| Background and objectIn recent years,with the rapid development of industrialization and urbanization in China,the problem of environmental pollution has become increasingly serious.Exogenous metals from the environment enter the human body through a variety of ways,causing the disorder of metal homeostasis and seriously threatening human health.Essential metals have important biological functions in the human body and play an important role in human health.Overexposure to non-essential and essential metals may lead to metabolic disorders in the body.Environmental chemical contamination is known to induce abnormal circRNAs expression through a variety of pathways,but the underlying molecular mechanisms remain unclear.CircRNAs are covalently closed continuous loops without 5 ’and 3’ends,which increases their structural stability and limits the degradation of exogenous ribonuclease.In addition,diseases associated with exposure to environmental chemicals are often associated with abnormal expression of specific circRNAs,which are often detected in tissues and body fluids.Based on these characteristics,circRNAs have potential application value as biomarkers of environmental chemical exposure related diseases.It has been reported that metal exposure can affect the circRNAs expression profile to varying degrees and cause related diseases.However,their role in the respiratory system remains to be explored.Our study found that circRNAs play an important role in the association between essential metal elements and respiratory diseases.The purpose of this study was to explore the circRNAs related to respiratory diseases;to assess the association between urinary internal exposure to essential metals and respiratory disease-related circRNAs expression levels;to investigate the possible mediating role of circRNAs in the association between essential metal exposure and respiratory diseases.MethodsBased on the case-control study design,101 patients with respiratory diseases and 161 healthy controls were recruited in Shijiazhuang City from March to April2018.The circRNAs expression profiles were detected in plasma samples of the two groups,and respiratory disease-related circRNAs were screened and their expression levels were detected.The concentration of seven essential metals in urine was determined by inductively coupled plasma mass spectrometry(ICP-MS).Mixed linear models and conditional logistic regression models were used to assess the relationship between urinary essential metals and respiratory disease-related circRNAs expression.Mediation analysis was used to further investigate the mediating role of respiratory disease-related circRNAs in the relationship between essential metal exposure and respiratory diseases in humans.Results1.Associations between plasma circRNAs and respiratory diseasesIn order to identify respiratory disease-related circRNAs,this study analyzed and compared the circRNAs expression profiles between the case group and the control group,and found a total of 1806 differentially expressed circRNAs.Further,18 circRNAs with the highest differentially expression verified by qRT-PCR were selected for association analysis with respiratory diseases.After adjusting several covariates,they were analyzed as continuous variables and categorical variables.Nine circRNAs were found to be significantly associated with respiratory diseases in both continuous and categorical variable models(i.e.,hsa＿circ＿0022279,hsa＿circ＿0022287,hsa＿circ＿0010050,hsa＿circ＿0010052,hsa＿circ＿0007146,hsa＿circ＿0076098,hsa＿circ＿0022305,hsa＿circ＿0035110,and hsa＿circ＿0008882).2.Associations between respiratory disease-related circRNAs and urinary essential metalsWe analyzed nine respiratory disease-related circRNAs in connection with the 7kinds of essential metal elements,collaborators in adjustment variables,the metal content as continuous and categorical variables were analyzed.In the continuous and categorical variables of analyses,urine manganese(Mn)and cobalt(Co)levels were significantly positively correlated with the expression of hsa＿circ＿0076098,and urine copper(Cu)and selenium(Se)levels were significantly negatively correlated with the expression of hsa＿circ＿0008882.3.Associations between urinary essential metals and respiratory diseasesIn the analysis of the relationship between respiratory diseases and essential metals in urine,the content of essential metals was analyzed as a continuous variable and a categorical variable.We estimated odds ratios(OR)and 95% confidence intervals(CI)of respiratory diseases by the urine metal levels.The model included metals(tertiles and log-transformed)was adjusted for age,height,weight,occupational hazard exposure,regular physical activity,smoking amount,passive smoking and included community.We did not observe any significant(all P trend values > 0.05).4.Mediating effects of circRNAs in the associations between the urinary essential metals and respiratory diseasesA mediation analysis of circRNAs expression in the association between the urinary essential metals and respiratory diseases is presented.The mediation model was adjusted for confounding factors.We found that significant mediation by expression level of hsa＿circ＿0076098 was observed in the models associating urinary manganese and cobalt with respiratory diseases,and significant mediation by expression level of hsa＿circ＿0008882 was observed in the models associating urinary copper and selenium with respiratory diseases.The ADEs of urinary manganese,cobalt,copper and selenium with respiratory diseases were-0.01(-0.08,0.06),-0.04(-0.08,0.02),-0.03(-0.13,0.06),and-0.13(-0.27,0.01),respectively.But we did not observe any significant(all P values > 0.05).An average causal mediation effect of urinary manganese and cobalt,mediated in part by expression level of hsa＿circ＿0076098,was significantly associated with respiratory diseases,with ACMEs of 0.01(0.0002,0.03)and 0.01(0.0006,0.04).The proportions mediated were 55.8% and 26.8%,respectively.And an average causal mediation effect of urinary copper and selenium,mediated in part by expression level of hsa＿circ＿0008882,was significantly associated with respiratory diseases,with ACMEs of 0.01(-0.0008,0.04)and 0.26(0.0009,0.06).The proportions mediated were 34.0% and 16.5%,respectively.These results suggest that circRNAs may be an important mediating factor in the association between essential metals and respiratory diseases.ConclusionsIn conclusion,the present study found that the occurrence of respiratory diseases was significantly correlated with the increased expression of hsa＿circ＿0076098,while the occurrence of respiratory diseases was significantly correlated with the decreased expression of hsa＿circ＿0008882.We further investigated that urine manganese(Mn)and cobalt(Co)levels were significantly positively correlated with the expression of hsa＿circ＿0076098,and urine copper(Cu)and selenium(Se)levels were significantly negatively correlated with the expression of hsa＿circ＿0008882.CircRNAs play an intermediary role between metal and respiratory diseases.These findings suggest that circRNAs may be an important mediator in the association between essential metals and respiratory diseases,and further studies are needed to confirm our findings and reveal the underlying mechanisms. |
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