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Scientific Reports Jun 2024While volatile organic compounds (VOCs) impair various organs, their influence on hearing loss (HL) has not been extensively researched. We aimed to identify the...
While volatile organic compounds (VOCs) impair various organs, their influence on hearing loss (HL) has not been extensively researched. We aimed to identify the association between VOCs and HL or high-frequency hearing loss (HFHL). We extracted data on age, sex, pure tone audiometry, hypertension, occupational noise exposure, and creatinine-corrected urine VOC metabolite concentrations from the eighth Korea National Health and Nutrition Survey. Among the VOC metabolites, N-acetyl-S-(benzyl)-L-cysteine (BMA, P = 0.004), N-acetyl-S-(phenyl)-L-cysteine (SPMA, P = 0.027), and N-acetyl-S-(3,4-dihydroxybutyl)-L-cysteine (DHBMA, P < 0.001) showed associations with HL. Additionally, HFHL exhibited significant associations with BMA (P = 0.005), 3- and 4-methylhippuric acid (3, 4 MHA, P = 0.049), mandelic acid (MA, P = 0.015), SPMA (P < 0.001), N-acetyl-S-(3-hydroxypropyl)-L-cysteine (3-HPMA, P < 0.001), and DHBMA (P < 0.001). After controlling other factors, DHBMA were associated with HL (P = 0.021) and HFHL (P = 0.014) and exhibited a linear association with the mean hearing level (β = 0.054, P = 0.024) and high-frequency hearing level (β = 0.045, P = 0.037). Since 1,3-butadiene may act as an ototoxic material, early screening for workers exposed to 1,3-butadiene and reducing exposure to 1,3-butadiene in everyday life may be helpful to prevent further HL.
Topics: Humans; Butadienes; Female; Male; Middle Aged; Hearing Loss; Volatile Organic Compounds; Republic of Korea; Adult; Occupational Exposure; Aged; Nutrition Surveys; Audiometry, Pure-Tone
PubMed: 38839853
DOI: 10.1038/s41598-024-63757-7 -
The Journal of Biological Chemistry Jun 2024Hearing crucially depends on cochlear ion homeostasis as evident from deafness elicited by mutations in various genes encoding cation or anion channels and transporters....
Hearing crucially depends on cochlear ion homeostasis as evident from deafness elicited by mutations in various genes encoding cation or anion channels and transporters. Ablation of ClC‑K/barttin chloride channels causes deafness by interfering with the positive electrical potential of the endolymph, but roles of other anion channels in the inner ear have not been studied. Here we report the intracochlear distribution of all five LRRC8 subunits of VRAC, a volume-regulated anion channel that transports chloride, metabolites, and drugs such as the ototoxic anti-cancer drug cisplatin, and explore its physiological role by ablating its subunits. Sensory hair cells express all LRRC8 isoforms, whereas only LRRC8A, D and E were found in the potassium-secreting epithelium of the stria vascularis. Cochlear disruption of the essential LRRC8A subunit, or combined ablation of LRRC8D and E, resulted in cochlear degeneration and congenital deafness of Lrrc8a mice. It was associated with a progressive degeneration of the organ of Corti and its innervating spiral ganglion. Like disruption of ClC-K/barttin, loss of VRAC severely reduced the endocochlear potential. However, the mechanism underlying this reduction seems different. Disruption of VRAC, but not ClC-K/barttin, led to an almost complete loss of Kir4.1 (KCNJ10), a strial K channel crucial for the generation of the endocochlear potential. The strong downregulation of Kir4.1 might be secondary to a loss of VRAC-mediated transport of metabolites regulating inner ear redox potential such as glutathione. Our study extends the knowledge of the role of cochlear ion transport in hearing and ototoxicity.
PubMed: 38838775
DOI: 10.1016/j.jbc.2024.107436 -
BioRxiv : the Preprint Server For... May 2024Our ability to hear and maintain balance relies on the proper functioning of inner ear sensory hair cells, which translate mechanical stimuli into electrical signals via...
Our ability to hear and maintain balance relies on the proper functioning of inner ear sensory hair cells, which translate mechanical stimuli into electrical signals via mechano-electrical transducer (MET) channels, composed of TMC1/2 proteins. However, the therapeutic use of ototoxic drugs, such as aminoglycosides and cisplatin, which can enter hair cells through MET channels, often leads to profound auditory and vestibular dysfunction. Despite extensive research on otoprotective compounds targeting MET channels, our understanding of how small molecule modulators interact with these channels remains limited, hampering the discovery of novel compounds. Here, we propose a structure-based screening approach, integrating 3D-pharmacophore modeling, molecular simulations, and experimental validation. Our pipeline successfully identified several novel compounds and FDA-approved drugs that reduced dye uptake in cultured cochlear explants, indicating MET modulation activity. Molecular docking and free-energy estimations for binding allowed us to identify three potential drug binding sites within the channel pore, phospholipids, and key amino acids involved in modulator interactions. We also identified shared ligand-binding features between TMC and structurally related TMEM16 protein families, providing novel insights into their distinct inhibition, while potentially guiding the rational design of MET-channel-specific modulators. Our pipeline offers a broad application to discover small molecule modulators for a wide spectrum of mechanosensitive ion channels.
PubMed: 38826329
DOI: 10.1101/2024.03.05.583611 -
Pediatrics and Neonatology May 2024We conducted a nationwide population-based case-control study to analyse potential predisposing factors for hearing loss (HL) that present during the fetal, perinatal,...
BACKGROUND
We conducted a nationwide population-based case-control study to analyse potential predisposing factors for hearing loss (HL) that present during the fetal, perinatal, and postnatal periods in prematurely born children.
METHODS
This study enrolled 21,576 children born at < 37 weeks of gestation; 3,596 with HL and 17,980 with normal hearing born between 2002 and 2015, matched for sex, age at diagnosis, and enrollment time. Data were abstracted from the concatenation of three nationwide databases for overall risk factors till the diagnosis of HL.
RESULTS
Maternal HL, maternal diabetes, particularly type 1 diabetes mellitus, and at or before 32 weeks of gestation were the major obstetric risk factors for HL. Prematurely born children who were born via cesarean section and received a combination of antenatal steroids and magnesium sulfate exhibited a significantly reduced risk of developing HL. Ear malformation was a critical predictor for HL. The major postnatal risk factors included seizure and ototoxic drugs use. Premature infants diagnosed with more than 1 diagnosis of bronchopulmonary dysplasia, necrotizing enterocolitis, and intracerebral hemorrhage were at an increased risk of developing HL. Congenital CMV infection and recurrent acute otitis were also independent postnatal factors for HL in prematurely born children.
CONCLUSION
To reduce the incidence of childhood HL in prematurely born children, aggressive management of premature birth-related consequences and treatable causes and longitudinal audiological follow-up with early detection and adequate intervention are crucial.
PubMed: 38811322
DOI: 10.1016/j.pedneo.2024.04.006 -
Otolaryngologia Polska = the Polish... Jun 2024<b><br>Introduction:</b> Immune checkpoint inhibitors (ICIs) and T-cell therapies are a modern, well-established cancer treatment. The priority of... (Review)
Review
<b><br>Introduction:</b> Immune checkpoint inhibitors (ICIs) and T-cell therapies are a modern, well-established cancer treatment. The priority of oncological treatment is to cure cancer. However, treatment-related toxicities, i.e. immune-related adverse events (irAEs), continue to emerge and are not that well understood yet. ICIs can cause profound, multiple, and diverse irAEs - the sequelae of unknown mechanisms. One of the organs susceptible to collateral damage is the hearing organ. Complications related to hearing, tinnitus, and balance disorders are extremely burdensome and significantly impair many aspects of the quality of life of patients and survivors.</br> <b><br>Aim:</b> The aim of the work is to review the literature in the area of ototoxicity of ICIs.</br> <b><br>Materials and method:</b> A systematic search of the Web of Science, PubMed, and Embase databases for studies published until 1 March 2022 was conducted.</br> <b><br>Results:</b> Reported clinical symptoms ranged from sudden bilateral hearing loss and imbalance to mild hearing loss or tinnitus with preserved hearing. It was found that the median time from ICI initiation to hearing loss development was 3 months. The hearing impairment was secondary to bilateral sensorineural hearing loss in the majority of patients (>60%), and at least one other irAE accompanied the hearing loss in 2/3 of patients. Hearing loss significantly improved in 45.7% of the patients.</br> <b><br>Conclusions:</b> The majority of cases of ICI-related hearing loss presented in the literature were reversible. Therefore, it is important to develop and implement routine therapeutic algorithms. Further research is needed to define the true prevalence of ICI-related hearing loss, optimal diagnostics, and management.</br>.
Topics: Humans; Immune Checkpoint Inhibitors; Ototoxicity; Male; Female; Hearing Loss; Neoplasms; Middle Aged
PubMed: 38808639
DOI: No ID Found -
Radiotherapy and Oncology : Journal of... May 2024To identify dosimetric predictive factors of sensorineural hearing loss (SNHL) in children after cranial radiation therapy (RT) in a single institution using dosimetric...
PURPOSE
To identify dosimetric predictive factors of sensorineural hearing loss (SNHL) in children after cranial radiation therapy (RT) in a single institution using dosimetric data from the French National Registry PediaRT.
METHODS AND MATERIALS
Complete audiological follow-up data were available for 44 children treated with cranial RT between 2014 and 2021 at our institution. The median age at the time of RT initiation was 9 years (range: 2-17 years). No children presented with hearing loss prior to treatment. SNHL was defined as a Chang ototoxicity grade ≥ 1a or higher.
RESULTS
Median audiometric follow-up duration was 51 months. Seven children (16 %) developed SNHL with a median time to occurrence of 33 months (range, 18-46 months). The estimated SNHL cumulative rate at 2 years post-RT was 4,5% ± 3,1% and at 5 years was 21 % ± 7.2 %. Multiple Cox regression models showed that the association of the age at radiotherapy and the dosimetric values to the inner ear canal and cochlea were the most significant predictive factors of SNHL occurrence. No child who received less than 35 Gy on average to both cochleae (n = 26) suffered from SNHL, whereas the 5-year SNHL cumulative incidence for the children who received greater than or equal to 35 Gy on average to either cochlea (n = 18) was 51.8 % ± 15.1 %.
CONCLUSION
Doses received by the inner ear canal and cochlea, associated with the age at RT initiation, are the main predictive factors for radiation-induced SNHL. A median dose to either cochlea over 35 Gy significantly increases the risk of SNHL and justify close audiometric monitoring to detect and equip hearing loss at an early stage.
PubMed: 38806115
DOI: 10.1016/j.radonc.2024.110346 -
Revista Medica de Chile Jun 2023Ototoxicity is a side effect of drugs and medications that usually leads to bilateral and symmetric sensorineural hearing loss that commonly affects the high-frequency...
BACKGROUND
Ototoxicity is a side effect of drugs and medications that usually leads to bilateral and symmetric sensorineural hearing loss that commonly affects the high-frequency range initially, with or preceded by tinnitus. Possible ototoxic side effects of calcineurin inhibitor immunosuppressants have been suggested, but this remains unclear. Therefore, this study aims to evaluate audiological changes in patients undergoing transplantation receiving immunosuppressive treatment with calcineurin inhibitors.
METHODS
Prospective cohort study. Adult patients undergoing liver or kidney transplantation treated with calcineurin inhibitors were included. Pure-tone audiometry, distortion product otoacoustic emissions, and the Tinnitus Handicap Inventory questionnaire were completed at baseline, one, three, and six months after transplantation. Hearing thresholds were compared and correlated with plasma concentrations of calcineurin inhibitors.
RESULTS
Seventeen patients were included, 59% males, with a median age of 54.7 years (29-68 years). Twelve patients underwent liver transplantation, four underwent kidney transplantation, and one patient underwent both. The medianfollow-up was 5.8 months (4-8 months). Significant pure-tone average shifts were observed in two patients. Both cases presented fluctuations in their hearing levels, which were not bilateral or symmetrical and affected the higher frequencies. All patients received tacrolimus within the therapeutic range during the follow-up period. Three different patients exceeded the expected range once; however, they were rapidly corrected and did not correlate with any changes in hearing.
CONCLUSIONS
It appears that tacrolimus does not cause hearing loss when levels are within the therapeutic range for a follow-up period of six months post-transplantation.
Topics: Humans; Male; Middle Aged; Female; Adult; Calcineurin Inhibitors; Immunosuppressive Agents; Prospective Studies; Kidney Transplantation; Aged; Liver Transplantation; Follow-Up Studies; Ototoxicity; Audiometry, Pure-Tone; Tacrolimus; Hearing Loss, Sensorineural; Time Factors
PubMed: 38801378
DOI: 10.4067/s0034-98872023000600702 -
Laryngoscope Investigative... Jun 2024Cisplatin is known to cause inner ear dysfunction. There is growing evidence that cisplatin-induced demyelination of spiral or Scarpa's ganglion neurons may play an...
OBJECTIVES
Cisplatin is known to cause inner ear dysfunction. There is growing evidence that cisplatin-induced demyelination of spiral or Scarpa's ganglion neurons may play an additional role in drug-induced ototoxicity alongside afferent neuron injury. As Schwann cells produce myelin, there may be an opportunity to reduce ototoxic inner ear damage by promoting Schwann cell viability. This work describes a cellular model of cisplatin-induced Schwann cell injury and investigates the ability of the antioxidant N-acetylcysteine to promote Schwann cell viability. A local delivery system of drug-eluting microparticles was then fabricated, characterized, and investigated for bioactivity.
METHODS
RSC96 rat Schwann cells were dosed with varying concentrations of cisplatin to obtain a dose curve and identify the lethal concentration of 50% of the cells (LC). In subsequent experiments, RSC96 cells were co-treated with cisplatin and both resuspended or eluted N-acetylcysteine. Cell viability was assessed with the CCK8 assay.
RESULTS
The LC dose of cisplatin was determined to be 3.76 μM ( = 2.2 x 10). When co-dosed with cisplatin and a therapeutic concentration of resuspended or eluted N-acetylcysteine, Schwann cells had an increased viability compared to cells dosed with cisplatin alone.
CONCLUSION
RSC96 Schwann cell injury following cisplatin insult is characterized in this in vitro model. Cisplatin caused injury at physiologic concentrations and N-acetylcysteine improved cell viability and mitigated this injury. N-acetylcysteine was packaged into microparticles and eluted N-acetylcysteine retained its ability to increase cell viability, thus demonstrating promise as a therapeutic to offset cisplatin-induced ototoxicity.
LEVEL OF EVIDENCE
N/A Laryngoscope, 2023.
PubMed: 38765675
DOI: 10.1002/lio2.1256 -
Journal of Surgical Case Reports May 2024Auditory processing is initiated within the primary auditory cortex, concealed within the sylvian fissure bilaterally on a collection of gyri described as Heschl's Gyrus...
Auditory processing is initiated within the primary auditory cortex, concealed within the sylvian fissure bilaterally on a collection of gyri described as Heschl's Gyrus (HG). Glial neoplasms localized to or involving HG are rare. The main symptoms of these tumours are complex partial seizures characterized by auditory features. Here, we describe an unusual case of bilateral tinnitus and hemi-paraesthesia associated with a HG diffuse astrocytoma. Bilateral tinnitus secondary to intrinsic brain tumours is atypical. Bilateral tinnitus is frequently observed in patients with noise-induced hearing loss, presbycusis, ototoxic medication, and metabolic and psychiatric disease. In the case we present, the synchronous sensory and auditory symptoms are likely due to seizure activity affecting the primary auditory and somatosensory cortex. In a patient presenting with chronic, bilateral tinnitus with no known underlying otologic disease which is associated with hemi-body paraesthesia, we would advocate for consideration of brain imaging to exclude pathology in HG.
PubMed: 38764736
DOI: 10.1093/jscr/rjae317 -
Frontiers in Molecular Neuroscience 2024Hearing loss constitutes a major global health concern impacting approximately 1.5 billion people worldwide. Its incidence is undergoing a substantial surge with some... (Review)
Review
Hearing loss constitutes a major global health concern impacting approximately 1.5 billion people worldwide. Its incidence is undergoing a substantial surge with some projecting that by 2050, a quarter of the global population will experience varying degrees of hearing deficiency. Environmental factors such as aging, exposure to loud noise, and the intake of ototoxic medications are implicated in the onset of acquired hearing loss. Ototoxicity resulting in inner ear damage is a leading cause of acquired hearing loss worldwide. This could be minimized or avoided by early testing of hearing functions in the preclinical phase of drug development. While the assessment of ototoxicity is well defined for drug candidates in the hearing field - required for drugs that are administered by the otic route and expected to reach the middle or inner ear during clinical use - ototoxicity testing is not required for all other therapeutic areas. Unfortunately, this has resulted in more than 200 ototoxic marketed medications. The aim of this publication is to raise awareness of drug-induced ototoxicity and to formulate some recommendations based on available guidelines and own experience. Ototoxicity testing programs should be adapted to the type of therapy, its indication (targeting the ear or part of other medications classes being potentially ototoxic), and the number of assets to test. For multiple molecules and/or multiple doses, screening options are available: (otic cell assays), (cochlear explant), and (in zebrafish). In assessing the ototoxicity of a candidate drug, it is good practice to compare its ototoxicity to that of a well-known control drug of a similar class. Screening assays provide a streamlined and rapid method to know whether a drug is generally safe for inner ear structures. Mammalian animal models provide a more detailed characterization of drug ototoxicity, with a possibility to localize and quantify the damage using functional, behavioral, and morphological read-outs. Complementary histological measures are routinely conducted notably to quantify hair cells loss with cochleogram. Ototoxicity studies can be performed in rodents (mice, rats), guinea pigs and large species. However, in undertaking, or at the very least attempting, all preclinical investigations within the same species, is crucial. This encompasses starting with pharmacokinetics and pharmacology efficacy studies and extending through to toxicity studies. In life read-outs include Auditory Brainstem Response (ABR) and Distortion Product OtoAcoustic Emissions (DPOAE) measurements that assess the activity and integrity of sensory cells and the auditory nerve, reflecting sensorineural hearing loss. Accurate, reproducible, and high throughput ABR measures are fundamental to the quality and success of these preclinical trials. As in humans, otoscopic evaluations are routinely carried out to observe the tympanic membrane and auditory canal. This is often done to detect signs of inflammation. The cochlea is a tonotopic structure. Hair cell responsiveness is position and frequency dependent, with hair cells located close to the cochlea apex transducing low frequencies and those at the base transducing high frequencies. The cochleogram aims to quantify hair cells all along the cochlea and consequently determine hair cell loss related to specific frequencies. This measure is then correlated with the ABR & DPOAE results. Ototoxicity assessments evaluate the impact of drug candidates on the auditory and vestibular systems, de-risk hearing loss and balance disorders, define a safe dose, and optimize therapeutic benefits. These types of studies can be initiated during early development of a therapeutic solution, with ABR and otoscopic evaluations. Depending on the mechanism of action of the compound, studies can include DPOAE and cochleogram. Later in the development, a GLP (Good Laboratory Practice) ototoxicity study may be required based on otic related route of administration, target, or known potential otic toxicity.
PubMed: 38756707
DOI: 10.3389/fnmol.2024.1379743