The impacts of different anticoagulants and long-term frozen storage on multiple metal concentrations in peripheral blood: a comparative study.

It is important but remains unclear whether ethylenediaminetetraacetic acid (EDTA) and sodium heparin anticoagulants have different impacts on the levels of various metals in peripheral blood after long-term frozen storage. The concentrations of 22 metals (Al, As, Ba, Ca, Cd, Cr, Co, Cu, Mn, Mg, Mo, Ni, Fe, Pb, Rb, Se, Sn, Sb, Sr, Ti, V, Zn) in whole blood, blood cells and plasma from 22 healthy participants were determined twice, 18 months apart, using inductively coupled plasma mass spectrometry (ICP-MS). The mean percentage error (MPE) and intraclass correlation coefficient (ICC) were calculated to evaluate the impact of the anticoagulants and long-term frozen storage on metal concentrations, respectively. The concentrations of Sb and Ba in whole blood, blood cells and plasma were significantly altered by EDTA and sodium heparin at two measurement timepoints (P < 0.05 and MPE > 80%). In EDTA tubes, the Ti and Ni concentrations in blood cells were changed significantly; and in heparin tubes, the concentrations of Ni and Mo in blood cells and Sb in plasma were also altered (P < 0.05 and MPE > 80%). The ICCs of 11 metals in whole blood, 15 metals in blood cells and 16 metals in plasma remained unchanged in EDTA tubes, and 16 metals in whole blood, 15 metals in blood cells and 17 metals in plasma remained unchanged in heparin tubes (ICC > 0.40). Our study suggested the use of EDTA tubes to determine Sb concentrations in peripheral blood and heparin tubes to determine Ba concentrations. Additionally, heparin tubes may be more suited for determining multiple metal concentrations in whole blood, whereas for blood cells and plasma either EDTA or heparin tubes could be used.

Mediated relationships between multiple metals exposure and fasting blood glucose by reproductive hormones in Chinese men.

Previous studies have reported metals exposure contribute to the change of fasting blood glucose (FBG) level. However, the roles of reproductive hormones in their associations have not been fully elucidated. The aim of the study is to investigate the associations of multiple serum metals with reproductive hormones, and to further explore potential roles of reproductive hormones in relationships between metals exposure and FBG level. A total of 1911 Chinese Han men were analyzed by a cross-sectional study. We measured serum levels of 22 metals by inductively coupled plasma mass spectrometer (ICP-MS). FBG, total testosterone (TT), estradiol (E2), follicle stimulating hormone (FSH), and sex hormone-binding globulin (SHBG) levels were determined. Least absolute shrinkage and selection operator (LASSO) regression models were conducted to select important metals, and restricted cubic spline models were then used to estimate dose-response relationships between selected metals and reproductive hormones. We also conducted mediation analyses to evaluate whether reproductive hormones played mediating roles in the associations between metals and FBG. We found significant inverse dose-dependent trends of copper, tin and zinc with E2; zinc with SHBG; copper and nickel with TT, while significant positive dose-dependent trend of iron with E2, respectively. Moreover, approximately inverted U-shaped associations existed between lead and SHBG, iron and TT. In addition, E2, SHBG and TT were negatively associated with FBG level. In mediation analyses, the association of copper with FBG was mediated by E2 and TT, with a mediation ratio of 10.4% and 22.1%, respectively. Furthermore, E2 and SHBG mediated the relationship of zinc with FBG, with a mediation ratio of 7.8% and 14.5%, respectively. E2 mediated 11.5% of positive relationship between tin with FBG. Our study suggested that the associations of metals exposure with FBG may be mediated by reproductive hormones.

Sex-specific associations of plasma metals and metal mixtures with glucose metabolism: An occupational population-based study in China.

Studies with multi-pollutant approach on the relationships between multiple metals and fasting plasma glucose (FPG) are limited. Few studies are available on the potential sex-specific associations between metal exposures and glucose metabolism. We explored the associations between 22 plasma metals and FPG level among the 769 participants from the manganese-exposed workers healthy cohort in China. We applied a sparse partial least squares (sPLS) regression followed by ordinary least-squares regression to evaluate multi-pollutant association. Bayesian kernel machine regression (BKMR) model was used to deal with metal mixtures and evaluate their joint effects on FPG level. In the sPLS model, negative associations on FPG levels were observed for plasma iron (belta = -0.066), cobalt (belta = -0.075), barium (belta = -0.109), and positive associations for strontium (belta = 0.082), and selenium (belta = 0.057) in men, which overlapped with the results among the overall participants. Among women, plasma copper (belta = 0.112) and antimony (belta = 0.137) were positively associated with elevated FPG level. Plasma magnesium was negatively associated with FPG level in both sexes (belta = -0.071 in men and belta = -0.144 in women). The results of overlapped for plasma magnesium was selected as the significant contributor to decreasing FPG level in the multi-pollutant, single-metal, and multi-metal models. BKMR model showed a significantly negative over-all effect of six metal mixtures (magnesium, iron, cobalt, selenium, strontium and barium) on FPG level among the overall participants from all the metals fixed at 50th percentile. In summary, our findings underline the probable role of metals in glucose homeostasis with potential sex-dependent heterogeneities, and suggest more researches are needed to explore the sex-specific associations of metal exposures with risk of diabetes.

The associations of multiple metals mixture with accelerated DNA methylation aging.

Aging is a leading cause of mortality for the elderly and DNA methylation age is reported to be predictive of biological aging. However, few studies have investigated the associations between multiple metals exposure and accelerated aging in the elderly. We performed a pilot study of 288 elderly participants aged 50-115 years and measured genome-wide DNA methylation and 22 blood metals concentrations. Measures of DNA methylation age were estimated using CpGs from Illumina HumanMethylation EPIC BeadChip. Linear mixed regression and Bayesian kernel machine regression (BKMR) models were used to estimate the individual and overall associations between multiple metals and accelerated methylation aging. Single metal models revealed that each 1-standard deviance (SD) increase in log-transformed vanadium, cobalt, nickel, zinc, arsenic, and barium was associated with a -2.256, -1.318, 1.004, -1.926, 1.910 and -1.356 changes in ΔAge, respectively; meanwhile, for aging rate, the change was -0.019, -0.013, 0.010, -0.018, 0.023, and -0.012, respectively (all P < 0.05). The BKMR models showed reverse U-shaped associations of the overall metals mixture with ΔAge and aging rate. Downward trends of ΔAge and aging rate were observed for increasing quantiles of essential metals mixture, but upward trends were observed for non-essential metals mixture. Further individual analysis of the BKMR revealed that the 95% confidence interval of ΔAge and aging rate associated with vanadium, zinc, and arsenic did not cross 0, when other metals concentrations set at 25th, 50th, and 75th percentile. Our findings suggest reverse U-shaped associations of the overall metals mixture with accelerated methylation aging for the first time, and vanadium, zinc, and arsenic may be major contributors driving the associations.

Co-exposure of serum calcium, selenium and vanadium is nonlinearly associated with increased risk of type 2 diabetes mellitus in a Chinese population.

BACKGROUND: Metals play an important role in type 2 diabetes mellitus (T2DM). This study aimed to explore the association of T2DM risk with single metal exposure and multi-metal co-exposure. METHODS: A case-control study with 223 T2DM patients and 302 controls was conducted. Serum concentrations of 19 metals were determined by inductively coupled plasma mass spectrometry (ICP-MS). Those metals with greater effects were screened out and co-exposure effects of metals were assessed by least absolute shrinkage and selection operator (LASSO) regression. RESULTS: Serum calcium (Ca), selenium (Se) and vanadium (V) were found with greater effects. Higher levels of Ca and Se were associated with increased T2DM risk (OR = 2.23, 95%CI: 1.38-3.62, Ptrend = 0.002; OR = 3.16, 95%CI: 1.82-5.50, Ptrend < 0.001), but higher V level was associated with decreased T2DM risk (OR = 0.58, 95%CI: 0.34-0.97, Ptrend < 0.001). Serum Ca and V concentrations were nonlinearly associated with T2DM risk (Poverall < 0.001, Pnonliearity < 0.001); however, Se concentration was linearly associated with T2DM risk (Poverall < 0.001, Pnonliearity = 0.389). High co-exposure score of serum Ca, Se and V was associated with increased T2DM risk (OR = 3.50, 95%CI: 2.08-5.89, Ptrend < 0.001) as a non-linear relationship (Poverall < 0.001, Pnonliearity = 0.003). CONCLUSIONS: This study suggest that higher levels of serum Ca and Se were associated with increased T2DM risk, but higher serum V level was associated with decreased T2DM risk. Moreover, co-exposure of serum Ca, Se and V was nonlinearly associated with T2DM risk, and high co-exposure score was positively associated with T2DM risk.

Associations of prenatal exposure to multiple metals with testicular volume and anogenital distance in infant boys: A longitudinal cohort study.

BACKGROUND: Human are widely exposed to multiple metals, some of which have suspected reproductive toxicity, but no human studies have investigated the developmental effects of prenatal metal exposure. OBJECTIVES: We aimed to evaluate the associations between prenatal multiple metal exposure and reproductive development in boys at 2-3 years using multi-pollutant approach. METHODS: This prospective study used data of 564 mother-child pairs recruited from the Guangxi Birth Cohort Study. Twenty serum metal concentrations were measured. Least absolute shrinkage and selection operator (LASSO) penalized regression was used to identify independent associations between prenatal multiple metal exposure and testicular volume (TV), and anogenital distance (AGD). Adjusted estimates were then obtained using multiple linear regression analysis, and the regression tree method was used to explore the interactions. RESULTS: Boys in the highest quartile of prenatal lead exposure had a 0.064 mL (95% CI: -0.124, -0.004) smaller ln-transformed TV, 0.060 cm (95% CI: -0.110, -0.011) shorter ln-transformed anopenile distance (AGDap), and 0.115 cm (95% CI: -0.190, -0.039) shorter ln-transformed anoscrotal distance (AGDas) than boys in the lowest quartile (all Ptrend < 0.05). Chromium was inversely with ln-transformed AGDap (ß = -0.078, 95% CI: -0.127, -0.030) and ln-transformed AGDas (ß = -0.113, 95% CI: -0.188, -0.038), while stibium was positivity associated with ln-transformed AGDap (ß = 0.091, 95% CI: 0.046, 0.136) and strontium was positivity associated with ln-transformed AGDas (ß = 0.120, 95% CI: 0.051, 0.189) (all Ptrend < 0.05). And the critical window of vulnerability may be the late pregnancy (the second and third trimester). Moreover, we detected interaction effects between lead, chromium and stibium on AGDap; lead, chromium and strontium on AGDas. CONCLUSIONS: The results suggest that prenatal exposure to lead, chromium, stibium and strontium may affect TV and/or AGD in infant boys. Potential mechanisms for the complex metal interactive effects during vulnerable periods are worthy of further investigation.

High manganese exposure decreased the risk of high triglycerides in workers: a cross-sectional study.

BACKGROUND: Manganese (Mn) participates in lipid metabolism. However, the associations between Mn exposure and dyslipidaemia is unclear. METHODS: This was a cross-sectional study. Data were collected from the 2017 the Mn-exposed workers healthy cohort (MEWHC). Finally, 803 occupationally Mn-exposed workers included in the study. The workers were divided into two groups. The grouping of this study was based on Mn-Time Weighted Averages (Mn-TWA). The high-exposure group included participants with Mn-TWA greater than 0.15 mg/m3. The low-exposure group included participants with Mn-TWA less than or equal to 0.15 mg/m3. Mn-TWA levels and dyslipidaemia were assessed. RESULTS: After adjustment for seniority, sex, cigarette consumption, alcohol consumption, high-fat diet frequency, medicine intake in the past two weeks, egg intake frequency, drinking tea, WHR, and hypertension, Mn-TWA levels was negatively correlated with high triglycerides (TG) risk in workers overall (OR = 0.51; 95% CI: 0.36, 0.73; p <  0.01). The results of males and females were consistent (OR = 0.53; 95% CI: 0.34, 0.81; p <  0.01) and (OR = 0.47; 95% CI: 0.24, 0.94; p <  0.01), respectively. By performing interactions analyses of workers overall, we observed no significant interactions among confounders. Mn-TWA levels and pack-years on high TG risk (relative excess risk for the interactions (RERI = 2.29, 95% CI: - 2.07, 6.66), (RERI) = 2.98, 95% CI: - 2.30, 8.26). Similarly, smoking status, drinking status, high-fat diet frequency, and Waist-to-Hip Ratio (WHR) showed non-significant interactions with Mn-TWA levels on high TG risk. CONCLUSIONS: This research indicates that high Mn exposure was negatively related to high TG risk in workers.

Occupational exposure to manganese and risk of creatine kinase and creatine kinase-MB elevation among ferromanganese refinery workers.

BACKGROUND: Elevated exposure to manganese (Mn) could induce cardiovascular dysfunction. However, limited research is available on the effects of occupational Mn exposure on myocardial enzymes. We aimed to evaluate the relationships between Mn exposure and myocardial enzyme elevation among Mn-exposed workers. METHODS: Data were from a follow-up investigation of a Mn-exposed workers healthy cohort in 2017. A total of 744 workers were divided into low-exposure and high-exposure groups according to Mn time-weighted average (Mn-TWA) of less than or equal to 0.15 mg/m3 or greater than 0.15 mg/m3 , respectively. Serum levels of myocardial enzymes, including creatine kinase (CK) and creatine kinase-MB (CK-MB), lactic dehydrogenase, α-hydroxybutyrate dehydrogenase, and aspartate transaminase, were assessed, as well as airborne Mn exposure levels. RESULTS: After adjustment for sex, body mass index, seniority, education, current smoking status, current drinking status, and hypertension, Mn-TWA levels were positively associated with the risk of CK elevation (odds ratio [OR] = 1.47 (95% confidence interval [CI]: 1.18-1.83) per interquartile range [IQR] increase), and risk of CK-MB elevation [OR = 1.57 (95% CI: 1.03-2.38) per IQR increase]. In a stratified analysis, Mn-TWA levels were positively correlated with CK elevation in workers of seniority greater than 19 years, male workers, current smokers, and drinkers. CONCLUSION: Our results suggest that occupational exposure to Mn is associated with increased risk of CK and CK-MB elevation. The potential mechanisms of the associations between airborne exposure to Mn and increased risk of these myocardial enzyme elevations warrant further investigation.

Non-linear association of serum molybdenum and linear association of serum zinc with nonalcoholic fatty liver disease: Multiple-exposure and Mendelian randomization approach.

The homeostasis imbalance of metals is closely associated with nonalcoholic fatty liver disease (NAFLD). A total of 1594 and 566 Chinese Han men were enrolled in cross-sectional and longitudinal analyses, respectively. We measured the serum concentrations of 22 metals by ICP-MS. The traditional and the LASSO regression methods were used to construct multiple-metals models, respectively. We performed Mendelian randomization (MR) analysis to confirm the causal relationship between NAFLD and metals using three NAFLD-related SNPs as instrumental variable. After adjustment in the six-metal model, only depressed molybdenum and elevated zinc were associated with a higher NAFLD risk, in both cross-sectional and longitudinal analyses. In the twelve-metal model, similar results were still observed. Moreover, dose-response relationships were non-linear for molybdenum and positively linear for zinc with NAFLD risk. In MR analysis, no causal associations were found from NAFLD to molybdenum and zinc. Our results support that serum molybdenum levels were non-linearly associated with NAFLD risk in Chinese men, whereas serum zinc levels showed a positively linear association. Moreover, MR analysis indicated the changes in serum molybdenum and zinc levels might be not caused by NAFLD, further confirmed our findings in cross-sectional and longitudinal analyses.

Associations between manganese exposure and multiple immunological parameters in manganese-exposed workers healthy cohort.

BACKGROUND: Manganese (Mn) ions play a crucial role in the immune response. The immunotoxicity of Mn is rarely reported compared with the neurotoxicity of Mn. OBJECTIVES: The purpose of this study was to investigate the associations between chronic Mn exposure and immunological parameters in occupational Mn-exposed workers. METHODS: A total of 538 workers were selected from the follow-up of manganese-exposed workers healthy cohort (MEWHC) in 2017. We divided the workers into the low-exposure group and the high-exposure group by the cutoff of the manganese-time weighted average (Mn-TWA) setting at 0.15 mg/m3. We examined serum immunological parameters by the immunoturbidimetric method and leukocyte counts and ratios in blood routine. Then we used the generalized linear model analyses and spline analyses to explore the associations between external exposure of Mn and multiple immunological parameters adjusted for variables. Based on the epidemiological analyses, we used Elisa (enzyme-linked immune sorbent assay) to detect plasma complement C3 of Mn-exposed rats. RESULTS: In male workers, the mean value of complement C3 was 1.20 ±â€¯0.16 g/L in the high-exposure group, which was significantly lower as compared to the low-exposure group (1.25 ±â€¯0.18 g/L, P = 0.023). The generalize linear models' analyses showed that complement C3 value had a significantly negative association with external exposure of Mn included adjustment for variables (ß = -0.04, P = 0.035). Moreover, in male rats, the high-exposure group also had a lower level of complement C3 compared with the low-exposure group (P < 0.001). None significant association was observed in immunological parameters among female workers and rats (all P > 0.05). CONCLUSIONS: Mn exposure from inhalable dust was associated with decreased complement C3 among occupationally Mn-exposed male individuals but not in female workers, which was further confirmed by the rat model. Further research into the possible mechanism of C3 reduction is needed in the future.

Plasma metals and serum bilirubin levels in workers from manganese-exposed workers healthy cohort (MEWHC).

Few studies specifically address the possible associations between multiple-metal exposures and liver damage among the occupational population. This study aimed to explore the cross-sectional relationships of plasma metals with liver function parameters. For 571 on-the-spot workers in the manganese-exposed workers healthy cohort (MEWHC), we determined liver function parameters: total bilirubin (TBILI), direct bilirubin (DBILI), indirect bilirubin (IBILI), alanine transaminase (ALT) and aspartate transaminase (AST). Total concentrations of 22 plasma metals were measured by ICP-MS. The LASSO (least absolute shrinkage and selection operator) penalized regression model was applied for selecting plasma metals independently associated with liver function parameters. Multiple linear regression analyses and restricted cubic spline (RCS) were utilized for identifying the exposure-response relationship of plasma metals with liver function parameters. After adjusting for covariates and selected metals, a 1-SD increase in log-10 transformed levels of iron was associated with increases in the levels of TBILI, DBILI and IBILI by 20.3%, 12.1% and 23.7%, respectively; similar increases in molybdenum for decreases in levels of TBILI, DBILI and IBILI by 6.1%, 2.6% and 8.3%, respectively. The effect of a 1-SD increase in plasma copper corresponded decreases of 3.2%, 3.4% and 5.0% in TBILI, AST and ALT levels, respectively. The spline analyses further clarified the non-linear relationships between plasma iron and bilirubin whilst negative linear relationships for plasma molybdenum and bilirubin. Plasma iron was positively whilst plasma molybdenum was negatively associated with increased serum bilirubin levels. Further studies are needed to validate these associations and uncover the underlying mechanisms.

The association between serum iron status and risk of asthma: a 2-sample Mendelian randomization study in descendants of Europeans.

BACKGROUND: Observational studies present conflicting results about a possible association of iron status with asthma risk, pointing to potential modifiable targets for prevention. OBJECTIVE: The aim of this study was to use Mendelian randomization (MR) to estimate associations between iron status and asthma risk. METHODS: We used the Genetics of Iron Status consortium to identify genetic variants that could be used as instrumental variables for the effect of systemic iron status. The following sets of instruments were used: a conservative set (instruments restricted to variants with concordant relations to 4 iron status biomarkers) and a liberal set (instruments selected using variants associated with at least 1 of 4 iron status biomarkers). Associations of these genetic variants with asthma risk were estimated in data from the Trans-National Asthma Genetics Consortium (TAGC) and the GABRIEL consortium (A Multidisciplinary Study to Identify the Genetic and Environmental Causes of Asthma in the European Community). Data on the association of genetic variants with iron status and with asthma were combined to assess the influence of iron status on asthma risk. RESULTS: In the conservative approach, the MR OR of asthma was 1.00 (95% CI: 0.91, 1.10) per SD increase in iron, 0.96 (95% CI: 0.78, 1.18) in log-transformed ferritin, 0.99 (95% CI: 0.93, 1.06) in transferrin saturation, and 1.03 (95% CI: 0.93, 1.14) in transferrin in the TAGC dataset (none of the values were statistically significant). An age at onset-stratified analysis in the GABRIEL dataset suggested no effect of iron status in childhood onset, later onset, or unknown age at onset asthma. Findings from the liberal approach were similar, and the results persisted in sensitivity analyses (all P > 0.05). CONCLUSIONS: This MR study does not provide evidence of an effect of iron status on asthma, suggesting that efforts to change iron concentrations will probably not result in decreased risk of asthma.

Associations between multiple serum metal exposures and low birth weight infants in Chinese pregnant women: A nested case-control study.

To investigate the associations between prenatal exposure to single metal and multiple metals and the risk of low birth weight (LBW), we conducted a nested case-control study of 246 LBW and 406 NBW mother-infant pairs based on a prospective birth cohort study. 22 serum metals were detected by inductively coupled plasma quadruple mass spectrometry (ICP-MS). Categorical analyses showed serum Co and Ti were associated with LBW (Co: 3rd vs 4th. quartile: OR = 1.83, 95%CI: 1.14-2.92, Ptrend = 0.043; Ti: 2nd vs. 4th quartile: OR = 0.51, 95% CI: 0.32-0.81, P trend = 0.051), especially gestational age >13 weeks (Co: 3rd vs. 4th quartile: OR = 1.94, 95% CI: 1.13 - 3.32, Ptrend = 0.043; Ti: 2nd vs. 4th quartile: OR = 0.50, 95% CI: 0.30 - 0.84, P trend= 0.073). Cubic spline analyses showed serum Co and serum Ti had non-linearity associations with LBW (Co: P for overall = 0.048, P-nonlinearity = 0.014; Ti: P for overall = 0.015, P- nonlinearity = 0.008). In multi-metal compound exposure model, 15 metals selected by elastic net model were significantly associated with the increased risk of LBW and OR (95%CI) was 5.14 (2.81-9.40). Our study suggested that lower level serum Co was positively associated with LBW and lower level serum Ti was negatively associated with LBW, especially gestational age >13 weeks, and both of them had non-linearity dose-relationships with LBW. And multi-metal compound model was significantly associated with LBW compared with single metal model.