Tinnitus and Self-Perceived Hearing Handicap in Firefighters: a Cross-Sectional Study

Firefighters are susceptible to auditory dysfunction due to long-term exposure to noise from sirens, air horns, equipment, and tools used in forcible entry, ventilation, and extrication. In addition, they are exposed to ototoxic chemicals, particularly, during overhaul operations. Studies indicate that 40% of firefighters have hearing loss in the noise-sensitive frequencies of 4 and 6 kHz. Noise-induced hearing loss (NIHL) is often accompanied by tinnitus, which is characterized by ringing noise in the ears. The presence of phantom sounds can adversely affect the performance of firefighters. However, there has been limited research conducted on the prevalence of tinnitus in firefighters. We enrolled firefighters from Michigan, with at least 5 years of continuous service. The hearing handicap inventory for adults (HHIA) was used to determine the difficulty in hearing perceived by the firefighters and the tinnitus functional index (TFI) was used to determine the severity of tinnitus. Self-perceived hearing handicap was reported by 36% of the participants, while tinnitus was reported by 48% of the participants. The TFI survey indicated that 31% perceived tinnitus as a problem. More importantly, self-perceived hearing handicap was significantly associated with the incidence of tinnitus in firefighters, suggesting a potential link between occupational exposure to ototraumatic agents and tinnitus in firefighters

Molecular regulation of auditory hair cell death and approaches to protect sensory receptor cells and/or stimulate repair following acoustic trauma

International audienceLoss of auditory sensory hair cells (HCs) is the most common cause of hearing loss. This review addresses the signaling pathways that are involved in the programmed and necrotic cell death of auditory HCs that occur in response to ototoxic and traumatic stressor events. The roles of inflammatory processes, oxidative stress, mitochondrial damage, cell death receptors, members of the mitogen-activated protein kinase (MAPK) signal pathway and pro- and anti-cell death members of the Bcl-2 family are explored. The molecular interaction of these signal pathways that initiates the loss of auditory HCs following acoustic trauma is covered and possible therapeutic interventions that may protect these sensory HCs from loss via apoptotic or non-apoptotic cell death are explored

Putative LMO4 signaling in cisplatin-induced ototoxicity.

<p>Cisplatin induces cochlear oxidative stress by activating NOX3, which eventually could facilitate the nitration of cochlear LMO4. We reported a cisplatin-induced decrease in the expression of LMO4 in the cochlea (J Biol Chem 2012, 287: 18674–18686). LMO4 has been reported to act as a scaffold by associating with IL-6 receptor glycoprotein 130 and enable the activation of JAK1, TYK2, and STAT3 (J Biol Chem 280: 12747–12757). Since activated STAT3 facilitates the up-regulation of anti-apoptotic genes, the cisplatin-induced decrease in LMO4 levels, probably due to proteolytic degradation of nitrated LMO4, appears to eventually compromise the STAT3-mediated anti-apoptotic machinery, resulting in ototoxicity. Moreover, LMO4 binds with BRCA1 and ESR1 and negatively regulates their activation (Cancer Res 65: 10594–10601). Since BRCA1 directly binds with STAT1, which has been reported to facilitate cisplatin ototoxicity, and ESR1 binds with STAT3 and inhibits its activity, the cisplatin-induced up-regulation of ESR1 and down-regulation of STAT3 in the cochlea suggests that the LMO4 signaling in cisplatin ototoxicity probably involves STAT3-mediated apoptotic pathway to induce cochlear apoptosis.</p

Distribution of Lmo4 in the cochlea.

<p>Immunolocalization with anti-Lmo4 detected the expression of Lmo4 proteins in the spiral ganglion, stria vascularis, and organ of Corti of rat cochlea. In the merged panels (bottom row), red indicates immunoreactivity to Lmo4, green indicates actin staining (phalloidin), and blue indicates nuclear staining (DAPI). A section obtained from the basal turn of the organ of Corti is illustrated. The images are representative samples from 2 animals.</p

Cisplatin-induced decrease in cochlear protein levels of Stat3.

<p>Immunoblots show cisplatin-induced decrease in cochlear Stat3 levels (***p<0.001) and reversal with Trolox co-treatment (**p<0.01). Stat3 expression was normalized with that of actin, and results are expressed as mean ± SE, n = 3.</p

Nitrative Stress and Auditory Dysfunction

Nitrative stress is increasingly recognized as a critical mediator of apoptotic cell death in many pathological conditions. The accumulation of nitric oxide along with superoxide radicals leads to the generation of peroxynitrite that can eventually result in the nitration of susceptible proteins. Nitrotyrosine is widely used as a biomarker of nitrative stress and indicates oxidative damage to proteins. Ototoxic insults, such as exposure to noise and ototoxic drugs, enhance the generation of 3-nitrotyrosine in different cell types in the cochlea. Nitrated proteins can disrupt critical signaling pathways and eventually lead to apoptosis and loss of sensory receptor cells in the cochlea. Accumulating evidence shows that selective targeting of nitrative stress attenuates cellular damage. Anti-nitrative compounds, such as peroxynitrite decomposition catalysts and inducible nitric oxide synthase inhibitors, prevent nitrative stress-mediated auditory damage. However, the role of nitrative stress in acquired hearing loss and its potential significance as a promising interventional target is yet to be fully characterized. This review provides an overview of nitrative stress mechanisms, the induction of nitrative stress in the auditory tissue after ototoxic insults, and the therapeutic value of targeting nitrative stress for mitigating auditory dysfunction

Targeting nitrative stress for attenuating cisplatin-induced downregulation of cochlear LIM domain only 4 and ototoxicity

Cisplatin-induced ototoxicity remains a primary dose-limiting adverse effect of this highly effective anticancer drug. The clinical utility of cisplatin could be enhanced if the signaling pathways that regulate the toxic side-effects are delineated. In previous studies, we reported cisplatin-induced nitration of cochlear proteins and provided the first evidence for nitration and downregulation of cochlear LIM domain only 4 (LMO4) in cisplatin ototoxicity. Here, we extend these findings to define the critical role of nitrative stress in cisplatin-induced downregulation of LMO4 and its consequent ototoxic effects in UBOC1 cell cultures derived from sensory epithelial cells of the inner ear and in CBA/J mice. Cisplatin treatment increased the levels of nitrotyrosine and active caspase 3 in UBOC1 cells, which was detected by immunocytochemical and flow cytometry analysis, respectively. The cisplatin-induced nitrative stress and apoptosis were attenuated by co-treatment with SRI110, a peroxynitrite decomposition catalyst (PNDC), which also attenuated the cisplatin-induced downregulation of LMO4 in a dose-dependent manner. Furthermore, transient overexpression of LMO4 in UBOC1 cells prevented cisplatin-induced cytotoxicity while repression of LMO4 exacerbated cisplatin-induced cell death, indicating a direct link between LMO4 protein levels and cisplatin ototoxicity. Finally, auditory brainstem responses (ABR) recorded from CBA/J mice indicated that co-treatment with SRI110 mitigated cisplatin-induced hearing loss. Together, these results suggest that cisplatin-induced nitrative stress leads to a decrease in the levels of LMO4, downregulation of LMO4 is a critical determinant in cisplatin-induced ototoxicity, and targeting peroxynitrite could be a promising strategy for mitigating cisplatin-induced hearing loss