project has been completed, and the number of available SNPs for analysis in introns, exons, and promoter sites, has increased from 9.7 million in 2006 to over 82 million nonsynonymous SNPs as of Gencode release 22/Ensembl version 79 (16). This explosion of publically available data provides opportunities for exploration of large populations vulnerable to noise-induced hearing loss.
Different regional populations may have diverse SNPs because of global genetic drift, preventing the drawing of general conclusions from a specific population. Thus, an important SNP in one part of the world may not be relevant on another continent, depending upon population haplotype (17). In Chinese populations, researchers found a “multiple-locus model” consisting of GJB2, SOD2, and CAT to be associated with NIHL (18), and a Brazilian cohort identified a combination of GSTM1 and GSTT1 and mitochondrial haplogroup L1 more susceptible (19). Yang et al. (20) found that although separate SNP analysis of three HSP70 polymorphisms did not show significance, analysis revealed a threefold increased risk when particular haplotypes were combined. This combination approach of looking at correlation with several genes at a time speaks to the interaction of intersecting cellular pathways and isoforms. Thus, the ear may compensate for a single SNP because of redundant systems; however, an increased number of enzymes with nonsynonymous SNPs in a given study subject may provide a smaller margin for repair after acoustic trauma. In addition to population haplotypes, it is thus important to consider interacting pathways and complexes in addition to discrete genes.
Application of animal studies to human populations is crucial for scientific validation, but challenging. SNPs and haplotypes in a given species may or may not correlate with findings in human population studies (13,19). However, within that caveat, researchers using RNA sequencing have identified new pathways that can then be applied to humans, including multiple genes upregulated in immune response to noise (21,22), metalloproteinases (23), glutamate metabolism (24), and other genes related to apoptosis, metabolism, and membrane function (24). The multiple individual pathways identified in animal literature speak for the need of close examination of intermingling enzymatic routes to pinpoint effective interventional treatment.
Areas of genes identified in 77 genomics articles included immunology and inflammation (21,22,25,26), apoptosis (27–30), response to stress (31,32), in particular heat shock factor response (11,33), signal transduction (23,26,34), potassium recycling (30,35,36), and cellular adhesion molecules (37,38), among others. Twenty-eight articles were human industrial noise studies, predominantly looking at SNPs from candidate genes using PCR in specific populations, i.e., Polish, Han Chinese, and Swedish, with one article using genome-wide association study (GWAS) technology related to impact noise that found a previously unidentified gene SNP, nucleolin, to be significantly represented in the noise-sensitive population (p <0.01 after correction) (39).
Candidate population studies predominantly focused on SNPs occurring in exons, whereas intron and promoter SNPs and other noncoding elements were rarely addressed. Increasing evidence shows that intron SNPs may dysregulate protein isoform expression, whereas promoter SNPs may affect mRNA expression (39–41). These human population studies have focused on oxidative stress (9), the potassium-recycling pathway (4,11,12), heat shock proteins (10,11,41), mitochondrial DNA variants (19), and adhesion molecules (5,7,42), among others. Although some of these studies found significance, once again, they were not always replicated in other populations (13,43).
The remaining 49 articles were animal studies, including 19 articles using genetically altered mice, 18 PCR studies, 19 immunohistochemistry on candidate genes, two studies performing GWAS microarrays, seven with other selected microarray formats, and seven articles exploring RNA sequencing, uncovering numerous genes within the immune system (21–23,44). The lone mouse GWAS study confirmed Nox3 as a gene critical for protection against NIHL, with significant protection at high frequencies, and isolated the ribbon synapse as a cochlear area of protection (45). The compendium totals 158 genes and isoforms (see Table 1). Although there were three articles investigating specific microRNAs, these miRNAs have not been included in the Reactome program as of this date, and are not included in the list analyzed by Reactome (46–48).
In a study comparing genetic differences and similarities in several animal species via RNA sequencing, differences were found in the immune systems, which speaks for the necessity to ultimately adapt laboratory findings to humans (21,23,24,44). Nevertheless, the mammalian genes found to be crucial in the laboratory can be compared to humans pathways. Genes studied individually in the laboratory have focused on those related to apoptosis of the inner and outer hair cells after acoustic trauma, including caspase-3, caspase-9, bcl-2, c-Jun N-terminal kinase (JNK), p38 mitogen-activated protein kinases (46,49–51), as well as proteins involved in inflammation, i.e., ICAM-1, NF kappaβ, 5 (MCP-5), monocyte chemoattractant protein 1, MIP-1beta, P-selectin, PECAM-1, and IL-6 (38,52–55).
In RNA-sequencing studies, 61 genes have been recognized in the immune system that are up- or down-regulated in several mammalian species, with identification of upstream transcriptional regulators predicted to activate them (21). Other transcription factors responsive to acoustic trauma include JAK/STAT3, HSF1, c-FOS, EGR1, Nf kappaB, AP1, and CREB1 (21,33,35,56–61). Since these upstream regulators may control expression of a pathway rather than a single gene, they may ultimately provide the key to intervention to prevent hearing loss secondary to acoustic trauma.
Yet another activity where SNPs have been examined involves the cochlea's necessity to maintain its electric potential across fluid compartments. Studies suggest a dysregulation of potassium channels, including KCNE1, KCNJ10, KCNQ1, and KCNQ4, may lead to degradation of the endolymphatic potential, with an ensuing adjustment of gene expression coordinated between the disparate cells of the cochlea (10,24,62,63). Other pathways include maintenance of extracellular matrix organization, which, in the case of the cochlea, would include the tectorial and basilar membranes (64) as well as signal transduction proteins, among others.
Although the literature on NIHL is extensive and well researched, in the past decade, through the emerging field of epigenetics, it has become clear that individual proteins and genes are not the entire picture. Although a few articles examined miRNA interactions with noise (44,47), and miR183, mir96, and mir182 may control multiple genes related to the cochlea, no literature was found in the emerging fields of methylation patterns of DNA, histone markers, copy-number variations, and long noncoding RNA regulation in response to noise (47). Only 20% of the genome is translated into proteins in humans; on the other hand, greater than 80% of DNA is transcribed into RNA (65). Untranslated DNA is no longer considered “junk DNA,” but is transcribed into long noncoding RNA (lncRNA) greater than 200 nucleotides in length, miRNA, and small nucleolar RNA (snoRNA) of approximately 20 to 22 nucleotides in length. These RNAs are involved in expression of groups of genes, since they “sit” on DNA and RNA segments, permitting or precluding transcription (66,67). MiRNAs, noncoding RNAs consisting of 20 to 22 nucleotides, modulate mRNA level by degradation of processed mRNA (68). They provide posttranscriptional/pretranslation control of RNAs, and a few have been characterized pre- and postacoustic trauma in the laboratory (46,68).
Thus, although all the studies are contributory, genetic material constitutes a part of cellular molecular pathways to be considered in the context of a system with many equilibrating proteins, molecules, genes, DNA, and RNA that reacts to a changing environmental stimulus. For the purposes of this literature review, Reactome is used as a construct to help organize animal and human population studies into unified patterns of cellular interaction (1,2).
DATA SOURCES AND METHODS
PubMed was accessed using the following search terms: “noise-induced hearing loss,” “noise,” “acoustic trauma,” “acoustic injury,” AND “cochlea” AND “gen*,” OR “epigenetics,” OR “miRNA,” OR “long noncoding RNA,” and similar terms, for the previous 15 years. All articles had been peer reviewed and consisted of either human or mammalian studies, studies using transgenic mice, and/or measurements of genes pre- and postnoise trauma. Only mammalian species with mature animals were included, since avian species can regenerate hair cells following noise and newborn murine species show some ability to regenerate as well (69). Noise was either induced in the laboratory, in industry, or in a military setting, and included either impulse or continuous noise (PMIDs available upon request)—ototoxicity and age-related studies were not included. Both temporary and permanent threshold shifts were used, as a temporary threshold shift has been shown to lead to permanent cochlear damage (70). Only studies that demonstrated a significant change in audiogram pre- and postnoise, concomitant with fold change >1.5 and p values <0.05 with correction for multiple genes via Benjamini-Hochberg or Bonferroni correction were included. Also included were changes in hearing sensitivity based on comparison of genetically altered animals, including GWAS studies (30,54,71).
In regards to human studies of SNPs, p values <0.05 with correction for multiple genes were identified. Although candidate genes should be compared with the total number of human SNPs, and power calculations should include the frequency of alleles in the population as well, many of these studies were completed before the Human Genome Project, and had no access to these data. These were included when found to be duplicated in animal studies.
Genes expressed were confirmed histologically in cochlear tissues via immunohistochemistry, microarrays, GWAS, or RNA sequencing, and verified by PCR. Either audiograms or, for animal studies, auditory brainstem response and/or otoacoustic emissions measured hearing loss. This review was restricted to cochlear studies, i.e., brain gene expression was not addressed, and quantitative trait locuses were not included unless they identified specific genes.
DATA EXTRACTION AND DATA SYNTHESIS
Identifiers according to HGNC or UniProt accession numbers were uploaded into the analysis program at http://reactome.org with duplicate names removed. The individual reactions identified were then aggregated into the major pathways of the Reactome program.
Genes labeled via HGNC symbol are listed in Table 1. Of 158 gene symbols placed into Reactome for analysis, 28 were not found in the program, leaving 130 for analysis. The genes not found were either cochlea-specific isoforms, i.e., prestin and nox2, or have not been curated into Reactome as of yet. The 130 genes were placed into the “Analysis” section of Reactome. The program matches these 130 genes to pathways, and provides a pictogram of significant pathways (see Fig. 1).
The Reactome analysis program lists entities found in each pathway, along with a ratio of those genes found versus the total molecules in the pathway, with a p value signifying “overrepresentation,” i.e., a larger number than would be expected if the set were random, with a Benjamini-Hochberg correction (see Table 2). Although the analysis includes all 621 entities, only the top 20 are itemized here. The list also includes a false discovery rate for each entity, indicating the expected proportion of rejected genes that were incorrect rejections. The entire list is available by downloading the gene list in Table 1 into the analysis section online.
FINDINGS AND DISCUSSION
Data reveals that these 130 genes are integrated into 621 reactions in reaction to acoustic trauma. Significant modulation of the cellular response to stress and heat stress, HSF1-dependent transactivation, and HSF1 activation are “overrepresented” by genes shown to be either up-regulated or down-regulated in response to acoustic trauma (p values <1.0E-12). Also significant are interleukin-6 family signaling, adherens junctions interactions, and the toll-like receptor 4 cascade (p values 3.06E-6, 6.07E-6, and 5.67E-6, respectively). These pathways may be used as a guideline for further avenues of investigation (see Table 2).
For reference, as of January 2016, Reactome contains 8,464 proteins including isoforms, 8,557 complexes, 8,770 reactions, and 1,887 pathways (72). The Human Genome Project has profiled 17,294 proteins, accounting for an estimated 84% of all homo sapiens proteins, as of April 2014 (73). Thus, the Reactome website has curated approximately 48% of the human genome into connecting pathways.
Figure 1 shows the noise-induced hearing loss analysis overlaid on a graphical representation of all the Reactome pathways. NIHL-related pathways are observed in darker colors, showing where these cochlear genes fit into general cellular systems, and each line emanating from the center of a system constitutes a separate subpathway. Examination of this map reveals an emphasis in our data set on reactions involved in signal transduction, the immune system, cellular response to stress, and others. The lightest lines constitute reactions either not studied or found to have no effect on hearing loss from acoustic trauma. On the website, clicking on pathway names opens windows into details of each reaction participating in the system, separated by organelle, and showing connecting pathways.
The cellular response to stress includes 44 of the genes uploaded, constituting 4.2% of the genes identified as related to general cellular stress response. Likewise, the literature has identified 18 modulated genes in the heat shock factor 1-dependent transactivation pathway of a total of 59 in the entire pathway, 0.5%, but with a p value of 2.22E-16. The interleukin-6 family signaling pathway consists of five genes, IL6, SOCS3, JAK2, STAT1, and STAT3, all have which been found to be important in NIHL.
One example of a detailed subpathway is diagramed in Figure 2. The program hones in on a particular set of related reactions, in this case, a portion of the cellular response to stress involving HSF1 that occurs in the cytosol, with connections to nucleoplasm through the HSF1 trimer. Dark olive areas indicate significant genes uploaded into the program. This diagram is a part of a larger illustration involving connected reactions in other organelles, allowing for a good overview of significant genes involved, their specific interactions and involvement in protein complexes, and location within the cell.
Another example of a portion of an interconnected pathway is observed in Figure 3, showing IL-6 interacting with membrane protein receptors as part of two separate pathways, directly with IL6 receptor, as well as a complex of Il-6:sIl6Receptor:sgp130 stimulating the intramembrane protein JAK. Both Il6 and JAK were found to be significantly changed in expression as a result of acoustic trauma (55,56).
Many of these genes are involved in several pathways; NF-kB is an integral part of the inflammasome, Toll-like receptor 4 pathway, and C-type lectin receptors (CLR). Another example, catalase (CAT), is a key protein in detoxification of ROS as well as negative regulation of NF-kappaB transcription factor and negative regulation of apoptosis (74). As an aside, overexpression of CAT, superoxide dismutase, and PRDX6, among others, has been found to be protective of hearing as a result of noise (75–79); however, until recently it has been impossible to calculate copy number variations in humans. With this recent capability through RNA sequencing, it might be possible to explore overexpression protection of the cochlea in human studies.
Thus, it can be observed that acoustic trauma affects not isolated genes and proteins, but activates many pathways in the cell in response to damage. When these pathways are weakened, by SNPs, for instance, the entire cellular milieu is affected, and these interactions must be considered for successful intervention in both treatment and prevention of NIHL.
The organization of information on the genomics of noise-induced hearing loss by categorizing genes and proteins into cellular systems is important for seeing the larger picture of where specific genes, proteins, and epigenetic entities fit together. It is clear that when one affects one particular pathway, other pathways are affected, and it is crucial to be aware of these connections for interventions involved in prevention and future treatment of noise-induced hearing loss. In this literature review, 21 of 23 cellular pathways were altered in response to acoustic trauma.
It is clear that much work has been done in the areas of cellular stress and attenuation, heat shock factor activation and its regulation, detoxification of ROS, and immune system signaling. Research may be directed toward other pathways that have been less characterized, such as chromatin organization, for example. Although a few miRNAs have been studied, the position of noncoding RNA, and other epigenetic factors, such as histone methylation and DNA methylation, remains a challenge for the future. These noncoding elements may have over-arching control of the delicate cochlear molecular homeostasis. The development of whole genome sequencing and GWAS will allow further laboratory discoveries and more detailed population studies, respectively.
In conclusion, genes and SNPs involved in NIHL remain a fruitful topic for investigation. Appropriate tools are being developed and refined to explore the interface of environment and cellular mechanisms. New avenues of research in the characterization of the cochlea's response to acoustic trauma; in therapeutic intervention; and in identification of those populations at risk promise important new insights into the mechanism of noise-induced hearing loss.
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