| Heavy metals are metal elements with a density greater than 4.5 g/cm3 and are natural components of earth’s crust which cannot be degraded.In recent decades,with the acceleration of urbanization and industrialization and the rapid development of transportation,energy,metallurgy and other industries,heavy metal pollution in China has become increasingly serious and received widespread attention.Total environmental exposure refers to the total amount of contaminants possible nvironmental media,including air,drinking water,food,and skin contact and is a comprehensive index of environmental pollutants exposure in the population.Total human environmental exposure can provide exposure levels of the general population,with a known precision and accuracy,through all possible environmental media simultaneously.The main source of heavy metal exposure for the general population is diet.Diet and drinking water intake are the main exposure routes.In the past,most studies have focused on residents near contaminated areas,and there was a lack of investigations on heavy metal exposure of the general population.The first part aims to assess the total environmental exposure levels of heavy metals and the contribution ratio of each exposure pathway to clarify the total exposure characteristics of environmental heavy metals.Glucose and lipids are important sources of energy for cells and the body.The homeostasis of glucose and lipid metabolism is an important guarantee for the body to cope with the changes of internal and external environment.Although the roles of diet,lifestyle factors and genetics have been well studied,the impact of environmental exposures remains underappreciated.There is growing epidemiological evidence that environmental factors such as heavy metals are associated with the risk of abnormal glucose and lipid metabolism.The evidence concerning the association between heavy metal exposure and glucose nd lipid metabolism was inconsistent,possiblly due to differences in metal exposure levels,sample size of subjects and research design.The mixture of multiple metals may have complex non-linear exposure associations and potential interaction with the levels f biomarkers which cannot be figured out by using traditional multivariable parametric regression approaches.Therefore,it is necessary to further study the relationship between heavy metal exposure and glucose and lipid metabolism from the perspective of the combined exposure of multiple metals.Compared with external environmental exposure,internal environmental exposure can ccurately reflect the total amount of pollutants entering the human body through multiple pathways and can avoid the influence of the difference of individual absorption rate.Internal exposure is the key to reveal the association between pollutants and health effects.In the second part of this study,we used a fixed panel study design to explore the possible associations between heavy metal exposure and glucose and lipid metabolism.Part Ⅰ:Different pathways of heavy metal exposure and their contribution to total xposureObjective:This part aimed to investigate the exposure characteristics of environmental heavy metals,determine the total environmental exposure,clarify the contribution ratio of each exposure pathway and assess the risk of total exposure to the metal environment in the study population.Methods:We conducted a longitudinal panel study in 110 healthy adults in Baoding city,Hebei,China,and followed them between 2017 and 2018 with four repeated visits in summer,autumn and spring.A unified diet was adopted to control the potential bias from diet.We collected samples of individual PM2.5 quartz membranes,food,and drinking water samples of each subject in different seasons.The concentrations of eight heavy metals in samples were detected by inductively coupled plasma mass spectrometry（ICP-MS）:cadmium（Cd）,chromium（Cr）,manganese（Mn）,iron（Fe）,nickel（Ni）,zinc（Zn）,copper（Cu）,lead（Pb）.Referring to the“Chinese Group Exposure Parameters Manual”revised and issued by the Ministry of Environmental Protection of China in 2013,we estimated the total exposure levels of heavy metals and the contribution ratio of exposure media and compared their differences between seasons.The total exposure levels of heavy metals were finally compared with the U.S.Environmental Protection Agency（USEPA）recommended reference dose（Rf D）（μg/kg.bw/d）.Results:1.The detection rate of metals in PM2.5 was greater than 99%.The concentrations of Fe were the highest（Median:2.51–4.01μg/m3）and Cd were the lowest（0.00-0.01μg/m3）.There were significant seasonal differences of heavy metals concentrations in PM2.5（P>0.05）.The detection rate of metals in food was greater than99%,with the highest concentrations of Fe（877.96–1224.95μg/kg）and the lowest concentrations of Cd（0.67–0.87μg/kg）.There were significant seasonal differences of eavy metals concentrations in food except Cr and Ni（P>0.05）.The detection rate of metals in drinking water was greater than 90%.The concentrations of Zn were the highest（2.23–7.68μg/L）and Cd were the lowest（0.01–0.03μg/L）.There were significant seasonal differences of heavy metals concentrations in drinking water except Mn（P>0.05）.2.The highest exposure levels in PM2.5 were Fe（0.11–0.17μg/kg.bw/d）and the lowest were Cd(1.81×10-04–2.23×10-04μg/kg.bw/d).There were significant seasonal differences of exposure levels of heavy metals in PM2.5（P<0.05）.The highest exposure levels in food were Fe（142.00–196.00μg/kg.bw/d）and the lowest were Cd（0.11–0.14μg/kg.bw/d）.There were significant seasonal differences of exposure levels of heavy metals in food except Cr and Ni（P>0.05）.The highest exposure levels in drinking water were Fe（0.27–0.42μg/kg.bw/d）and the lowest were Cd(2.77×10-05–7.34×10-05μg/kg.bw/d).There were significant seasonal differences of exposure levels of heavy metals in drinking water except Mn（P<0.05）.3.The heavy metals in food contributed more to the total exposure levels,with the xposure contributions of food was greater than 99%.Drinking water was the secondary contributor to total exposure in addition to Cr and Ni.4.The total exposure levels of Fe were the highest（181.09μg/kg.bw/d）,followed by n（132.75μg/kg.bw/d）and Mn（58.06μg/kg.bw/d）.The total exposure levels of Cd（0.13μg/kg.bw/d）were the lowest.There were significant seasonal differences of total exposure levels of heavy metals（P<0.05）.Compared with the Rf D of the USEPA,the total exposure level of Cu in winter was higher than the Rf D and other metals’total exposure levels were lower than Rf D.Conclusions:Food was the main contributor to total exposure.There are significant seasonal differences between heavy metal exposure levels and total environmental exposure levels through different exposure pathways.During the survey,the total environmental exposure of Cu in winter was higher than the Rf D recommended by USEPA.Part Ⅱ:Associations of urinary metals levels with glucose and lipid metabolism Objective:This study is to explore associations of urinary metals levels with glucose and lipid metabolism based on a fixed panel study.Methods:The subjects of this part were the same as those in Part I.Urine and blood samples were collected at each follow-up.The concentrations of urinary Cd、Cr、Mn、Fe、Ni、Zn、Cu、Pb were detected by ICP-MS.The levels of serum total cholesterol（TC）,triglyceride（TG）,low density lipoprotein cholesterol（LDL-C）,oxidized low ensity lipoprotein（Ox-LDL）and high density lipoprotein cholesterol（HDL-C）were measured by Mindray BS-200 automatic biochemistry analyzer.Insulin,receptor for advanced glycation end-products（RAGE）,insulin resistance factor（resistin）were determined by the commercially available assay kits and the Luminex 200 platform.We performed linear mixed-effect models and Bayesian kernel machine regression（BKMR）to assess associations between exposure associations of urinary metals levels with glucose and lipid metabolism parameters.Results:1.The detection rate of urinary metals was above 99%.The concentrations of Zn（Median:487.25μg/L）were the highest,and the concentrations of Cd（0.07μg/L）were the lowest.Except for Fe and Ni,there was a significant difference in urine heavy metals among seasons（P>0.05）.After the correction of urine gravity,there was a significant correlation between metals except for Pb and Cd,with spearman correlation coefficients ranging from 0.015-0.782（P<0.05）.2.After adjustment of the possible confounders,the multiple metals linear mixed-effect odels showed that Cd was positively associated with Resistin（β=1.96,95%CI:0.62,3.31,P<0.05）,Zn was positively associated with TC（β=1.20,95%CI:0.21,2.21,P<0.05）and LDL-C（β=1.98,95%CI:0.55,3.44,P<0.05）,Mn was negatively correlated with HDL-C（β=-0.98,95%CI:-2.09,-0.15,P<0.05）and Ni was negatively correlated with Insulin（β=-3.84,95%CI:-6.66,-0.93,P<0.05）.3.The BKMR analyses showed significantly positive associations between urinary Zn with serum TC and LDL-C and negative associations between urinary Mn with serum HDL-C,which were consistent with the associations observed both in linear mixed-effect models.A potential non-linear relationship between Pb and Resistin levels was also observed.Furthermore,BKMR models showed significantly negative interaction effects of Zn and Cd,Mn and Cd,Pb and Zn on TC levels（P<0.05）while no significant interaction effects of heavy metals on the other glucose and lipid metabolism parameters.Conclusions:Our results suggested that exposure to heavy metals can affect glucose and lipid metabolism.The effects of multiple metals on glucose and lipid metabolism may have potential interactions. |
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