| Background and ObjectivesNoise has direct and indirect harmful effects on human health.Among these,noiseinduced hearing loss(NIHL)has become one of the major public health problems.Because of its complex pathogenesis,there is still no specific treatment.In addition,long-term noise exposure can also damage the nervous,cardiovascular,endocrine and digestive systems,and is associated with hypertension,diabetes,obesity and various metabolic diseases.Therefore,it is necessary to understand the metabolic changes caused by noise exposure and to explore biomarkers that can identify and diagnose NIHL.Based on untargeted metabolomics technology,this study explored the changes of metabolic profiles caused by noise exposure,analyzed the metabolic pathways that might be disturbed by noise,and screened biomarkers that could identify and diagnose NIHL,so as to provide a reference for risk assessment and early prevention and control of health damage caused by occupational noise exposure.Methods1.Based on the prospective cohort of occupational noise exposed workers in an iron and steel plant in Henan Province established by the research group in 2006,30 workers with noise exposure and normal hearing were randomly selected as the noisereceiving control group(NHL)according to the inclusion and exclusion criteria.30 workers with noise exposure and high-frequency hearing loss were randomly selected as the noise-receiving case group(HL)according to 1:1 matching.At the same time,according to the basic characteristics of age,length of service and body mass index,each pair of case and control workers exposed to noise were matched with a worker who works in the same factory without noise and has normal hearing as the non-noise control group(Control).The basic clinical information and plasma samples of three groups of subjects(a total of 90 subjects,30 subjects/group)were collected for metabolomic analysis.The HL group was combined with the NHL group to form a noise receiving group(Noise),and the plasma metabolites of control group and noise group were compared to explore the effects of occupational noise exposure on the metabolome;The HL group was compared with the NHL group to explore the relevant metabolic pathways that may be involved in occupational noise hearing loss.Both comparison groups were based on Orthogonal partial least squares discriminant analysis(OPLS-DA)with a value of variable importance of projection(VIP)≥ 1 and differential metabolites were screened by wilcoxon rank sum test with a P value <0.05.Significant differential metabolites were enriched for pathway analysis based on the Kyoto Encyclopedia of Genes and Genomes(KEGG)database.Diagnostic efficacy of potential differential metabolites as biomarkers of NIHL was examined by ROC curve analysis.2.According to the cumulative noise exposure of occupational noise population,the noise exposure rat model was constructed.24 Wistar male rats were randomly divided into three groups,the low noise group(LN,n=8)and the high noise group(HN,n=8)were exposed to noise intensities of 95 d B and 105 d B SPL,respectively,for 4 h per day for 30 days,and the control group(Ctr,n=8)were pseudo-exposed to background noise(≤40 d B SPL).At the end of the last noise exposure,auditory brainstem response(ABR)thresholds were measured and serum samples were collected for metabolomic analysis.According to the screening criteria of differential metabolites in the above population study,the differential metabolites in the Ctr and LN comparison groups and the Ctr and HN comparison groups were screened for enrichment analysis.Finally,the differential metabolic pathways of occupational population and experimental animals were compared and analyzed to explore the correlation between the results,so as to further verify the results of the study population.Results1.Basic information about the occupational group.The threshold of binaural high frequency hearing in the Noise group(including NHL group and HL group)was significantly higher than that in the Control group(P < 0.001).Age,smoking,alcohol consumption,hypertension and body mass index were equally distributed between the two groups.The mean binaural high-frequency hearing threshold was significantly higher in the HL group than in the NHL group(P < 0.001),while the remaining factors did not differ statistically between the two groups.2.Plasma differential metabolites and differential metabolic pathways in the occupational group.According to the screening criteria for significant differential metabolites,a total of469 differential metabolites were screened in the Noise and Control groups and 63 differential metabolites in the NHL and HL groups under positive and negative ion patterns.Among them,20 metabolites such as arachidonic acid and ceramides(C17-sphinganine,N-stearoylsphingosine)and linoleic acid and L-histidine were found to be significantly different in both comparison groups.Pathway enrichment analysis showed that a total of 54 metabolic pathways were enriched for differential metabolites between the Noise and Control groups,and 10 significant metabolic pathways were enriched for differential metabolites between the NHL and HL groups.Among them,retrograde endocannabinoid signaling,sphingolipid signaling pathway,Fc gamma R-mediated phagocytosis,vitamin digestion and absorption,and phospholipase D signaling pathway were significantly enriched metabolic pathways in the two comparison groups.Six differential metabolites that were significant in all three comparison groups,including 7.alpha.-hydroxydehydroepiandrosterone,adenine,Pro-Trp,3.beta,7.alpha.-dihydroxy-5-cholesteric acid,calcitriol,and D-lyxose.Their area under cure(AUC)of these metabolites for diagnosing NIHL were 0.607,0.626,0.720,0.703,0.640 and0.592,respectively,which were all greater than 0.5.3.Changes in hearing thresholds in the noise-exposed rat modelABR measurements after noise exposure showed that ABR thresholds were significantly higher in the LN and HN groups at Click,2k,4k,8k,and 16 k HZ frequencies compared to the Ctr group,and exposure to noise intensities of 95 d B SPL and 105 d B SPL for 30 days caused hearing impairment in the experimental rats.4.Serum differential metabolites and differential metabolic pathways in ratsAccording to the screening criteria,a total of 70 kinds of differential metabolites were screened in the serum of rats in Ctr and LN groups,and 98 kinds of differential metabolites in Ctr and HN groups,among which lipids and lipid molecular metabolites accounted for the largest proportion.The metabolic pathways that were significantly different between the Ctr and LN groups mainly involved three metabolic pathways:primary bile acid biosynthesis,thiamine metabolism,and bile secretion,while 16 metabolic pathways were enriched in the Ctr and HN groups.Among the differential metabolic pathways screened in animal experiments,the five metabolic pathways include aldosterone synthesis and secretion,bile secretion,central carbon metabolism in cancer,c AMP signaling pathway and alcoholism coincide with the differential metabolic pathways in occupational population research.ConclusionNoise exposure and NIHL can affect multiple metabolic pathways.Among them,the retrograde endocannabinoid signaling,sphingolipid signaling pathway,vitamin digestion and absorption,Fc receptor-mediated phagocytosis and phospholipase D signaling pathway are related to the occurrence of NIHL in occupational population.Aldosterone synthesis and secretion,bile secretion,central carbon metabolism in cancer,c AMP signaling pathway and alcoholism may play an important role in a variety of negative health effects of noise exposure.7.alpha.-hydroxydehydroepiandrosterone,adenine,Pro-Trp,3.beta,7.alpha.-dihydroxy-5-cholesteric acid,calcitriol,and Dlyxose may be biomarkers for early recognition of NIHL at the metabolome level. |
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