Besides age-related hearing loss, NIHL is the second most common form of hearing loss [10]. However, excess noise is one of the major preventable causes of hearing loss. The distinct pathology of NIHL is the loss of hair cells in the Organ of Corti. Since mammals including humans do not have the ability to regenerate hair cells, NIHL could be irreversible. Outer hair cells (OHCs) are more vulnerable to noise exposure than the inner hair cells. Similarly, the basal region of the organ of Corti is more susceptible to noise induced injury compared to the low-frequency apical region. The microscopic features of NIHL include the destruction of OHCs, floppy stereocilia, fusion and loss of stereocilia, loss of adjacent supporting cells, complete disruption of the organ of Corti, progressive Wallerian degeneration, and loss of primary auditory nerve fibers.

Significant achievements have been made in the understanding of the cellular and molecular mechanisms of NIHL which could be helpful in developing therapeutic strategies. Cochlear injury due to excessive noise can occur through mechanical and metabolic mechanisms both. Noise exposures of around 115–125 dB SPL, mechanical injury tends to dominate. However, in most circumstances, the level of noise exposure to the ear is <115 dB, and the damage is mainly metabolically driven [11]. A complex interplay of genetic and environmental factors leads to oxidative stress at the molecular level. Oxidative stress theory for noise-induced cochlear injury asserts that acoustic overexposure causes production of reactive oxygen species (ROS) and reactive nitrogen species which oxidize cell membrane lipids, intracellular proteins, and DNA, production of pro-inflammatory cytokines interleukin-6 (IL-6) and tumour necrosis factor α(TNF-@), vasoactive lipid peroxidation products such as isoprostanes leading to reduced cochlear blood flow, disproportionate release of neurotransmitters such as glutamate, and increase in intracellular calcium happens. A vital element of cochlear microcirculation is the diameter of the spiral modiolar artery, a branch of the anterior inferior cerebellar artery, which joins the lateral cochlear wall to form the stria vascularis. The spiral modiolar artery has been demonstrated to constrict during and after exposure to noise [12]. Glutamate excitotoxicity, GSH depletion, excessive increases in intracellular calcium, and ischemia reperfusion can all lead to mitochondrial injury and have been implicated in noise injury to the cochlea [11]. Mitochondrial membranes become permeable and release respiratory enzyme molecules (e.g., cytochrome c) that activate cell death effector proteins (e.g., caspases). Programmed cell death pathways involve calpain, caspases, and c-Jun N-terminal kinase Jun molecules. Cochlear antioxidant defences (antioxidant enzymes, heat shock proteins [HSPs], trophic factors, vitamins C and E, and glutathione [GSH]) gets exhausted. Both inflammatory and immune responses are key mechanisms in the cochlear defensive response to noise and if unregulated, contribute to inner ear damage and hearing loss. Transforming growth factor β (TGF-β) is a key regulator of both of these responses, and high levels of this factor have been associated with cochlear injury in animal models [11].

Another new opportunity of research in this area has opened yet another dimension– that of genetic predilection to NIHL. Rick A Friedman identified the Nox3, which is almost exclusively expressed in the inner ear, as a key gene predisposing to NIHL [13]. An increased susceptibility to NIHL may rely on the SNPs of several other genes, including the groups of oxidative stress genes, K + ions recycling genes, monogenic deafness genes, as well as mitochondrial genes [14]. Another study by Kowalski et al. identified one of the most interesting candidate genes CDH23 encoding Cadherin 23 which is a component of stereocilia tip links in patients with high susceptibility to noise confirming this CDH-23 genetic variant may modify the susceptibility to NIHL development in humans [15]. Cadherins, the calcium-dependent proteins, hold cells anchored at adherens junctions to form tissues and organs. The cadherin of interest named otocadherin or CDH23 is localized to the stereocilia of the OHCs. Reduction of or missing otocadherin weakens the cell and allows stereocilia to be more easily physically harmed by loud sounds and by aging [16,17].

Exposure to severe noise can induce HSPs, and exposure to moderate intensity noise has been reported to confer protection against noise-induced damage to hearing. Some haplotypes of hsp70 genes could possibly be associated with a higher predisposition to NIHL [18]. In the inner ear, P2X2 receptors are supposed to regulate sound transduction and auditory neurotransmission, OHC electromotility, inner ear gap junctions, and K + recycling [19]. The absence or mutation of P2X2 receptor increases vulnerability to NIHL. Apoptosis of cell is executed by a family of cysteine proteases called caspases [20]. X-linked inhibitor of apoptosis suppresses caspase-3 activity and may decrease NIHL. Proteins of the Bcl2 family have been involved in regulating sensory cell survival and control of apoptotic pathways modulating neuronal cell death, including NIHL [21]. The Bcl2 family consists of a group of proapoptotic and antiapoptotic molecules that regulate caspase activation. The mechanisms of sensory hair cell degeneration in response to different ototoxic stimuli share a terminal common pathway: caspase activation. Inhibition of caspases delays or prevents hair cell death and may possibly preserve hearing/balance function. Inhibition of mitogen-activated protein kinases (MAPK) defends against noise-induced hair cell death [22]. BclxL plays an essential role in the prevention of sensory cell death following TTS levels of noise, and PTS exposure provokes the expression of Bak and with that, cell death [21].

Glutathione-S-transferase (GST) enzymes are vital for antioxidant protection. Genetic variability in GST enzymes upsurges vulnerability to damage from oxidation. It has been proposed that an person with a null genotype is more prone than his peers to develop NIHL when exposed to excessive noise [12]. There are also some genetic mutations that lessen predisposition to NIHL. A1555G or other mitochondrial variants in the MTRNR1 and MTTS1 have been postulated as factors that lessen susceptibility to NIHL [12]. The additional research on the genetic susceptibility to NIHL has focused on human 8-oxoG DNA glycosylase1 (hOGG1), a key enzyme in the human base excision repair pathway. This DNA repair has been demonstrated to be essential in maintaining hearing after noise exposure. The hOGG1 Cys/Cys genotype may have a lesser capacity for restoring 8-oxoG damage, and thus a higher vulnerability for NIHL [12].

Atoh1 (also known as math1) has been found to be essential for neurogenesis in the central and peripheral nervous system, and for the formation of several nonneural cell types. In the auditory system, Atoh1 gene plays a crucial role in hair cell differentiation during development. The hallmark of mechanosensory hair cells is stereocilia, where mechanical stimuli are transformed into electrical signals. While hair cells in lower vertebrates and the mammalian vestibular system can spontaneously redevelop lost stereocilia, mammalian cochlear hair cells do not retain this capability during the developmental process. Atoh1 as a gene has been found to be critical for promoting repair/regeneration of stereocilia and maintaining injured hair cells in the adult mammal cochlea [23].