Hearing loss is the most common initial symptom in patients with sporadic vestibular schwannomas (SVS). Hearing preservation is an important goal of both conservative and surgical therapy. However, the mechanism of SVS-associated hearing loss remains unclear. Thus, we performed this systematic review to summarize the current understanding of hearing loss in the SVS and distill a testable hypothesis to further illuminate its underlying mechanism.A systematic review querying four databases  was performed to identify studies evaluating hearing loss in patients with SVS and exploring the potential mechanisms of hearing impairment.etc.); (2) ten studies investigate the potential role of cochlear dysfunction in hearing deterioration, including structural abnormality, protein elevation in perilymph, and cochlear malfunctioning; (3) two studies looked into SVS-induced impairment of auditory pathway and cortex; (4) in the rest nine studies, researchers explored the molecular mechanism underlying hearing loss in SVS, which involves molecular and genetic alterations, inflammatory response, growth factors, and other tumor-associated secretions.A total of 50 articles were eligible and included in this review. After analysis, the retrieved studies could be categorized into four types: (1) 29 studies explore the relationship between hearing loss and the growth pattern of the tumor (e.g., tumor size/volume, growth rate, tumor location, Multiple factors may contribute to the hearing impairment in SVS, including the growth pattern of tumor, cochlear dysfunction, impairment of auditory pathway and cortex, genetic and molecular changes. However, our current understanding is still limited, and future studies are needed to explore this multifactorial hypothesis and dig deeper into its underlying mechanism. With the technical advantages in diagnostic techniques and the extension of human life span, the incidence rate of VS has increased steadily from 3 to 34 cases per million every year over the past 40 years . SporadiHearing loss is the initial symptom of SVS and its incidence exceeds more than 90% at the presentation . In mostetc.), pathological alteration in the inner ear, aberrant inflammatory response, gene mutation, aberrant DNA methylation, etc. , two reviewers independently evaluated these references via the titles, abstracts, and full-texts to screen for eligible reports based on predetermined inclusion and exclusion criteria.A systematic search of the published literature was conducted in the Medline, PubMed, Web of Science, and Embase databases for articles regarding hearing loss in SVS between January 2000 and Dec 2020. And a comprehensive search term was developed using Boolean keywords: “acoustic neuroma(s)”, “vestibular schwannoma(s)”, “hearing loss”, “hearing impairment”, “hypoacusis” and “transitory deafness”. After removing the duplicates To rule out the confounding variables from surgery and radiotherapy, the included clinical study must contain either wait-and-scan or presurgical data. The other inclusion criteria involve: 1) the original reports on the hearing loss in SVS; 2) the studies published between Jan 2000 and Dec 2020; 3) English literature. The exclusion criteria involve 1) case reports or series with the number of patients less than ten; 2) other types of the literature including reviews, book chapters, conference abstracts, editorial notes, letters, etc.; 3) the studies reporting neurofibromatosis type 2, bilateral VS and neoplasms other than VS; 4) the studies investigating the hearing level after surgery and radiation; 5) the studies in which the treatment outcome is served as main findings; 6) unavailable full-texts and non-English literature. If any disagreement occurred about the eligibility of the literature, it would be resolved by consensus after thoroughly discussing with a third researcher.via their titles, abstracts, and full-texts, and the references list of eligible studies was reviewed subsequently for additional studies. Finally, 50 studies were selected according to the inclusion and exclusion criteria and were involved in the systematic analysis ; (2) the studies looked into the pathological changes of the inner ear  and their potential association with hearing loss; (3) the studies evaluated tumor-induced impairment of auditory pathway and cortex, which might lead to progressive hearing deterioration; (4) the studies investigated the underlying molecular and genetic mechanism of SVS-associated hearing loss.The incidence of SVS increases dramatically in recent years because of the advantages of modern imaging examination, especially magnetic resonance imaging (MRI). Hearing loss is present in more than 90% of patients, but its underlying mechanism remains unclear. In this study, we systematically searched the literature on this topic in the past 20 years, and 50 studies were eligibly included. Based on our primary findings, the retrieved studies could be categorized into four types: (1) the studies explored the relationship between hearing loss and the growth pattern of the tumor , etc., serves as the primary focus in the studies regarding hearing loss in SVS. In this review, we retrieved 29 studies on this topic. Among them, 14 papers reported the association between tumor size/volume and hearing loss , pathologic data demonstrating atrophy and destruction of the cochlear nerve, morphological and functional alterations in the auditory pathway, The hypothesized pathogenesis of hearing loss in SVS involves mechanical compression of cochlear nerves and brainstem. Intuitively, the larger tumor may lead to severer compression, which will affect their blood supply and lead to neurosensory hearing deficits by subsequent ischemic changes. However, in this systematic review, the majority of the retrieved studies  suggest the degree of hearing loss do not correlate with tumor size/volume –23. At tVia employing similar volumetric imaging parameters, Bathla et al. revealed that the anteroposterior, mediolateral dimensions, and the tumor volume correlated with both PTA and SDS in small SVS (mean tumor volume ~5.5 ml)  , 26.To answer whether tumor size/volume affects hearing function in SVS, the reasonable solution is performing a meta-analysis. However, various un-unified parameters regarding the hearing function and tumor size in those researches make meta-analysis difficult. Thus, we summarized the key information of the literature in Tumor growth is another important physical feature of SVS. In a meta-analysis involving more than 4,000 patients, the average growth rate of newly diagnosed SVS is estimated to be 0.99–1.11 mm/year or 0.1–0.15 ml/year . The ratFirst of all, hearing loss could aggregate in the non-growth SVS. Graamans and his colleagues performed a retrospective investigation and analyzed the course of PTA and SDS along with the conservative treatment of non-growing tumors. They found that PTA revealed a significant increase in thresholds at almost all frequencies with a prominent decrease in speech discrimination in static SVS . SimilarTo further explore whether the hearing loss would aggregate in the growing tumors, the researchers performed the analysis in small or IAC tumors. In their rationale, tumor growth within the internal auditory canal would increase pressure on the auditory nerve and lead to hearing dysfunction. Unlike CPA tumors, the space in the IAC is extremely limited, and a tiny increase of tumor volume may result in a dramatic change of pressure. Under this logic, small SVS, especially within IAC, serve as a better subset to explore hearing loss and tumor growth. However, the current results remain controversial.via univariate and multivariate analysis. They concluded that hearing impairment was related significantly to rapid tumor growth (≥0.10 cm3/year)  and no-growth (≤1 mm/year) groups to analyze the difference in the change of mean PTA and SDS, and they found that there was a significant risk of hearing impairment in the growth tumors , 30. Addm3/year) . Conversm3/year) .In the rest studies, researchers applied linear or volumetric changes of the tumor size to assess the tumor growth. In 2007, Caye-Thomasen et al. analyzed the spontaneous course of hearing in 156 patients with IAC SVS. The correlation analysis showed that the PTA deterioration rate correlated positively with the absolute growth rate . With lovs. IAC) needs more solid evidence to support.Tumor location is also a key physical property of SVS and its association with hearing loss has been discussed widely. Generally, SVS can be classified as IAC tumors when they are only intracanalicular and as CPA ones when the tumors extend extracanalicularly and locate mainly in CPA. In this review, we found four studies comparing the difference in hearing loss between IAC and CPA SVS. In a retrospective study involving 72 patients, the researchers spotted that hearing deteriorated more significantly in CPA tumors . BesidesGenerally, SVS usually arises from the glial-Schwann cell junction within IAC, and current literature fails to establish the association between the origin of tumor and hearing. For the IAC SVS, researchers proposed that the tumors could be categorized into three subgroups, including fundus tumors , central tumors (CSF observed in both ends of IAC) and pours tumors (CSF only between tumor and cochlea) . HoweverAlthough the association between hearing and SVS subsite within IAC was weak, some research groups measured the pressure in the IAC and tried to correlate it with hearing outcomes. Badie et al. performed a pilot study and measured the preoperative intracanalicular pressure (ICaP) in 15 patients undergoing resection of SVS. Their findings suggested that ICaP directly correlated with the amount of tumor within IAC and a trendy inverse correlation between ICaP and hearing function . To furtThe measurement of ICaP is invasive and can be performed only during the surgery, which limits its application. Thus, some researchers turned to evaluate the extent of the tumor filling within IAC. This parameter directly correlates with ICaP and can be evaluated in MRI scans without invasive operation, which seems to be a promising alternative to ICaP. As noted in a recent report, Zhou et al. proposed a new MRI grading biomarker based on the percentage of tumor filling the inner auditory canal (TFIAC) to predict the hearing loss in SVS and defined the four grades accordingly with low TFIAC (<25%) in Grade I and high TFIAC in Grade IV (>75%). They found that the patients in TFIAC grade III experienced more significant hearing deterioration than Grade I patients, and TFIAC grade IV patients also had a higher rate of non-serviceable hearing . BesidesCochlear dysfunction is another leading cause of hearing loss in SVS. The cochlea is a subtle auditory organ located in the core of temporal bone. In this review, we found ten studies investigating this topic, including four reports on the structural abnormality of the cochlea , 37–39, First of all, SVS may lead to structural abnormality of the cochlea and affect hearing function. Histologically, degeneration and loss of spiral ganglion cells are the prominent pathologic finding in the cochlea ipsilateral to the tumor , 58, 59.Other than the structural abnormality of the cochlea, several studies observed elevated levels of protein in the perilymph of SVS, which exhibited a high fluid-attenuated inversion recovery (FLAIR) signal or a decreased signal on T2-weighted MRI scans –62. In oIn the functional assessment of cochlea, there is evidence that supports the cochlear origin of hearing loss in SVS. In a study applying the distortion products of otoacoustic emissions (DPOAEs), DPOAEs amplitudes in the tumor ear were decreased compared with the contralateral ear at multiple frequencies in SVS patients with early hearing loss . The DPOBesides the direct mechanical insults caused by tumors and secondary cochlear dysfunction, the rest sections of auditory pathway in brain can also be affected by SVS. Based on diffusion-weighted MR imaging, Rueckriegel et al. first visualized the different sections of the auditory pathway between the inferior colliculus and the auditory cortex in SVS patients by applying probabilistic tractography. Moreover, they observed a significant volume decrease in the lateral and diencephalic sections of the auditory pathway on the contralateral hemisphere . In the etc.   . Additio p=0.04) . In anotPrevious studies suggested the maladaptive activation of inflammation contributed to the SVS pathogenesis. Specifically, in the histological examination, prominent immune infiltration could be observed in the majority of SVS, which involved microglia/macrophage, lymphocytes, neutrophils, etc.  Further,via normalizing the tumor vasculature, improving vessel perfusion, and delivery of oxygenation , and fibroblast growth factor 2 (FGF2) were reported to be associated with hearing levels among SVS , 50, 70.genation , 72. In genation . HoweverAdditionally, extracellular vesicles and matrix metalloprotease 14 (MMP-14) in tumor-associated secretions were found to induce hearing loss in SVS. Soares et al. observed that Human VS cells could secret extracellular vesicles and transfer tumor-derived RNAs to cochlear cells. These extracellular vesicles from VS associated with poor hearing induced the apoptosis of spiral ganglion cells and destroyed the cultured cochlear explants . Recentletc.) are proposed to favor hearing preservation  can lead to dysregulation of multiple genes , which promote cell proliferation, impair DNA repair, cause peroxisomal dysfunction, etc. Besides, the tumor cells in SVS can secret extracellular vesicles, proinflammatory cytokines, and growth factors, which exert harmful effects via paracrine pathways in both cochlea and brain.Overall, multiple factors seem to be associated with hearing impairment in SVS. The growth pattern of tumor, cochlear dysfunction, impairment of auditory pathway and cortex, genetic and molecular alteration contribute to hearing deterioration. First of all, the growth pattern of the tumor may play a role in the pathogenesis of hearing loss. Larger tumor size, faster tumor growth, and more tumor extension within IAC possibly aggregate the mechanical compression of the cochlear nerve and brain stem, which impairs the transmission and processing of auditory signals. Secondly, SVS may also result in cochlear damage, characterized by structural abnormality and high protein levels in the perilymph, which subsequently have a negative influence on the pickup of auditory stimulus and generation of nervous impulses. Thirdly, the growth pattern of SVS, cochlear dysfunction, and long-term hearing dysfunction may impair and reframe the auditory pathway and cortex, which aggregate hearing loss. Fourthly, genetic alteration in SVS  and subsequently promote the secretion of ototoxic factor and tumorigenesis with distinct tumor growth pattern, which might impair the auditory related structures  via either directly mechanical compression or cytotoxicity via a paracrine pathway (Based on our findings, we proposed multi-level hypotheses that genetical and molecular changes in SVS might influence the various cellular activity (e.g., cell proliferation, peroxisomal dysfunction, DNA repair, angiogenesis, The original contributions presented in the study are included in the article/LW and HZ supervised and conceived the study, analyzed and interpreted data, and wrote and revised the manuscript. JG and YZ performed the study, searched the literature, collected and analyzed data, and wrote the first draft of the manuscript. JW searched the literature, collected and analyzed data. DL and FZ conceived the study and contributed to data interpretation and substantial revision of the manuscript. All authors contributed to the article and approved the submitted version.https://www.frontiersin.org/articles/10.3389/fonc.2021.687201/full#supplementary-materialThe Supplementary Material for this article can be found online at: Click here for additional data file.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Participants reported exposure to workplace noise, and the severity and duration of this exposure. Prior occupational noise exposure was associated with a 2-fold increased odds of moderate-to-severe hearing loss: multivariable-adjusted OR 2.35 (95% CI 1.45–3.79). Exposure to workplace noise for >10 years increased the odds of having any hearing loss  and moderate-to-severe hearing loss . Among participants reporting past workplace noise exposure at baseline the 10-year incidence of hearing loss was 35.5% versus 29.1% in those who had no workplace noise exposure. Workplace noise exposure was associated with a greater risk of incident hearing loss during the 10-year follow-up: multivariable-adjusted OR 1.39 (95% CI 1.13–1.71). Prior occupational noise exposure was not associated with hearing loss progression. Workplace noise exposure increased the risk of incident hearing loss in older adults. Our findings underscore the importance of preventive measures which diminish noise exposure in the workplace, which could potentially contribute towards reducing the burden of hearing loss in later life.There is paucity of population-based data on occupational noise exposure and risk of age-related hearing loss. Therefore, we assessed cross-sectional and longitudinal associations of past workplace noise exposure with hearing loss in older adults. At baseline, 1923 participants aged 50+ years with audiological and occupational noise exposure data included for analysis. The pure-tone average of frequencies 0.5, 1.0, 2.0 and 4.0 kHz (PTA Age-related hearing loss is the most frequent communication disorder and is associated with a greater risk of depression, impairs quality of life and the ability to conduct activities of daily living –5. It isAnimal models of auditory ageing have shown that repeated short-duration loud sound overstimulation accelerates the time-course of age-related hearing loss . There iAge-related and noise-induced hearing loss have important public health implications , 7, 10, The Blue Mountains Hearing Study (BMHS) was a population-based survey of age-related hearing loss conducted during 1997–2007 among participants of the Blue Mountains Eye Study (BMES) cohort . During 0.5-4KHz), defining any level of hearing loss as PTA0.5-4KHz >25 dB hearing level (HL), in the better of the two ears. This defined hearing loss as bilateral. Low frequency hearing loss was defined as a PTA0.5, 1, 2 KHz >25 dB HL in the better of the two ears. High frequency hearing loss was defined as a PTA4, 6, 8 KHz >40 dB HL in the better of the two ears. These classifications are the same as in The Epidemiology of Hearing Loss Study Reviewers' comments:Reviewer's Responses to QuestionsComments to the Author1. Is the manuscript technically sound, and do the data support the conclusions?The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented. Reviewer #1: YesReviewer #2: Partly**********2. Has the statistical analysis been performed appropriately and rigorously? Reviewer #1: YesReviewer #2: No**********3. Have the authors made all data underlying the findings in their manuscript fully available?PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.The Reviewer #1: YesReviewer #2: Yes**********4. Is the manuscript presented in an intelligible fashion and written in standard English?PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.Reviewer #1: YesReviewer #2: Yes**********5. Review Comments to the AuthorPlease use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. Reviewer #1: Thank you for your manuscript. Please find my comments and suggestions for your consideration below.ABSTRACT:Line 39: Participants reporting any past noise exposure at baseline (please add: were at a) greater risk of developing hearing loss 10 years later: multivariable-adjusted OR 1.67 (95% CI 1.19-2.33).INTRODUCTION:The term 'ageing' and 'aging' has been used interchangeably throughout this manuscript. Please use one spelling for consistency. My suggestion would be 'ageing'.The acronym 'ARHL' is introduced on line 61. Please add in brackets when first mentioned on line 50, first sentence.Line 75: please change 'expose' to 'exposure'.RESULTS(n=2015). 68 plus a further 15  were excluded (line 151-153). Line 154 says that this resulted in a total of 1923 subjects but 2015 minus 83 = 1932. Can you clarify and account for the missing 10 please?Line 155: '...679 participants who reported previous exposure to occupational noise and 1244 with no prior exposure'. This suggests that in total 679 participants reported occupational noise exposure. However, the 'N' for noise exposure in Tables 1 and 2 don't add up to 679. Please clarify.Can you describe how you categorised the severity of noise exposure (tolerable and severe) in your methods after line 130. Was 'mostly quiet' treated as no exposure; 'tolerable but able to hear speech' as tolerable; and 'unable to hear anyone speaking' as severe?DISCUSSION:Line 253 to 255, '...and that this appears to be related in part to the difficulties imposed by such protection upon communication with other workers, especially in an emergency (REF?)' Please add reference.Line 255: 'Indeed, in our study cohort we 'observed' only 10% of those exposed to occupational noise used any form of hearing protection devices'. I am not sure if you observed HPD use. Perhaps reword to: ' Indeed, in our study cohort 10% of those reporting exposure to occupational noise reported using any form of hearing protection devices'.Line 269 to 272: Is almost a direct quotation from the Dobie paper. That was a 2008 paper. Do Audiologists currently not provide counselling and periodic audiometry for those exposed to occupational and non-occupational noise exposure?Line 275 to 277: '...audiometric testing to measure hearing sensitivity rather than self-report...' Correct, but you relied on self-reported accounts of exposure to noise . Could this not be a limitation of your study? You touch on it by comparing recall bias of people with and without hearing impairment.My suggestion is to discuss (a paragraph) why hearing conservation programmes and efforts to prevent exposure to occupational noise has been successful or not successful. For example, line 263: 'Although, case studies show that significant reductions can be achieved, there is no evidence that this is realised in practice [27]'. Why?REFERENCES:There are a few dated references especially related to occupational noise and hearing protection use.. For example, reference 27. There is a recent Cochrane review that should be cited instead.Reviewer #2: The paper is well written and the authors are clearly experts in this area. This article warrants publication but could benefit from some changes, namely in the statistical approach. My comments are meant to improve this piece.IntroductionLine 50 – It seems something is missing, age-related hearing loss is more frequent compared to what?The introduction’s content around the disconnect between findings of noise-induced hearing loss in animal models versus large observational trials is appreciated but it would benefit from further discussion as to why the authors believe this disconnect is present and why their data will improve the literature .MethodsLines 79-80 – it seems the dates of the study are incongruent – the first line says 1997-2004 but the next line indicates data collected in 1992-1994. Please clarify.Was noise exposure measured only once?The section on noise exposure would benefit from a concrete definition of how noise will be models  in the statistical models in addition to describing the questions asked.For the authors’ consideration on the statistics: 1. Given the prevalence of hearing loss , it is likely that odds ratios overestimate the size effect, prevalence risk ratios would be more conservative and offer a more easily interpretable coefficient for the reader 2. Cox proportional hazard models could better examine the time-to-event incident hearing loss 3. Given the data available, linear fixed effects models could better characterize the longitudinal associationsResults/DiscussionThese sections are great. The attempts to place the current findings within the context of other studies is important and the discussion of prevention is well done.**********what does this mean?). If published, this will include your full peer review and any attached files.6. PLOS authors have the option to publish the peer review history of their article  digital diagnostic tool,  11 Jun 2021Reviewer #1:ABSTRACT:Line 39: Participants reporting any past noise exposure at baseline (please add: were at a) greater risk of developing hearing loss 10 years later: multivariable-adjusted OR 1.67 (95% CI 1.19-2.33).Author response: As suggested by the Reviewer we have now reworded this sentence. INTRODUCTION:The term 'ageing' and 'aging' has been used interchangeably throughout this manuscript. Please use one spelling for consistency. My suggestion would be 'ageing'.Author response: As requested, we have now used the term ‘ageing’ throughout our manuscript.The acronym 'ARHL' is introduced on line 61. Please add in brackets when first mentioned on line 50, first sentence.Author response: Apologies, we have now removed this acronym and replaced it with ‘age-related hearing loss.’Line 75: please change 'expose' to 'exposure'.Author response: We have now changed it to ‘exposure’.RESULTS(n=2015). 68 plus a further 15  were excluded (line 151-153). Line 154 says that this resulted in a total of 1923 subjects but 2015 minus 83 = 1932. Can you clarify and account for the missing 10 please?Author response: Apologies, this was a typographical error it should have been ‘1932’ not ‘1923’ we have now corrected this in the Results section.Line 155: '...679 participants who reported previous exposure to occupational noise and 1244 with no prior exposure'. This suggests that in total 679 participants reported occupational noise exposure. However, the 'N' for noise exposure in Tables 1 and 2 don't add up to 679. Please clarify.Author response: The N (%) presented in tables 1 and 2 denote those who had any, mild or moderate-severe hearing loss according to the different noise exposure variables (duration and/or severity). However, not all 679 participants exposed to noise had a hearing loss, hence, the N presented in these tables do not add up to 679 .Can you describe how you categorised the severity of noise exposure (tolerable and severe) in your methods after line 130. Was 'mostly quiet' treated as no exposure; 'tolerable but able to hear speech' as tolerable; and 'unable to hear anyone speaking' as severe? Author response: We now clarify in the Methods (lines 132-133) that: ‘Participants were classified as being exposed to ‘severe’ noise levels, if their response was that they were ‘unable to hear anyone speak’, all other responses were classified as a ‘tolerable’ level of noise.’DISCUSSION:Line 253 to 255, '...and that this appears to be related in part to the difficulties imposed by such protection upon communication with other workers, especially in an emergency (REF?)' Please add reference.Author response: We have now added a reference for this statement. Line 255: 'Indeed, in our study cohort we 'observed' only 10% of those exposed to occupational noise used any form of hearing protection devices'. I am not sure if you observed HPD use. Perhaps reword to: ' Indeed, in our study cohort 10% of those reporting exposure to occupational noise reported using any form of hearing protection devices'.Author response: Agreed. We have now reworded this sentence as suggested by the Reviewer.Line 269 to 272: Is almost a direct quotation from the Dobie paper. That was a 2008 paper. Do Audiologists currently not provide counselling and periodic audiometry for those exposed to occupational and non-occupational noise exposure?Author response: We have clarified this statement and have cited a 2018 reference to support this: ‘Moreover, audiologists and otolaryngologists see patients who have significant unprotected occupational and non-occupational noise exposure, and as such they play an important role in providing counselling, hearing protection and periodic audiometry for these patients [30].’Line 275 to 277: '...audiometric testing to measure hearing sensitivity rather than self-report...' Correct, but you relied on self-reported accounts of exposure to noise . Could this not be a limitation of your study? You touch on it by comparing recall bias of people with and without hearing impairment.Author response: Agreed. We have now added the following study limitation (line 283): ‘Limitations of the study include potential systematic recall bias: participants self-reported duration and severity of noise exposure and participants…’ My suggestion is to discuss (a paragraph) why hearing conservation programmes and efforts to prevent exposure to occupational noise has been successful or not successful. For example, line 263: 'Although, case studies show that significant reductions can be achieved, there is no evidence that this is realised in practice [27]'. Why?Author response: This is a good suggestion by the Reviewer and we have reworded this section in the Discussion (lines 266-276): ‘Currently, there is very low‐quality evidence that the use of hearing protection devices in well‐implemented hearing loss prevention programmes is linked to reduced hearing loss but this could not be demonstrated for other aspects, such as monitoring of noise levels, worker training or audiometry alone [28]. Additionally, engineering solutions such as new equipment, segregation of noisy equipment, installation of panels or curtains were shown to significantly reduce noise levels in control intervention case studies [28]. However, longitudinal research on the effects of engineering interventions to reduce noise is needed. For instance, field case studies with valid measures of personal noise doses of workers with prospective follow‐up would provide better evidence than what is currently available [28]. At a minimum, for an effective and successful hearing conservation program - noise surveys and monitoring, employee education, training, and motivation, hearing protection equipment, audiometric testing, and record-keeping, as well as noise control are important [29].’REFERENCES:There are a few dated references especially related to occupational noise and hearing protection use.. For example, reference 27. There is a recent Cochrane review that should be cited instead.Author response: We have now cited the 2017 Cochrane Review reference rather than the 2009 review, additionally we have added some more recent references. Reviewer #2:IntroductionLine 50 – It seems something is missing, age-related hearing loss is more frequent compared to what?Author response: Agreed. We have now reworded this sentence as the following: ‘Age-related hearing loss is the most frequent communication disorder…’The introduction’s content around the disconnect between findings of noise-induced hearing loss in animal models versus large observational trials is appreciated but it would benefit from further discussion as to why the authors believe this disconnect is present and why their data will improve the literature .Author response: Yes, the reviewer is correct about the lack of long term data on the association between noise exposure and hearing loss. However, in lines 74-76 we have already discussed the reason for the disconnect and how our study improves the literature: ‘Despite the burden of noise and age-related hearing loss, there are very few large population-based studies that have evaluated both the cross-sectional and longitudinal contribution of noise exposure to age-related hearing loss. Therefore, we propose to explore the prevalence, 10-year incidence and progression of hearing loss associated with occupational noise exposure among older adults aged 50+ years at baseline.’ Moreover, we have expanded a sentence in the Introduction (lines 62-65) to also further clarify this disconnect: ‘There is a paucity of longitudinal population-based studies that have investigated noise exposure and hearing decline and observational studies have thus far provided equivocal findings on the relationship between noise exposure and subsequent hearing loss in adults.’MethodsLines 79-80 – it seems the dates of the study are incongruent – the first line says 1997-2004 but the next line indicates data collected in 1992-1994. Please clarify.Author response: This is correct because in line 87-88 we indicate that while the Blue Mountains Eye Study started in 1992 (or BMES-1), hearing was only measured from BMES-2 onwards (i.e. from 1997-99). We have tried to clarify this better in the Methods now.Was noise exposure measured only once?Author response: No, noise exposure was measured throughout the 10-year period of the hearing study but for the purposes of the current report we analysed baseline noise exposure with the prevalence and incidence of hearing loss.The section on noise exposure would benefit from a concrete definition of how noise will be models  in the statistical models in addition to describing the questions asked.Author response: We have now clarified the specific variable definition (lines 129-132): ‘Based on whether a respondent answered ‘yes’ or ‘no’ to this question, they were classified as having any exposure to occupational noise or no exposure to occupational noise, respectively, and this was the specific variable included in statistical models.’For the authors’ consideration on the statistics: 1. Given the prevalence of hearing loss , it is likely that odds ratios overestimate the size effect, prevalence risk ratios would be more conservative and offer a more easily interpretable coefficient for the reader 2. Cox proportional hazard models could better examine the time-to-event incident hearing loss 3. Given the data available, linear fixed effects models could better characterize the longitudinal associationsAuthor response: We have taken these suggestions by the Reviewer into consideration, and we now present risk ratios obtained by using linear fixed effects for longitudinal data (i.e. using Poisson Regression approach to prospective studies with Log as link function) in Table 3 and all text in the manuscript has been updated accordingly.AttachmentPlosOne_Noise exposure & HL_rebuttal.docxSubmitted filename: Click here for additional data file. 15 Jul 2021Workplace Noise Exposure and the Prevalence and 10-Year Incidence of Age-Related Hearing LossPONE-D-21-00280R1Dear Dr. Gopinath,We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication.http://www.editorialmanager.com/pone/, click the 'Update My Information' link at the top of the page, and double check that your user information is up-to-date. If you have any billing related questions, please contact our Author Billing department directly at authorbilling@plos.org.An invoice for payment will follow shortly after the formal acceptance. To ensure an efficient process, please log into Editorial Manager at onepress@plos.org.If your institution or institutions have a press office, please notify them about your upcoming paper to help maximize its impact. If they’ll be preparing press materials, please inform our press team as soon as possible -- no later than 48 hours after receiving the formal acceptance. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information, please contact Kind regards,Peter Rowland Thorne, CNZM PhDAcademic EditorPLOS ONEAdditional Editor Comments :The reviewers comments have been amended appropriately.There are a few minor typographical errors as listed which should be addressed during processing of the manuscript:Line 52 Ageing-related degenerati(on) may..Line 232 ..the cochlea(r).Line 266 program - .Check consistency of spelling throughout (program vs programmeReviewers' comments: 22 Jul 2021PONE-D-21-00280R1 Workplace Noise Exposure and the Prevalence and 10-Year Incidence of Age-Related Hearing Loss Dear Dr. Gopinath:I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now with our production department. onepress@plos.org.If your institution or institutions have a press office, please let them know about your upcoming paper now to help maximize its impact. 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The prevalence of deafness was higher in children with ROP than those without ROP . There were significant differences in hearing impairment among the stages of ROP (p < 0.001). However, multivariate analyses and propensity score matching showed no significant association between ROP and hearing impairment at 18 months and 3 years after adjusting for prematurity-related variables . Conclusions: Among infants born with VLBW, hearing impairment was more common in those with ROP than in those without ROP at 18 months of age. However, there was no significant independent association between hearing impairment and ROP.Background: To investigate hearing impairment and its association with retinopathy of prematurity (ROP) among children born with very low birth weight . Methods: This prospective registry study included 7940 VLBW infants who underwent both ophthalmic (ROP) and hearing screening at the 70 participating centers of the Korean Neonatal Network. Hearing screening was performed using auditory brainstem response and/or automated otoacoustic emission testing. Hearing impairment, defined as a unilateral or bilateral hearing threshold of ≥40 dB on the auditory brainstem response threshold (ABR-T) test, was evaluated and compared between children with and without ROP at the corrected ages of 18 months and 3 years. Results: The frequency of infants who did not undergo hearing screening at near-term ages was higher in the ROP group than in the no-ROP group (18.2% vs. 12.0%,  Retinopathy of prematurity (ROP) is a retinal vasoproliferative disease mediated by vascular endothelial growth factor (VEGF), which may threaten vision in preterm infants ,2. DespiIn addition to the visual disabilities directly caused by ROP-related complications, hearing impairment may also affect the infants with ROP as preterm infants are at risk of major neurosensory impairments, including visual and hearing ones . Both imIn the present study, we aimed to investigate hearing impairment in infants with and without ROP in a large prospective cohort of infants born with very low birth weight . In this cohort consisting of Korean VLBW infants with ophthalmic and hearing assessment, we intended to explore the relationship between ROP and hearing impairment, as well as between the two types of sensory impairment.n = 1462). Among the 8621 infants with VLBW, those with hearing outcomes evaluated using well-established neonatal screening methods (n = 7940) were included in our analyses. Among them, the hearing outcomes assessed in 2863 infants at 18 months or 3 years of age were analyzed using univariate or multivariate analyses. The Korean Neonatal Network (KNN) is a prospective national registry of infants with VLBW, which was established in 2013 by 70 participating hospitals with governmental support from the Korea Centers for Disease Control and Prevention. The registry included clinical data on ROP details and systemic conditions, prenatal/perinatal factors, maternal factors, systemic or ROP management, and hearing assessments. Among the 10,424 infants enrolled between January 2013 and December 2017 in the registry, 1803 were excluded because they had not undergone ophthalmic examination, mainly due to death associated with preterm birth-related complications  less than 30 weeks . All incFor hearing screening, we used automated auditory brainstem response and/or automated otoacoustic emission testing at near-term ages . If newbWe divided the infants into groups based on the presence of ROP (without ROP and with ROP). The treated infants were further separated according to treatment modalities, including laser photocoagulation alone, anti-VEGF therapy alone, and both. Visual impairment was defined as unilateral or bilateral blindness based on examination by an ophthalmologist.Data on maternal characteristics, neonatal characteristics, and ROP details were collected from the registry. Patients with comorbidities, including necrotizing enterocolitis , cerebral palsy , and bronchopulmonary dysplasia  ,13, werep < 0.05.We compared the maternal and neonatal clinical characteristics and comorbidities of prematurity between infants with and without ROP, as well as between the treatment groups. We also compared the hearing outcomes between groups separated based on the presence of ROP and the treatment modalities, including laser photocoagulation, anti-VEGF therapy, and both laser and anti-VEGF therapy. Propensity score matching was performed including perinatal demographics such as GA and birthweight and clinical characteristics such as intraventricular hemorrhage (IVH), clinical sepsis, and BPD, and infants were divided into prematurity-matched groups with and without ROP. A chi-squared test or Fisher’s exact test for categorical variables and a Student’s t-test or analysis of variance (ANOVA) for continuous variables were used to compare groups. Multivariate regression was used to analyze the associations between hearing outcomes and ROP, as well as those between the outcomes and treatment modalities, by adjusting for other confounding variables including GA, sex, BPD, IVH, clinical sepsis, and periventricular leukomalacia (PVL). Values for continuous variables are presented as the mean ± standard deviation. Statistical analyses were performed using SPSS software . Statistical significance was set at Of the 7940 infants who underwent hearing and ophthalmic screening, 2480 (31.2%) had ROP. Among the 2863 infants with both ophthalmic and hearing examinations at follow-up visits, 982 infants (34.3%) had ROP, consisting of 305 (31.1% of ROP infants), 336 (34.2%), 336 (34.2%), 5 (0.5%), and 0 with maximal stages 1, 2, 3, 4, and 5, respectively. The outcomes in terms of ROP and functional  impairment among the infants receiving both hearing and ophthalmic assessments are summarized in p < 0.001). Several maternal characteristics and neonatal comorbidities, including pregnancy-induced hypertension, chorioamnionitis, respiratory distress syndrome, sepsis, necrotizing enterocolitis, BPD, IVH, and patent ductus arteriosus ligation, were significantly different between infants with and without ROP. However, the differences in GA, birth weights, and other comorbidities between the groups were remarkably reduced between the two groups with propensity score matching  received ROP treatment, including laser photocoagulation alone , anti-VEGF therapy alone , or both treatments .Among the 7940 infants who underwent both ROP and hearing screening, 452 of 2480 infants with ROP failed to pass the hearing screening, whereas 657 of 5460 infants without ROP did. Accordingly, the prevalence of those who did not pass the hearing screening was 18.2% and 12.0% among the infants with and without ROP, respectively, which was significantly different.Among the 2863 children with a hearing assessment at follow-up visits, 2751 and 666 received the assessment at the first and second follow-up visits, respectively. Hearing impairment was noted in 73 and 12 infants at the first and second visits, respectively, resulting in a 2.7% and 1.8% prevalence of hearing impairment, respectively. Bilateral hearing impairment was noted in 35 (1.3%) and 5 (0.8%) infants, and deafness was noted in 5 (0.2%) and 2 (0.3%) infants at the first and second visits, respectively.p = 0.015) and GA (p = 0.038), respectively, with the odds ratios of 1.30 , 1.05–1.60) and 0.72 , respectively. Accordingly, after adjusting for other demographic- or prematurity-associated factors, hearing impairment was not significantly associated with ROP at 18 months or 3 years of age.In multivariate analyses, however, ROP showed no significant association with hearing impairment at the first or second follow-up visit. The clinical factors associated with that at the first and second visit were IVH .Using the data of a large number of VLBW infants registered in a nationwide cohort, our study revealed the frequency of both ROP and hearing impairment and explored the association between them. To the best of our knowledge, this is the first longitudinal cohort study to evaluate the relationship between ROP and hearing impairment.With hearing outcomes obtained longitudinally at near-term, and 18 months and 3 years after birth, the present study suggests that the infants born with VLBW and also ROP may be at risk of hearing impairment at early developmental periods. However, hearing development may be affected by multiple clinical and prematurity-related factors, and adjustment for the factors, either multivariate regression analyses or propensity score matching, resulted in a non-significant association between hearing impairment and ROP or visual impairment.Preterm birth is known to increase the risk of neurodevelopmental delay and neurosensory impairment . FurtherA national register study of preterm infants performed in Finland showed that the overall prevalence of hearing loss among infants with GA < 32 weeks was 2.46%, similar to 2.65% in our study, and hearing impairment decreased with advancing gestational age [Stadio et al. showed that in newborns who were hospitalized in neonatal intensive care units, the incidence of hearing loss was increased in those with retinopathy compared to that in those without . In thisHowever, hearing is clinically important for children with ROP as visually deprived infants with ROP should rely on auditory perception for their development. Hearing loss and ROP may share a common pathogenic background or be affected by various factors such as prematurity, mechanical ventilation, sepsis, and neurological disorders ,21,22. TRisk factors for ROP suggested by previous studies include maternal factors , prenatal and perinatal factors (chorioamnionitis and premature rupture of membrane), infant factors (low gestational age , small bSeveral limitations of this study warrant careful consideration when interpreting the results. First, although this study was performed in a prospective manner, selection bias is likely to be present as hearing assessments were performed at follow-up visits in only 2863 of 10,424 infants. In particular, only 666 patients with available data on ROP examination received hearing assessments at the second visit, which might have resulted in significant selection bias. This was due to a follow-up loss of a significant portion of the infants at subsequent visits , which mAmong VLBW infants, the frequency of hearing impairment at 18 months of age was higher in those with ROP than in those without ROP; however, ROP was not independently associated with hearing impairment after adjusting for prematurity and other clinical factors. Furthermore, visual impairment was not significantly associated with hearing impairment in children born with VLBW. This might suggest different pathogenic mechanisms between ROP and hearing impairments.


Ceratonova shasta is a myxozoan pathogen that causes enteronecrosis in economically important salmonids from the Pacific Northwest of North America. This cnidarian parasite has host-specific genotypes with varying virulence, making it a powerful system to decipher virulence mechanisms in myxozoans. Using C. shasta genome and transcriptome, we identified four proteases of different catalytic types: cathepsin D (aspartic), cathepsin L and Z-like (cysteine) and aminopeptidase-N ; and a stefin (cysteine protease inhibitor), which implied involvement in virulence and hence represent target molecules for the development of therapeutic strategies. We characterized, annotated and modelled their 3D protein structure using bioinformatics and computational tools. We quantified their expression in C. shasta genotype 0  and IIR  in rainbow trout Oncorhynchus mykiss, to demonstrate that there are major differences between the genotypes during infection and parasite development. High proliferation of genotype IIR was associated with high expression of the cathepsin D and the stefin, likely correlated with high nutrient demands and to regulate cell metabolism, with upregulation preceding massive proliferation and systemic dispersion. In contrast, upregulation of the cathepsin L and Z-like cysteine proteases may have roles in host immune evasion in genotype 0 infections, which are associated with low proliferation, low inflammation and non-destructive development. In contrast to the other proteases, C. shasta aminopeptidase-N appears to have a prominent role in nematocyst formation in both genotypes, but only during sporogenesis. Homology searches of C. shasta proteases against other myxozoan transcriptomes revealed a high abundance of cathepsin L and aminopeptidase homologs suggesting common gene requirements across species. Our study identified molecules of potential therapeutic significance for aquaculture and serves as a baseline for future research aimed at functional characterisation of these targets.Proteases and their inhibitors play critical roles in host-parasite interactions and in the outcomes of infections.  Entamoeba spp., Trypanosoma spp. and other protozoans, Fasciola hepatica, Leishmania mexicana, Host-parasite interactions involve an arsenal of different molecules, including proteases and their inhibitors, which are ubiquitous in parasites. These molecules have central roles in parasite life cycles, including invasion, migration, feeding and immunomodulation of host responses , and repCeratonova shasta to high disease risk in Chinook salmon at the Klamath River (USA)  . No effeer (USA) , suggester (USA)  have alli genome , 2.6% (2criptome  or 6.1% proteome . It furtproteome  or strucproteome  in some Ceratonova shasta (syn. Ceratomyxa shasta) is a myxozoan parasite that can cause acute enteronecrosis in economically and ecologically valuable salmon species in the rivers of the Pacific Northwest of North America. C. shasta infection initiates when actinospores invade the fish through the gills, and the parasite migrates to the target organ, the intestine  that differ in virulence  to determine the organization of these genes at both DNA and RNA levels. To confirm the genes were of parasite origin, we designed gene-specific primers using NCBI/Primer-BLAST , including a DNase step, and quantified using NanoDrop at the CQLS. Detection of genomic DNA contamination and quality of RNA was determined as described in C. shasta reference genes GAPDH, NADH and HPRT-1 , a no-template control, and ROX as the passive reference. Cq mean was calculated for each sample and inter-plate correction applied when necessary (Cq +/- 0.5). Relative gene expression was calculated as fold change using 2-ΔΔCq method (-ΔCq) to the reference genes. Differences in fold and relative changes were analyzed for statistical significance with SigmaPlot 13.0  using Tukey´s method for multiple comparisons after one-way ANOVA or t-test for normally distributed data. For non-normally distributed data, a Kruskal-Wallis with Dunn’s multiple comparison was performed.qPCR and relative gene expression analyses were performed as described in q method , being ΔC. shasta proteins were predicted to obtain more information about structural differences to known models and their potential effect on function. Using ORFinder .The secondary and 3D structures of the selected a server . The stea server  implemenTetracapsuloides bryosalmonae, Sphaerospora molnari, Myxobolus cerebralis, Myxobolus squamalis, Henneguya salminicola and Kudoa iwatai to compare their protease repertoire with that of our model organism transcriptome, C. shasta (genotype IIR). Similar searches were done for myxozoan stefins in a previous publication  to confirm their homology and shared conserved domains . Expression of this gene was only fully quantified in replicate fish at 29 dpe for type 0 (only one type 0 fish at 22 dpe), and showed similar expression for IIR at both time points (22 & 29 dpe). Unlike stefin, cathepsin D and aminopeptidase-N, both cysteine proteases were highly expressed by genotype 0 throughout the infection, with the highest relative change observed in this study. Cathepsin L in type 0 had a significant increase at 15 dpe and onwards in the infection. Cathepsin-Z showed a similar trend in type 0, with high expression that increased over time. Cysteine proteases showed low expression levels for genotype IIR throughout the infection, with a small increase at 15 dpe  and cathepsin D (up to 39-fold change). Stefin and cathepsin D were upregulated at all time points in IIR infections. Stefin had an 18 to 20-fold upregulation in IIR, with a peak at 15 dpe (63-fold change). Cathepsin D had an early peak at 7 dpe with a 39-fold change. Aminopeptidase-N was only upregulated late in the infection, at 22 and 29 dpe, with 4- and 2-fold changes, respectively. Both cysteine proteases were downregulated in genotype IIR throughout the infection . Two gene isoforms were detected in the transcriptome showing 3 bp differences  in the typical aspartic conserved motifs , an active site flap (Y flap loop) and a posttranslational cleavage site.The genome region encoding ferences 4, and 1C. shasta cathepsin D (ab initio (C. shasta cathepsin D possessed 87% of residues in the most favored regions (see Ramachandran plot in C. shasta and tick cathepsin D (PDB: 5N7N) zymogens showed a strong overlap in their structures  and five S2 subsites , which compose the S2 pocket.The genomic sequence encoding cathepsin L was 1,086 bp and contained 4 introns (23-24bp). Only a single isoform was recovered from the transcriptome 4. CDS wC. shasta cathepsin L (C. shasta cathepsin L model had 86% residues positioned in the most favored regions (C. shasta cathepsin L zymogen and Fasciola hepatica procathepsin L1 (PDB: 2O6X) showed a strong structural overlap  were observed. We identified four isoforms in the transcriptome with a similarity of 97-99%  , with cysteine-type peptidase activity and involved in the lysosomal pathway. Primary organization of cathepsin Z , an active site mini loop  and five S2 subsites . C. shasta cathepsin Z did not contain the two highly conserved ERFNIN and GNFD motifs that are characteristic for the pro-regions of cathepsin L-like enzymes (The genome contig encoding inserts) 4. Inser enzymes .C. shasta cathepsin Z  showed a relatively complete structural overlap in the central part of both molecules while the terminal parts of C. shasta protein, especially the N-terminus, showed a substantial level of structural deviation from the superposed molecule, which was mainly caused by a different composition of amino acid residues  structurally overlapped in both molecules . Two isoforms were assembled with 99% similarity and a 21 bp insert in the 5’UTR region, which may suggest a splice junction in the 5’UTR region . Three of these sites were also annotated as zinc binding sites . Towards the C-terminus, an ERAP1-like C-terminal domain was predicted that is represented by 16 α-helices organized in 8 HEAT-like repeats forming a concave face towards the active site of the peptidase.The genomic sequence of R region 4. 2,567C. shasta aminopeptidase (ab initio (C. shasta aminopeptidase model showed 90% of the residues positioned in the most favored region (C. shasta cathepsin aminopeptidase and human aminopeptidase N (PDB: 4FYT) showed a relevant structural overlap in the central part of both molecules, while the terminal parts of C. shasta protein were much shorter compared to the superposed molecule due to the lack of 119 N-terminal and 15 C-terminal amino acid residues , with only one isoform assembled from the transcriptome  and the LP pair .The genomic sequence of criptome 4. 285/4C. shasta stefin  stefins showed that both proteins are very similar in their secondary and tertiary structures. The exceptions were the N- and C- terminals that, in C. shasta protein, were much shorter compared to the superposed molecule due to the lack of 36 N-terminal and 9 C-terminal amino acid residues  in stark contrast with the closest related species H. salminicola (2). M. cerebralis had the largest set of aminopeptidase homologs (12) followed by T. bryosalmonae (9). All myxozoan transcriptomes had at least one homologous sequence to each of C. shasta proteases (K. iwatai (missing cathepsin D and Z) and S. molnari (missing cathepsin Z). C. shasta cathepsin L sequence matched previously characterized proteases in T. bryosalmonae cathepsin L-like (contig_2419) and cathepsin L2 (contig_6351) (S. molnari cathepsin L1 (Smolnari_BS_DN24597_c0_g1_i1), cathepsin L2 (Smolnari_BS_DN24597_c0_g2_i1) and cathepsin L3 (Smolnari_BS_DN14729_c0_g1_i1) (Cathepsin L homologs were the most abundant proteases found in the myxozoan transcriptomes mined (71 sequences), followed by aminopeptidase homologs (39). roteases Table 2 ig_6351) , and in Ceratonova shasta proteases and one stefin and the in silico characterization and annotation of these molecules provides a first comprehensive overview of their protein characteristics and the differential uses of these enzymes between parasite genotypes with differing virulence ”  had structural similarities to pepsinogen, a major enzyme of gastric juice, which suggest that C. shasta cathepsin D is involved in host exploitation after protein digestion, similar to other parasites . However, it is unknown if myxozoans, as reduced cnidarians, possess this alternative pathway and if they could use it to evade the host immune system. In summary, we hypothesize that in genotype 0 infections, C. shasta cathepsin L aids in evading host immune responses and in preventing an acute inflammatory response, resulting in the chronic and long-lasting infections characterized by this low-virulence genotype, but the mechanisms used by the parasite to endure in the host are still unknown.Interestingly, functional annotation suggested that response . Althougresponse . These aM. squamalis and H. salminicola have large differences in their repertoire of cathepsin L homologs, which could be in line with the observed gene loss and simplification of H. salminicola genome  can be found in the article/The animal study was reviewed and approved by Oregon State University Institutional Animal Care and Use Committee under approval ACUP #4666.GA-B, AH, and JB conceived and designed the study. GA-B, SA, and PB-S collected, generated, and analyzed the data. AH and JB supervised and GA-B wrote the manuscript. All authors provided critical feedback and helped shape the research, analyses and manuscript.GA-B, AH, and wet lab work was funded by the Czech Science Foundation EXPRO grant #19-28399X . PB-S was funded by the Ministry of Education, Youth, and Sports of the Czech Republic grant # LTAUSA17201 and the Czech Science Foundation grant # 21-16565S. JB and SA were funded by the Bureau of Reclamation, U.S. Department of Interior through Interagency Agreement #R19PG00027, as part of its mission to manage, develop, and protect water and related resources in an environmentally and economically sound manner in the interest of the American public. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Mention of trade names does not imply U.S. Government endorsement.The views in this report are the authors’ and do not necessarily represent the views of Bureau of Reclamation.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


In nature, organic molecules with great structural diversity and complexity are synthesized by utilizing a relatively small number of starting materials. A synthetic strategy adopted by nature is pathway branching, in which a common biosynthetic intermediate is transformed into different end products. A natural product can also be synthesized by the fusion of two or more precursors generated from separate metabolic pathways. This review article summarizes several representative branching and converging pathways in fungal natural product biosynthesis to illuminate how fungi are capable of synthesizing a diverse array of natural products. Thus, the PKS CalA contributes both to pathway branching and convergence in the biogenesis of calbistrins.Calbistrins are structurally similar to lovastatin in that they have a polyketide chain attached to a decalin core; however, the biosynthesis of calbistrins and lovastatin somewhat differs. CalD, the enzyme responsible for the acylation reaction in the calbistrin pathway, performs a similar reaction to LovD to introduce the hexaketide moiety to decumbenone A  is an antifungal agent in the echinocandin class, obtained from the fungus Glarea lozoyensis . . 155), γPenicillium fungi . I. IPenici165) is obtained by genome mining in the fungus Aspergillus flavus and features a sesquiterpenoid core modified with dimethylcadaverine (166) and 5,5-dimethyl-l-pipecolic acid (167) . I. I175) a pathway .Fig. 20PFusarium species and possess characteristic tricarballylic ester moieties . I. IFusari183), butenyl carboxymethyl maleic anhydride (184) and its decarboxylated form 185 are enzymatically hybridized -like proteins BfL6 and BfL10, and the product yield is significantly increased in the presence of phosphatidylethanolamine-binding proteins (PEBPs) BfL5 and BfL9. Deoxyscytalidin (186) biosynthesis occurs in a similar manner to 183, except that octanoate is used as a building block instead of hexenoate  , bate Fig. A 140]. . 183), b89) Fig. B 141].F.F183), b190) are polyketide-derived fungal meroterpenoids synthesized in a distinct manner from those described above. The biosynthesis of these molecules employs a class I terpene cyclase, and therefore, the resultant terpene products need to be hybridized with a polyketide molecule at a later biosynthesis stage. In the biosynthesis of xenovulene A, the sesquiterpene hydrocarbon humulene (191) and the tropolone quinomethide (192) undergo a hetero [4 + 2] cycloaddition reaction catalyzed by AsR5 to give 193 with the meroterpenoid scaffold  using two tropolone orthoquinone molecules (195)  ar95) Fig. B [143, 1196) is an azaphilone family natural product biosynthesized by the fusion of preasperpyranone (197) and a polyketide-derived aromatic aldehyde 198, which, unlike the other cases covered in this review, are generated by two separate gene clusters  iPenicillium brasilianum stems from the change of a few amino acid residues in the key dioxygenases [In this review, we summarize several representative examples of branching and converging pathways found in fungal natural product biosynthesis. Core synth(et)ases, such as PKSs, NRPSs, and terpene cyclases, undoubtfully contribute to the structural diversity of natural products by creating a large number of branching pathways, which is achieved by the diverse programming rules adopted by core synth(et)ases. However, pathway branching and converging at mid- and late-stage biosynthesis, which are performed by a variety of tailoring enzymes, are other major factors that generate the natural product diversity and complexity. It should be noted that only slight genetic changes can sometimes cause a pathway divergence; for example, the divergence of paraherquonin and acetoxydehydroaustin pathways in ygenases . The preygenases , 147, anygenases , the evoygenases , and theygenases . Future


The MutL family of DNA mismatch repair proteins (MMR) acts to maintain genomic integrity in somatic and meiotic cells. In baker’s yeast, the MutL homolog (MLH) MMR proteins form three heterodimeric complexes, MLH1-PMS1, MLH1-MLH2, and MLH1-MLH3. The recent discovery of human PMS2 (homolog of baker’s yeast PMS1) and MLH3 acting independently of human MLH1 in the repair of somatic double-strand breaks questions the assumption that MLH1 is an obligate subunit for MLH function. Here we provide a summary of the canonical roles for MLH factors in DNA genomic maintenance and in meiotic crossover. We then present the phenotypes of cells lacking specific MLH subunits, particularly in meiotic recombination, and based on this analysis, propose a model for an independent early role for MLH3 in meiosis to promote the accurate segregation of homologous chromosomes in the meiosis I division. The eukaryotic MutL homolog (MLH) family of DNA mismatch repair (MMR) proteins consists of three heterodimeric complexes conserved from baker’s yeast to humans. In baker’s yeast, they are referred to as MLH1-PMS1 (MutLα), MLH1-MLH2 (MutLβ), and MLH1-MLH3 (MutLγ) . In thisPhylogenetic studies provided evidence for the occurrence of ancient gene duplication events that led to the specialization of the MLH family of paralogs. Such work also indicated that the MLH1 outgroup diverged prior to the splits that led to the PMS1, MLH2, and MLH3 paralogs ,6,7,8. OTo explore new roles for the MLH family in meiosis, we first present the established roles for this family in various cellular contexts. Escherichia coli system. In E. coli, mismatch recognition by the MutS homodimer triggers ATP-dependent conformational changes, which convert MutS into a sliding clamp capable of recruiting the MutL homodimer. The MutS-MutL complex then recruits the MutH endonuclease to nick the newly replicated unmethylated strand in a process temporally regulated by the activity of DNA adenine methyltransferase (Dam). The nicked DNA serves as an entry site for the unwinding of DNA by the UvrD helicase. Unwound single-stranded DNA is then digested by exonucleases to create a gap through the mismatch site that is repaired by DNA polymerase and ligase  heterodimers. MSH2-MSH6 primarily recognizes base–base mismatches and 1 nt insertion/deletion loops, and MSH2-MSH3 primarily recognizes insertion/deletion loops that can be as large as 17 nt in size ,13,14 FA. Recent mutants ,19,20,21Numerous in vitro biochemical and genetic studies in MMR have suggested a requirement for MLH1 as a subunit of all three heterodimers. All four eukaryotic MLH proteins possess an N-terminal ATP binding domain, an unstructured linker, and a structured C-terminal domain. The asymmetric binding of ATP to MLH1 and its MLH partner triggers conformational changes that facilitate the coordinated condensation of the N-terminal domains of the complex, bringing them in close proximity to the C-termini ,23. AccoE. coli MutL, which lacks endonuclease activity and instead relies on MutH for strand-specific nicking [Although MLH1-PMS1, MLH1-MLH2, and MLH1-MLH3 share many similarities in their modes of action during MMR, distinctions can be made between their structure, mechanisms of recruitment, substrate specificity, and strand-nicking specificity . First,  nicking ,28,29,30 nicking . MLH1-ML nicking .Second, the variation in functionality between MLH complexes is reflected in their recruitment and substrate specificity in MMR. MLH1-PMS1 is recruited to repair base–base mismatches and insertion/deletion loops by either MSH2-MSH6 or MSH2-MSH3. MLH1-MLH2 also appears to be recruited to mismatches by both MSH2-MSH6 or MSH2-MSH3, but its exact function is less well understood, and it is considered an accessory factor ,7. InterMLH1, PMS1 , and MLH3 to trinucleotide repeat expansions in human diseases such as Huntington’s (CAG expansions in the HTT gene) and myotonic dystrophy type I (CTG/CAG expansions in the DMPK gene) [Genome-wide-association studies in human patients, as well as genetic studies in baker’s yeast, mice, and human cell cultures, have linked PK gene) ,41,42,43PK gene) ,44,45,46In the context of a nonreplicating cell, repeat sequences are hypothesized to form single-stranded loops that can be excised to yield expansions or contractions following repair synthesis D. If theMeiosis is the process by which sexually reproducing eukaryotes create four haploid cells from a single diploid cell via one round of DNA replication, followed by two consecutive rounds of cell division culminating in the production of four genetically distinct haploid cells ,48,49,50S. cerevisiae and higher eukaryotes, recombination leading to crossing over is initiated in meiotic prophase with the formation of SPO11 induced double-strand breaks that occur genomewide [In nomewide ,54,55,56nomewide ,58. Oncenomewide ). Alternnomewide ,4. Curionomewide ,61,62.In the major CO pathway, extended D-loops are stabilized by the meiosis-specific MSH family complex MSH4-MSH5 along with other members of the functionally diverse ZMM family, including ZIP1-4, MER3, and SPO16 (reviewed in ). This sIn the Class II CO pathway , double Holliday junctions that arise independently of ZMMs are cleaved without orientation bias primarily by the structure-selective nuclease MUS81-MMS4  to result in a roughly 50:50 mixture of CO and NCO products ,68,69,70MLH1 or MLH3 results in decreases in crossing over and spore viability, as well as increases in meiosis I (MI)-nondisjunctions [2E(X)4E metal-binding motif of MLH3 (mlh3-D523N) abolishes the endonuclease activity of budding yeast MLH1-MLH3 in vitro, and confers mlh3∆-like phenotypes in vivo [Numerous genetic studies in yeast and mice have indicated that both MLH1 and MLH3 are critical for meiotic CO formation ,72,73,74unctions ,76,77,78 in vivo ,29,78. T in vivo ). MLH1-M in vivo ,65,66. R in vivo . It is s in vivo .An intact double Holliday junction is a symmetric molecule that must be asymmetrically cleaved by MLH1-MLH3 in the Class I pathway to yield only CO products. Recent studies have shed light on the mechanism of imparting asymmetry by analyzing heteroduplex DNA tracts following CO formation ,82. UsinMLH factors have been thought to primarily function as heterodimers with MLH1 as the common binding partner. In this section, we will attempt to consolidate observations within the literature hinting at expanded roles for the MLH family, in addition to proposing explanations for these findings.MLH1, PMS2, MLH3, and MSH2 in human TK6 B cells and found that PMS2 and MLH3 were important for the repair of double-strand breaks, whereas MLH1 and MSH2 appeared dispensable, providing evidence for roles in human cells for PMS2 and MLH3 independent of MMR  is that PMS2 and MLH3 act as homodimers. Indeed, in silico analysis suggests that PMS2 and MLH3 are capable of homo/heterodimerization , and MLH−/−Pms2 background [Some of the earliest speculation of noncanonical MLH complexes in meiosis came from cytological work in mice in the early 2000s. Lipkin et al.  noticed ckground . This lockground ,19,20, i−/−Pms2 mice, indicating that deletion of a single MLH factor could lead to a redistribution of MLH factors throughout the genome , are correlated with low meiotic spore viability in baker’s yeast due to increased prevalence of MI-nondisjunction events where both homologs segregate toward the same pole during the first meiotic division ,88,89,90Δ mms4Δmlh1 and Δ mms4Δmlh3) displayed 6 to 17-fold reductions in COs. Curiously, other combinations of Class I and Class II mutants (Δ mms4Δmsh5 and Δ mms4Δ mlh1Δmsh5) exhibited smaller defects (4 to 6-fold reductions) in crossing over than Δ mms4Δmlh1 and Δ mms4Δmlh3 mutants. Why might Δ mms4Δmsh5 and Δ mms4Δ mlh1Δmsh5 mutants show weaker CO defects, given that both Class I and Class II CO pathways are expected to be disrupted? One possibility is that the presence of MSH4-MSH5 obstructs alternative resolution pathways , thus accounting for the dramatic CO defect observed in Δ mms4Δmlh1 and Δ mms4Δmlh3 double mutants  and Δ mms4Δmlh3 (62%) double mutants were found to be relatively high compared to Δmsh5 (36%), Δ mlh1Δmsh5 (37%), and Δ mms4Δmsh5 (19%) mutants [Δ mms4Δ mlh1Δmsh5 triple mutants mimicking Δ mms4Δmsh5 double mutants in terms of CO defects. However, the differential relationship between spore viability and crossing over exhibited by these mutants is inconsistent with the expectation that crossing over and spore-viability defects manifest from the same underlying mechanistic failure. Rather, the presence of MSH4-MSH5 appears to be refractory to chromosome segregation defects, independently of its pro-crossover role.Despite the well-established role for COs as the primary providers of interhomolog linkage, other data paint a more complicated picture of homolog-segregation methods. Argueso et al.  and Nishsee also ). Surpri mutants ,77,78,89Δ mms4Δmlh1 or Δ mms4Δmlh3 meiotic yeast cells would each receive roughly 6–7 COs, well below the minimum threshold of 16 needed for each chromosome to receive at least one CO. Although the exact numbers of COs per cell may differ greatly from this extrapolation, these results are inconsistent with the notion that COs are required for proper meiosis I chromosome segregation in yeast. Indeed, CO-independent means of chromosome segregation have been well documented in other species, primarily through centromeric pairing and/or pairing at repetitive sequences . Togethmlh3∆ mutants exhibited a higher frequency of MI-nondisjunctions compared to mlh1∆ mutants. This result was unexpected because prior studies indicated that mlh1∆ mutants displayed spore viabilities less than or equal to mlh3∆ mutants, and mlh1∆ and mlh3∆ mutants displayed similar decreases in crossing over [mlh1 N-terminal mutants mirrored the phenotype of mlh3∆ mutants, whereas mlh3 linker mutants closely resembled mlh1∆. The authors proposed a number of possible explanations for this apparent paradox between MI-nondisjunction and spore viability phenotypes. First, it could be that the assayed chromosome (chromosome VIII) is nonrepresentative of global disjunction among all 16 chromosomes. It is known that chromosome size impacts the density of double-strand-break hotspots, crossover rates, and interference [mlh1∆ is due to moderate MI-nondisjunction due to CO defects plus haplolethal mutations that arise during replication resulting from the absence of MLH1-PMS1. Conversely, the spore-viability defect observed in mlh3∆ cells may be entirely due to excess MI-nondisjunction.Claeys, Bouuaert, and Keeney  performeing over . Curiousrference ,92,93,94mlh1 and mlh3 yeast mutants were not seen in prior studies of spore viability. To explain why these phenotypes manifest, Claeys, Bouuaert, and Keeney [mlh1∆ and mlh3 linker mutants, joint molecules remain long enough to promote biorientation of homologs, but are ultimately resolved by structure-selective nucleases into a mixture of COs and NCOs or disassembled by STR. In this model, mlh3∆ and mlh1 N-terminal mutants are unable to stabilize early recombination intermediates, thus experiencing higher levels of chromosome mis-segregation.Importantly, these hypotheses only explain why the differential nondisjunction phenotypes of d Keeney  propose Sordaria and mice have suggested that MSH4-MSH5 foci tend to diminish around early to mid-pachynema, the same timeframe in which MLH3 foci (early pachynema) and MLH1 foci (mid-pachynema) are observed to form [mlh3∆ and nuclease-dead mlh3 mutants exhibit increased BLM (SGS1 in yeast) foci formation in zygonema [To understand the above observations, we hypothesize that MSH4-MSH5 and MLH3 cooperate in an early stage of meiotic recombination to stabilize Holliday junction intermediates. In this model, accurate chromosome segregation is promoted by two distinct mechanisms: joint molecule stabilization and CO formation. First, Holliday junction binding by MSH4-MSH5 and other ZMMs provides a semistable intermediate to which MLH3 alone is recruited. We view this as being analogous to the role for stabilizing intermediates in somatic recombination that could explain observations made in Rahman et al. . Once re to form ,95,96 . Togethiewed in ,80, suggMLH2 leads to increases in spore viability of ZMM mutants zip4∆ and msh4∆ without increasing overall CO numbers, presumably due to longer heteroduplexes counterbalancing the joint molecule stabilization lost in the absence of ZMMs [MLH1 and MLH3 mutants may thus be explained as follows. In mlh1∆ mutants, MLH3 is free to displace MSH4-MSH5 and stabilize Holliday junctions, while the absence of MLH1-MLH2 results in more stable heteroduplexes. Similarly, mlh3-linker mutants experience only moderate levels of MI-nondisjunction because mlh3-linker mutants are defective for displacement of MSH4-MSH5 due to defects in Holliday junction binding. In these mutants, MSH4-MSH5 may remain bound to Holliday junctions, acting to biorient homologs. Also, the presence of mlh3-linker mutants may sequester a portion of MLH1, keeping MLH1-MLH2 levels in check. Contrastingly, in the absence of MLH3, a portion of the MLH1 pool may bind to MLH2, limiting the extent of gene conversion tracts, thus destabilizing recombination intermediates, all while lacking the pro-Holliday junction stabilization provided by MLH3, culminating in high meiosis I nondisjunction levels.In summation, this model predicts a transient MLH1-independent role for MLH3 in stabilizing early recombination intermediates, thus promoting accurate chromosome segregation via a mechanism separate from its late role in double Holliday junction resolution. Such a model is consistent with studies of MLH2, suggesting it functions with MLH1 to limit the extent of heteroduplex tract lengths . DeletioIn this review, we first presented the current state of the literature concerning the known roles for MLH factors in various aspects DNA metabolism. We then proposed a model to explain the numerous enigmatic MLH mutant phenotypes spanning over two decades. Namely, we proposed that MLH3 functions independently from MLH1, acting early in meiosis to stabilize nascent Holliday junctions, simultaneously promoting CO-independent homolog stabilization, in addition to directing recombination intermediates down to the Class I interfering CO pathway. We supported this hypothesis with data from several model organisms encompassing an amalgamation of cytological, genetic, and biochemical analyses. Our goal was to encourage research and promote speculation into rethinking how the MLH proteins are thought to function. As discussed in prior sections, the recent confirmation that human PMS2 and MLH3 not only function in somatic homologous recombination, a new role for MLH proteins, but do so independently of MSH2-MSH6, MSH2-MSH3, and MLH1, begs the question as to whether MLH proteins possess the ability to homodimerize, heterodimerize with unidentified partners, and perform biologically relevant functions via hitherto unexplored mechanisms. We present one such model that is readily testable. For example, this model predicts physical interactions with early meiotic factors that could be detectable in vitro or in vivo by immunoblot assays. Additionally, in vitro biochemistry using purified MLH factors in noncanonical combinations may elucidate new functionality (see ). Taken


IntroductionNoise or noise pollution is a phenomenon that causes an auditory sensation considered unpleasant, undesirable, and annoying, which may present a danger to health in general and the auditory system in particular. The objective of this study was to evaluate the impact of noise pollution among workers in a brewery in the city of Conakry.Patient and methodsThis is a prospective descriptive study, of two months' duration  carried out in the industrial unit of the Limited Company of Breweries of Guinea (SOBRAGUI). We included all the workers of the company exposed to noise pollution in their workplaces, after their informed consent.ResultsThe age of the workers varied between 22 and 70 years, with a mean age of 44.14 ± 8.07 years. We noted a male predominance of 99.22% (n=128) cases. The average duration of exposure was 14.28 ± 6.78 years, with variations ranging from one year to 35 years. Among the auditory disorders, we noted tinnitus in 63.8% (n=74), hypoacusis in 56.9% (n=66), and auditory fatigue in 52.6% (n=61) of cases. These signs were often associated with each other and with other extra-auditory symptoms in the same worker. Audiometry revealed a moderate to severe hearing loss in 13.8% (n=16) and profound deafness in 0.9% (n=1) of cases. The impact of noise pollution on workers' performance was reflected in concentration difficulties in 57.7% (n=67) of cases.ConclusionNoise pollution is present in the SOBRAGUI bottling line. It has a negative impact on the health of workers and alters their work performance. Noise or noise pollution is a phenomenon that causes an auditory sensation that is considered unpleasant, undesirable, and annoying, and that may present a danger to health in general and the auditory system in particular . AccordiIn Canada, a study of the impact of hearing conservation programs on the incidence of noise-induced hearing loss in 22,376 workers had shown a threshold shift of 10 dB or more in at least 2,839 of them [In France, a medical risk surveillance survey in 2010 had reported that long-term noise exposure (more than 20 hours per week) at high levels (≥85 dB/(A)) affected 4.8% of employees, of which the sectors most concerned were industry (16.8%) and construction (10.5%) .In Algeria, Hammoudi N et al., in a study on the relationship between noise and blood pressure in an airport environment, had reported hypertension in 9.25% of ground staff and 16.63% of aircrew .In Tunisia, Brahem A et al. had shown in 2019 that, after exposure to a sound level varying between 75 dB and 103 dB for eight hours, almost all the employees of an electricity company had declared irritability, nervousness, and ringing in the ears [In Côte d'Ivoire, Yeboué-Kouamé BY et al., in a study on the assessment of noise risk at 881 workstations in 2018, had revealed that 60% of the workstations assessed exposed employees to more than 85 dB(A) and 33.5% to more than 90 dB(A) over a working time of more than two hours daily .In Guinea, very little data are available on occupational risks related to noise pollution in companies, and the regulations on noise in the workplace remain insufficient. This represents a major handicap for social security and occupational risk prevention organizations. The objective of this study was therefore to evaluate the impact of noise pollution on workers in the bottling line of a brewery in Conakry.This is a cross-sectional, descriptive, two-month study , carried out in the industrial unit of the Limited Company of Breweries of Guinea (SOBRAGUI). We included in this study all workers of all ages and genders working in the bottling line of the said company and who gave their informed consent. We administered a pre-established questionnaire to each of the workers staying temporarily or for a long time (between eight and 10 hours per day) at the bottling line where dosimetry had shown variable sound exposure thresholds between 85 and 95 dB (A). Systematic luminaire tonal audiometry was carried out at least 14 hours after the last exposure to noise in the workplace using a GSI 18 audiometer, meeting the ISO 11690-1.2 1996 standard. Audiometric tests were carried out in a soundproof cabin. Our data were captured using Kobocollect and analyzed using SPSS 21.0 software . The survey was conducted with strict respect for anonymity and moral and physical integrity while keeping the confidentiality of the study. This study was reviewed and approved by the ethics committee of the Faculty of Health Sciences and Techniques of the University of Conakry.Of the 350 workers at the Guinean Brewery Company (SOBRAGUI), 129 workers were interested in the investigation because they worked at the bottling line, i.e., 36.86% of cases. The age of the workers varied between 22 and 70 years with an average age of 44.14 ± 8.07 years. The 40 to 49 age group is the most represented, at 47.3% (n = 61) of cases. We noted a male predominance of 99.22% (n = 128) of the cases. Ninety-two (92) respondents, i.e., 71.3%, worked in the production sector, which includes the brewing and packaging units that are the most exposed to noise pollution with an average duration of exposure of 14.28 ± 6.78 years and extremes: 01 year and 35 years , hearing loss in 56.9% (n = 66) and hearing fatigue in 52.6% (n = 61) of cases. These signs were often associated with each other and with other extra-auditory symptoms in the same worker. All respondents were tested with an audiometer which revealed moderate to severe sensorineural hearing impairment in 13.8% (n = 16) and one case of profound sensorineural hearing loss  work in areas where noise levels exceed 85 decibels on average .The workers in the bottling line of the Société Anonyme des Brasseries de Guinée are mostly adults with a mean age of 44.14 ± 8.07 years. Hinson AV et al., in Benin, report an average age of 35.6 ± 10.4 years with extremes of 17 and 68 years . This reDespite the correct use of protective equipment, the exposure time of our workers was particularly long. The majority spent eight and 10 hours in a noisy working environment, exposed to machine noise for several years. The same was true in the countries of the sub-region, with an average duration of exposure to noise of 11.2 years in Burkina Faso .The impact of this noise nuisance was more or less marked in almost 90% of our respondents. This included tinnitus, hearing loss, and hearing fatigue. Oubian S et al., in a study on the impact of noise pollution on the quality of life of power plant workers in Burkina Faso, found 34% hearing loss . All noise-exposed workers underwent an audiometric test showing some degree of hearing loss. This result would be comparable to that reported by Shahid A et al., in Pakistan, who reported 79% hearing loss greater than or equal to 25 dB loss . The impact of noise pollution on workers' performance in the workplace was evident, resulting in decreased productivity and increased work-related accidents. In addition, social and family life was compromised for most of these workers due to noise pollution .Noise pollution is present at the SOBRAGUI bottling line. It negatively impacts the health of workers and affects their work performance. Measures to improve the working environment at the bottling line of this industrial unit must be put in place in order to reduce not only the threshold but also the time of exposure of workers to noise pollution.