The Role Of Inflammatory Response In Cognitive Impairment Of Workers Exposed To Occupational Aluminum

Objective:Conduct a cross-sectional study on occupational aluminum exposure population to elucidate the role of inflammatory response in cognitive impairment caused by occupational aluminum exposure.Methods:In 2019,a study was conducted in a large aluminum plant in Shanxi province using a whole-group sampling method with a sample of 516 workers from aluminum electrolysis operations and maintenance shop workers.In this study,general profile information of the workers was collected,plasma aluminum concentration was determined using Inductively Coupled Plasma Mass Spectrometry（ICP-MS）,and the study subjects were divided into Q1,Q2,Q3,and Q4 groups according to blood aluminum concentration by quartile method;occupational epidemiological survey was used questionnaires were used to collect general information about the study subjects,including age,gender,marital status,education level,occupational history,disease history and lifestyle habits;a combination of questionnaires was used to test the cognitive function of the workers,including the Montreal Cognitive Assessment Scale,the Auditory Word Test,and the Connections Test.Enzyme-linked Immuno Sorbent Assay（ELISA）was used to test the microglia M1 and M2 phenotypic markers CD86and CD206 and the microglia activation marker Ionized calcium bindingadaptor molecule-1（Iba-1）,pro-inflammatory factors Interleukin-1β（IL-1β）,Interleukin-18（IL-18）and anti-inflammatory factors Interleukin-4（IL-4）,Interleukin-10（IL-10）,and inflammatory vesicles NOD-like receptor thermal protein domain associated protein 3（NLRP3）.The risk of cognitive impairment due to plasma aluminum concentration,microglia M1 and M2 phenotypic markers,and pro-inflammatory and anti-inflammatory factors was analyzed using logistic regression models;the relationship between plasma aluminum concentration,microglia M1 and M2 phenotypic markers,and pro-and anti-inflammatory factors and cognitive scores was also analyzed using generalized linear models,and the presence of a dose-response relationship was determined using trend tests.response relationship.The Bayesian network model was further used to predict and evaluate the risk of the above factors on cognitive dysfunction in occupational aluminum workers,and the predictive effect of the model was evaluated by plotting the operating characteristic（ROC）curve of the study subjects and calculating the area under the curve（AUC）.Finally,the public factors and their representative variables in the field of cognitive dysfunction were screened by factor analysis,based on which ANOVA was used to compare the differences in public factor scores,and multiple linear regression was used to analyze the relationship between plasma aluminum concentration,microglia phenotype,inflammatory factors and cognitive function.Results:1.Basic information and cognitive function scores of the study subjectsA total of 516 aluminum plant workers,all male,aged 21-59 years,with M(P₂₅,P₇₅)plasma aluminum concentrations of 51.83（25.13,82.28）μg/L were included in this study;based on the median and quartiles of blood aluminum concentrations.The differences in age,education level,monthly household income,BMI,smoking,alcohol consumption,years of receiving aluminum work,and type of work between the four groups were statistically significant（P<0.05）.The differences in Mo CA total score,naming,attention,verbal ability,abstraction,delayed recall,orientation,Trail making test-A（TMT-A）,Trail making test-B（TMT-B）,short term memory,long delayed recall,and delayed confirmation were statistically significant between the four groups（P<0.05）.2.Characterization of microglia activation markers in cognitive dysfunction due to occupational aluminum exposure2.1 Changes in the levels of microglia markers in study subjectsPlasma aluminum concentrations between the four groups M1 phenotype CD86,M2 phenotype CD206,and microglia activator Iba-1 levels were statistically significant（P<0.05）.2.2 Analysis of factors affecting microglia activation markers on cognitive function2.2.1 Analysis of the effects of microglia activation markers on cognitive function using logistic regressionWhether the study subjects suffered from cognitive dysfunction was used as the dependent variable,Model1 was unadjusted,and Model2 was adjusted for age,marital status,education level,monthly household income,BMI,years of receiving aluminum work,type of work,smoking and alcohol consumption as covariates on the basis of Model1 for logistic regression.According to the quartile results of blood aluminum,CD86,CD206,and Iba-1,blood aluminum,CD86,CD206,and Iba-1 are risk factors for cognitive impairment（OR>1,P<0.05）;The logarithmic conversion results of blood aluminum,CD86,CD206,and Iba-1 showed that blood aluminum,CD86,CD206,and Iba-1 have a cognitive impairment effect and are risk factors.The trend test showed that there was a dose-response relationship between plasma aluminum concentration,M1 phenotype CD86,M2 phenotype CD206,and microglia polarizer Iba-1 and cognitive dysfunction(P_trend<0.05).2.2.2 Analysis of the effect of microglia activation markers on cognitive function using multiple linear regressionThe cognitive function score of the study subjects was used as the dependent variable,Model1 was unadjusted,and Model2 was adjusted for age,marital status,education level,monthly household income,BMI,years of receiving aluminum work,type of work,smoking and alcohol consumption as covariates on the basis of Model1for multiple linear regression analysis.The results of adjusted multiple linear regression analysis showed that there was a negative correlation between plasma aluminum concentration,M1 phenotype CD86 of microglia,M2 phenotype CD206,and microglia polarizer Iba-1 and cognitive function score when they were quartered respectively（β<0,P<0.05）;When plasma aluminum concentration,CD86,CD206,and Iba-1 are continuous variables,they negatively affect cognitive function scores;The trend test showed that there was a dose-response relationship between plasma aluminum concentration,M1 phenotype CD86,M2 phenotype CD206,and microglia polarizer Iba-1 and cognitive function scores(P_trend<0.05).3.Characteristics of the role of inflammatory response in cognitive dysfunction due to occupational aluminum exposure3.1 Changes in the levels of inflammatory factors in the study populationThe differences in the levels of pro-inflammatory factors IL-1β and IL-18,anti-inflammatory factors IL-4 and IL-10,and inflammatory vesicles NLRP3 between the four groups of plasma aluminum concentrations were statistically significant（P<0.05）.3.2 Analysis of factors affecting inflammatory factors on cognitive function3.2.1 Analysis of the effects of inflammatory factors on cognitive function using logistic regressionWhether the study subjects suffered from cognitive dysfunction was used as the dependent variable,Model1 was unadjusted,and Model2 was adjusted for age,marital status,education level,monthly household income,BMI,years of receiving aluminum work,type of work,smoking and alcohol consumption as covariates on the basis of Model1 for logistic regression analysis.Press pro-inflammatory factor IL-1βThe results of quartile grouping with IL-18,anti-inflammatory factors IL-4 and IL-10,and NLRP3 content of inflammasomes showed pro-inflammatory factor IL-1βRisk factors for cognitive impairment（OR>1,P<0.05）;Pro-inflammatory factor IL-1βAfter logarithmic conversion with IL-18,anti-inflammatory factors IL-4 and IL-10,and inflammasome NLRP3,the results showed pro-inflammatory factor IL-1βIL-18,anti-inflammatory factors IL-4 and IL-10,as well as inflammasome NLRP3,have a cognitive impairment effect and are risk factors（β<0,P<0.05）.And trend testing shows that pro-inflammatory factor IL-1βThere is a dose-response relationship(P_trend<0.05)between IL-18,anti-inflammatory factors IL-4,IL-10,and NLRP3 and cognitive impairment.3.2.2 Analysis of the effects of inflammatory factors on cognitive function using multiple linear regressionThe cognitive function score of the study subjects was used as the dependent variable,Model1 was unadjusted,and Model2 was adjusted for age,marital status,education level,monthly household income,BMI,years of receiving aluminum work,type of work,smoking,and alcohol consumption as covariates on the basis of Model1 for multiple linear regression analysis.The adjusted multiple linear regression analysis results showed that the pro-inflammatory factor IL-1βThere is a negative correlation between cognitive function scores and IL-18,anti-inflammatory factors IL-4,IL-10,and NLRP3 in the Q4 group（β<0,P<0.05）;When IL-1β、When IL-4,IL-10,IL-18,and inflammasome NLRP3 are continuous variables,they negatively affect cognitive scores;And trend testing shows that pro-inflammatory factor IL-1β There is a dose-response relationship(P_trend<0.05)between IL-18,anti-inflammatory factors IL-4,IL-10,and NLRP3 and cognitive function scores.4.Characterization of the role of inflammatory factors in cognitive dysfunction due to occupational aluminum exposure predicted using Bayesian network models4.1 Bayesian network analysis of inflammatory response in cognitive dysfunction due to occupational aluminum exposureA Bayesian network model was constructed to predict the prevalence of cognitive dysfunction caused by inflammatory responses in occupational aluminum exposure as 49.5%;if all participants had plasma aluminum concentrations in the Q1（<25.13μg/L）group,the prevalence of cognitive dysfunction was 47.5%;if all participants had plasma aluminum concentrations in the Q4（≥82.28μg/L）group,the prevalence of cognitive dysfunction was 51.8%;if all participants had plasma aluminum concentrations and microglia phenotypic marker Iba-1（≥452.50 pg/L）for the Q4（≥82.28μg/L）group and M1 phenotype CD86（≥4.26 ng/L）,inflammatory vesicles NLRP3（≥8.25 ng/L）and pro-inflammatory factors IL-1β（≥48.34 pg/L）with IL-18（≥39.34 pg/L）,the prevalence of cognitive dysfunction was 66.7%when the M2 phenotype CD206（≥8.38 ng/L）,and the anti-inflammatory factor IL-4（≥128.73 pg/L）with IL-10（≥129.72 pg/L）were in the Q4 group.4.2 Bayesian network model validationThe ROC curve was used to measure the test efficacy of the model,and the AUC of the Bayesian network model for the effect of inflammatory response on cognitive dysfunction was 0.9621（95%CI:0.9470-0.9772）,indicating that the constructed Bayesian network model was effective.5 Characterizing the role of inflammatory factors on cognitive function impairment in workers with occupational aluminum exposure using factor analysis5.1 Public factor matrix of rotated cognitive function indicators in occupational aluminum exposed workersThe public factor matrix rotated by the maximum variance method,delayed recall,short-term memory,long delayed recall,and delayed confirmation had higher loadings on the 1st public factor,so public factor 1 was named memory;attention,Connectedness Test A,and Connectedness Test B had higher loadings on the 2nd factor,and public factor 2 was named attention;visuospatial and executive function,and orientation had higher loadings on the 3rd public factor higher,and public factor 3was named executive function;5.2 Public factor scores for different plasma aluminum concentrations and cytokine cognitive functionsPlasma aluminum concentration and pro-inflammatory factor IL-1β And IL-18,anti-inflammatory factors IL-4 and IL-10,inflammatory body NLRP3,M1 phenotype CD86,M2 phenotype CD206,and microglia activation marker Iba-1.The results of cognitive function scores among the four groups showed that there were statistically significant differences in the public factor 2 score,namely attention（P<0.05）.5.3 Multiple linear regression analysis of the effects of occupational aluminum exposure and cytokine levels on cognitive functionBlood aluminum,CD86,CD206,Iba-1,IL-1β、After quartile grouping and logarithmic conversion of IL-4,IL-10,IL-18 and NLRP3,the results showed that blood aluminum,CD86,CD206,Iba-1 and IL-1β、There is a negative correlation between IL-4,IL-10,IL-18,and NLRP3 and the factor scores of common factor 2（β<0,P<0.05）;Trend test results show that common factor 2 is associated with blood aluminum,M1 phenotype CD86,M2 phenotype CD206,microglia polarizer Iba-1,and proinflammatory factor IL-1β、There is a dose-response relationship between IL-18,anti-inflammatory factors IL-4,IL-10,and inflammasome NLRP3(P_trend<0.001).Conclusions:1.Plasma aluminum concentration,M1 phenotype CD86,M2 phenotype CD206,microglia polarizer Iba-1 pro-inflammatory factors IL-1βand IL-18,anti-inflammatory factors IL-4 and IL-10,and inflammatory vesicles NLRP3 are risk factors for developing cognitive dysfunction.2.Occupational aluminum exposure impairs workers’cognitive abilities,mainly affecting the attention domain;M1 phenotype CD86,anti-inflammatory factor IL-4mainly affect memory as well as the attention domain;M2 phenotype CD206 and microglia markers Iba-1,pro-inflammatory factors IL-1β and IL-18 and inflammatory vesicles NLRP3,anti-inflammatory factor IL-10 mainly affect the attention domain.The inflammatory response is involved in the cognitive impairment of workers caused by occupational aluminum exposure,and is mainly focused on the attention field.