Associations Between The Concentration Of Heavy Metals In Blood Cells Of Workers Exposed To Manganese And The Relative Telomere Length

Objective:Telomere length is considered as a biomarker of biological age and a risk factor of age-related diseases,and is associated with the occurrence and development of cardiovascular diseases,diabetes and cancer.Gradual telomere shortening is inevitable with age,but the rate of telomere shortening may be influenced by variables such as dietary patterns,physical activity and heavy metal exposure.Therefore,finding environmental factors that can affect telomere length is of great significance for the early prevention of chronic diseases.As a result of mining and smelting activities,large amounts of heavy metals are released into the environment,and heavy metal exposure,particularly those that cause oxidative stress,has been found to be associated with telomere length.Previous studies have focused more on the health-damaging effects of single metal exposure,but metals in the environment are often in the form of compound exposures.Assessing the health effects of single metal exposure may underestimate the true effects due to metal-to-metal interactions.Therefore,it is necessary and important to clarify the damage effect of multiple heavy metal exposure on telomeres.However,as far as we know,there are few studies on the relationship between heavy metal combined exposure and telomere length.Methods:1.Single metal model analysis of correlation between heavy metal concentration of blood cells and telomere length in workers exposed to occupational manganese（1）Study design and selection of study objects:a cross-sectional study design,based on manganese-exposed workers healthy cohort（MEWHC）,was used to select 809 manganese exposed workers who were followed up and completed telomere testing in 2017.（2）Biological samples:application of inductively Coupled Plasma Mass Spectrometer（Inductive Coupled Plasma Mass Spectrometer,icp-ms）of heavy metal concentration in the detection of occupational manganese exposure workers blood cells.（3）Statistical analysis:generalized linear regression model was used to analyze the influencing factors of heavy metal concentration and relative telomere length,as well as the correlation between a single metal and relative telomere length.2.Multiple-metals model analysis of correlation between heavy metal concentration of blood cells and telomere length in workers exposed to occupational manganese（1）Sudy design,study object selection and biological sample detection:the study population of the first part is taken as the study object.（2）Biological sample detection:the metal concentration of the first part was analyzed.（3）Detection of relative telomere length:The relative telomere length of peripheral blood leukocytes of manganese exposed workers was determined by real-time quantitative PCR.（4）Statistical analysis:the LASSO regression was used to screen the metals related to the relative telomere length,and the composite polymetallic exposure model was constructed in combination with generalized linear regression to analyze the relationship between the composite polymetallic exposure and the relative telomere length.The correlation between the concentration of heavy metals in blood cells and the relative telomere length and the dose-response relationship were calculated by generalized linear regression model,stratified analysis,and restricted cubic analysis.Results:1.Single metal model analysis of correlation between heavy metal concentration of blood cells and telomere length in workers exposed to occupational manganese（1）The influencing factors of telomere length mainly include job type,age and length of service.The relative telomere length of the low,medium and high exposure groups was lower than that of the control group.The relative telomere length of the 40～and 50～year old groups was lower than that of the 20～year old group.Workers with 10～20 years of service had shorter telomere lengths.（2）The concentrations of Mn,Co,Cu,Sb,As,Mo,Cd and Pb in blood cells were different by gender.Blood cell concentrations of As,Cd and Pb were significantly higher in smokers and drinkers.（3）The results of the single-metal model showed that:in the continuous variable model,the relative telomere length decreased by 0.12%,0.32%and 0.08%respectively for each 1%increase in blood cells.In the type-variable model,the concentrations of manganese,copper and lead in blood cells were negatively correlated with the relative telomere length(P_trend<0.05).In addition,stratified analyses showed significant correlations between blood cell concentrations of manganese,copper,and lead and telomere length in women.2.Multiple-metals model analysis of correlation between heavy metal concentration of blood cells and telomere length in workers exposed to occupational manganese（1）LASSO regression:Three metals,manganese,copper and lead,which are related to relative telomere length,were screened out by LASSO regression.（2）Multiple-metals model:manganese,copper and lead screened by LASSO regression were included in the generalized linear regression model at the same time.After adjusting for relevant factors,the results showed that for each 1%increase in the concentration of manganese and copper in blood cells,the relative telomere length decreased by 0.1%and 0.32%respectively.（3）Combined action of metals:taking Low Mn+Low Cu as a reference,the combined action of Low Mn+High Cu,High Mn+Low Cu and High Mn+High Cu is negatively correlated with the relative telomere length(P_trend<0.001).（4）Dose-response relationship:the nonlinear dose-response relationship between blood cell manganese concentration and telomere length was inverted"U"（Mn:P for overall<0.001,P for nonlinearity<0.001）;There is a linear dose-response relationship between blood cell copper concentration and relative telomere length（Cu:P for overall=0.002,P for nonlinearity=0.331）.（5）Interaction:in male workers,there was an interaction between age and the correlation between blood cell manganese concentration and relative telomere length(P_interation=0.042),and no interaction between age and blood cell manganese level in female workers on the correlation between blood cell manganese concentration and relative telomere length was found(P_interaction<0.05).Conclusion:（1）Among the 10 heavy metals in blood cells,the concentration of manganese in blood cells was in an inverted"U"shape with the relative telomere length,while the concentration of copper in blood cells was in a dose-response relationship with the relative telomere length,and the combined effect of the two could also shorten the relative telomere length.（2）In male workers,the interaction between manganese in blood cells and age shorted the relative telomere length.