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Cytotoxic effects of cisplatin occur primarily through apoptosis. Though several pro- and anti-apoptotic signaling molecules have been identified to play an important role in mediating the ototoxic, nephrotoxic, and neurotoxic side effects of cisplatin, the underlying mechanism is yet to be fully characterized. We reported that nitration of LIM domain-only 4 (LMO4), a transcriptional regulator, facilitates cochlear apoptosis in cisplatin-induced ototoxicity. However, its role in cisplatin-mediated nephrotoxicity and neurotoxicity is poorly understood. Therefore, HK2 and SH-SY5Y cells were used along with UBOC1 cells, to investigate the perturbations of LMO4 in cisplatin-induced cytotoxicity, in renal, neuronal, and auditory cells, respectively. Cisplatin induced an increase in the expression of active caspase-3, indicating cellular apoptosis, and increased the nitration of proteins, 24 h post treatment. Immunostaining with anti-nitrotyrosine and anti-LMO4 indicated that nitrotyrosine co-localized with LMO4 protein in cisplatin-treated cells. Immunoblotting with anti-LMO4 indicated that cisplatin induced a decrease in LMO4 protein levels. However, a corresponding decrease in LMO4 gene levels was not observed. Inhibition of protein nitration with SRI110, a peroxynitrite decomposition catalyst, attenuated cisplatin-induced downregulation of LMO4. More importantly, overexpression of LMO4 mitigated the cytotoxic effects of cisplatin in UBOC1 cells while a dose-dependent decrease in LMO4 protein strongly correlated with cell viability in UBOC1, HK2, and SH-SY5Y cells. Collectively, these findings suggested a potential role of LMO4 in facilitating the cytotoxic effects of cisplatin in auditory, renal, and neuronal cells.

Pollutants that contaminate the natural or built environment adversely affect the health of living organisms. Although exposure to many of them could be avoided or minimized by careful preventive measures, it is impossible to totally avoid exposure to all pollutants. Ototraumatic agents, such as noise, chemicals, and heavy metals, are pervasive pollutants, mostly produced by human activity, and are critical factors in inducing acquired hearing loss. More importantly, exposure to these pollutants often occurs concurrently and, therefore, the synergistic interactions potentiate auditory dysfunction in susceptible individuals. Epidemiological studies have provided compelling data on the incidence of auditory dysfunction after exposure to a number of ototraumatic agents in the environment, while animal studies have offered crucial insights for understanding the underlying molecular mechanisms. Together, they provide a framework for developing effective interventional approaches for mitigating the adverse impacts of environmental or occupational exposure to ototraumatic agents. This article provides a brief overview of the common pollutants that cause hearing loss.

Lmo4, a transcriptional regulator, appears to be a key player in mediating the cochlear pathology in cisplatin ototoxicity, as it controls cellular responses by modulating the formation of transcriptional complexes. We provided the first evidence of in vivo nitration of Lmo4 in cisplatin ototoxicity. Our data suggested that nitration of Lmo4 and associated decrease in its cochlear expression has the potential to play a pivotal role in cisplatin ototoxicity. However, the Lmo4 interactomes that signal the downstream events in the cochlea are poorly understood. Therefore, custom-made gene arrays were employed to evaluate the modulation of known binding partners or targets of Lmo4, in Wistar rats treated with 16 mg/kg cisplatin. RT-PCR analysis, 3 days post cisplatin treatment, indicated that cisplatin induced up/down regulation of multiple cochlear genes associated with Lmo4 signaling. The cochlear expression of Esr1 was significantly up-regulated by cisplatin treatment, while the expression of Stat3 was down-regulated. Co-treatment with Trolox, an otoprotective antioxidant, attenuated the cisplatin-induced modulation of 5 genes in the cochlea. Consistent with the changes observed at the gene level, immunoblots with anti-Stat3 indicated that cisplatin-induced decrease in cochlear protein levels were attenuated by Trolox co-treatment. These results suggest that cisplatin-induced decreases in the cochlear Lmo4 upon nitration, and associated modulation in the cochlear expression of its binding partners Esr1 and Jak1, probably facilitates the repression of Stat3, a downstream target of Lmo4 implicated in drug mediated apoptosis. Collectively, these findings provide insights on Lmo4 downstream events and indicate a potential role of Jak/Stat transcriptional machinery in relaying the Lmo4 protein signaling in cisplatin-induced ototoxicity.

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.

Cisplatin, a potent chemotherapeutic drug, induces ototoxicity, which limits its clinical utility. Cisplatin-induced oxidative stress plays a causal role in cochlear apoptosis while the consequent nitrative stress leads to the nitration of LIM domain only 4 (LMO4), a transcriptional regulator, and decreases its cochlear expression levels. Here, we show a direct link between cochlear LMO4 and cisplatin-induced hearing loss by employing a Lmo4 conditional knockout mouse model ( Lmo4 lox/lox ; Gfi1 Cre/+ ). Hair cell-specific deletion of Lmo4 did not alter cochlear morphology or affect hearing thresholds and otoacoustic emissions, in the absence of apoptotic stimuli. Cisplatin treatment significantly elevated the auditory brainstem response thresholds of conditional knockouts, across all frequencies. Moreover, deletion of Lmo4 compromised the activation of STAT3, a downstream target that regulates anti-apoptotic machinery. Immunostaining indicated that the expression of phosphorylated STAT3 was significantly decreased while the expression of activated caspase 3 was significantly increased in Lmo4 deficient hair cells, post-cisplatin treatment. These findings suggest an otoprotective role of LMO4 as cisplatin-induced decrease in cochlear LMO4 could compromise the LMO4/STAT3 cellular defense mechanism to induce ototoxicity.

Per- and polyfluoroalkyl substances (PFAS) are persistent environmental pollutants linked to adverse health effects. Recent epidemiological data suggest an association between PFAS exposure and hearing loss, but underlying mechanisms remain unclear. This study examined PFAS-induced auditory dysfunction in mice exposed to a mixture of five PFAS compounds (2 mg/L each) in drinking water for seven weeks. Ldlr mice were used due to their susceptibility to metabolic dysfunction, a risk factor for hearing loss. Auditory brainstem responses (ABR) indicated that PFAS exposure significantly elevated hearing thresholds by 18-33 dB across multiple frequencies. Distortion product otoacoustic emissions (DPOAEs) revealed impaired outer hair cell (OHC) function, and immunohistochemical analysis indicated a 20% OHC loss in the basal turn of the cochlea. In addition, PFAS exposure reduced ABR wave-1 amplitudes, and caused a 50% reduction in spiral ganglion cell density, indicating impaired auditory nerve function. Overall, this study provides the first evidence for PFAS-induced high-frequency hearing loss in mice. The findings further indicated that cochlear OHCs and spiral ganglion neurons are potential targets in PFAS-induced hearing loss. Together, these data suggest that PFAS exposure elicits a multifaceted ototoxic response, affecting both sensory and neural elements of the cochlea.

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.

Exposure to heavy metal lead can cause serious health effects such as developmental neurotoxicity in infants, cognitive impairment in children, and cardiovascular and nephrotoxic effects in adults. Hearing loss is one of the toxic effects induced by exposure to lead. Previous studies demonstrated that exposure to lead causes oxidative stress in the cochlea and disrupts ribbon synapses in the inner hair cells. This study investigated the underlying mechanism by evaluating the changes in the abundance of cochlear synaptosomal proteins that accompany lead-induced cochlear synaptopathy and hearing loss in mice. Young-adult CBA/J mice were given lead acetate in drinking water for 28 days. Lead exposure significantly increased the hearing thresholds, particularly at the higher frequencies in both male and female mice, but it did not affect the activity of outer hair cells or induce hair cell loss. However, lead exposure decreased wave-I amplitude, suggesting lead-induced cochlear synaptopathy. In agreement, colocalization of pre- and post-synaptic markers indicated that lead exposure decreased the number of paired synapses in the basal turn of the cochlea. Proteomics analysis indicated that lead exposure increased the abundance of 352 synaptic proteins and decreased the abundance of 394 synaptic proteins in the cochlea. Bioinformatics analysis indicated that proteins that change in abundance are highly enriched in the synaptic vesicle cycle pathway. Together, these results suggest that outer hair cells are not the primary target in lead-induced ototoxicity, that lead-induced cochlear synaptopathy is more pronounced in the basal turn of the cochlea, and that synaptic vesicle cycle signaling potentially plays a critical role in lead-induced cochlear synaptopathy.

Environmental exposure to heavy metal lead, a public health hazard in many post-industrial cities, causes hearing impairment upon long-term exposure. Lead-induced cochlear and vestibular dysfunction is well-documented in animal models. Although short-term exposure to lead at concentrations relevant to environmental settings does not cause significant shifts in hearing thresholds in adults, moderate- to low-level lead exposures induce neuronal damage and synaptic dysfunction. We reported that lead exposure induces oxidative stress in the mouse cochlea. However, lead-induced nitrative stress and potential damage to cochlear ribbon synapses are yet to be fully understood. Therefore, this study has evaluated cochlear synaptopathy and nitrative stress in young-adult mice exposed to 2 mM lead acetate for 28 days. Inductively coupled plasma mass spectrometry (ICP-MS) analysis indicated that this exposure significantly increased the blood lead levels. Assessment of hair cell loss by immunohistochemistry analysis and outer hair cell (OHC) activity by recording distortion product otoacoustic emissions (DPOAEs) indicated that the structure and function of the hair cells were not affected by lead exposure. However, this exposure significantly decreased the expression of C-terminal-binding protein-2 (CtBP2) and GluA2, pre- and post-synaptic protein markers in the inner hair cell synapses, particularly in the basal turn of the organ of Corti, suggesting lead-induced disruption of ribbon synapses. In addition, lead exposure significantly increased the nitrotyrosine levels in spiral ganglion cells, suggesting lead-induced nitrative stress in the cochlea. Collectively, these findings suggest that lead exposure even at levels that do not affect the OHCs induces cochlear nitrative stress and causes cochlear synaptopathy.

Noise-induced hearing loss (NIHL) is a major public health issue worldwide. Uncovering the early molecular events associated with NIHL would reveal mechanisms leading to the hearing loss. Our aim is to investigate the immediate molecular responses after different levels of noise exposure and identify the common and distinct pathways that mediate NIHL. Previous work showed mice exposed to 116 decibels sound pressure level (dB SPL) broadband noise for 1 h had greater threshold shifts than the mice exposed to 110 dB SPL broadband noise, hence we used these two noise levels in this study. Groups of 4-8-week-old CBA/CaJ mice were exposed to no noise (control) or to broadband noise for 1 h, followed by transcriptome analysis of total cochlear RNA isolated immediately after noise exposure. Previously identified and novel genes were found in all data sets. Following exposure to noise at 116 dB SPL, the earliest responses included up-regulation of 243 genes and down-regulation of 61 genes, while a similar exposure at 110 dB SPL up-regulated 155 genes and down-regulated 221 genes. Bioinformatics analysis indicated that mitogen-activated protein kinase (MAPK) signaling was the major pathway in both levels of noise exposure. Nevertheless, both qualitative and quantitative differences were noticed in some MAPK signaling genes, after exposure to different noise levels. Cacna1b , Cacna1g , and Pla2g6 , related to calcium signaling were down-regulated after 110 dB SPL exposure, while the fold increase in the expression of Fos was relatively lower than what was observed after 116 dB SPL exposure. These subtle variations provide insight on the factors that may contribute to the differences in NIHL despite the activation of a common pathway.