Cross-sectional and Longitudinal Associations Between Metal Mixtures and Serum C3, C4: Result from the Manganese­exposed Workers Healthy Cohort.

Exposure to metal mixtures compromises the immune system, with the complement system connecting innate and adaptive immunity. Herein, we sought to explore the relationships between blood cell metal mixtures and the third and fourth components of serum complement (C3, C4). A total of 538 participants were recruited in November 2017, and 289 participants were followed up in November 2021. We conducted a cross-sectional analysis at baseline and a longitudinal analysis over 4 years. Least Absolute Shrinkage and Selection Operator (LASSO) was employed to identify the primary metals related to serum C3, C4; generalized linear model (GLM) was further used to evaluate the cross-sectional associations of the selected metals and serum C3, C4. Furthermore, participants were categorized into three groups according to the percentage change in metal concentrations over 4 years. GLM was performed to assess the associations between changes in metal concentrations and changes in serum C3, C4 levels. At baseline, each 1-unit increase in log10-transformed in magnesium, manganese, copper, rubidium, and lead was significantly associated with a change in serum C3 of 0.226 (95% CI: 0.146, 0.307), 0.055 (95% CI: 0.022, 0.088), 0.113 (95% CI: 0.019, 0.206), - 0.173 (95% CI: - 0.262, - 0.083), and - 0.020 (95% CI: - 0.039, - 0.001), respectively. Longitudinally, decreased copper concentrations were negatively associated with an increment in serum C3 levels, while decreased lead concentrations were positively associated with an increment in serum C3 levels. However, no metal was found to be primarily associated with serum C4 in LASSO, so we did not further explore the relationship between them. Our research indicates that copper and lead may affect complement system homeostasis by influencing serum C3 levels. Further investigation is necessary to elucidate the underlying mechanisms.

Associations of metal mixtures with thyroid function and potential interactions with iodine status: results from a cross-sectional study in MEWHC.

Few studies are available on associations between metal mixture exposures and disrupted thyroid hormone homeostasis; particularly, the role of iodine status was ignored. Here, we aimed to explore the cross-sectional relationship of blood cell metals with thyroid homeostasis and explore the potential modifying effect of iodine status. Among 328 workers from the manganese-exposed workers healthy cohort (MEWHC), we detected thyroid function parameters: thyroid stimulating hormone (TSH), total triiodothyronine (TT3), free triiodothyronine (FT3), total tetraiodothyronine (TT4), free tetraiodothyronine (FT4) as well as calculated sum activity of peripheral deiodinases (GD) and thyroid's secretory capacity (GT). Inductively coupled plasma mass spectrometry (ICP-MS) was used to measure 22 metal concentrations in blood cells. Based on the consistent results of least absolute shrinkage and selection operator (LASSO) and Bayesian kernel machine regression (BKMR) analyses, there were significant positive associations between copper and TSH (ß = 2.016), iron and FT4 (ß = 0.403), titanium and GD (ß = 0.142), nickel and GD (ß = 0.057), and negative associations between copper and FT4 (ß = - 0.226), selenium and GD (ß = - 0.332), among the participants. Interestingly, we observed an inverted-U shape relationship between magnesium and FT4. Furthermore, we found a synergistic effect between arsenic and copper on the TSH level, while antagonistic effects between nickel and copper as well as nickel and selenium on the TSH level. We observed a modified effect of iodine status on association between strontium and GD (Pinteraction = 0.026). It suggests metal mixture exposures can alter thyroid homeostasis among the occupational population, and deiodinase activity had a modified effect on association between strontium and GD. Validation of these associations and elucidation of underlying mechanisms require further researches in the future.

Zinc homeostasis may reverse the synergistic neurotoxicity of heavy metal mixtures in Caenorhabditis elegans.

Heavy metal mixtures can cause nerve damage. However, the combined effects of metal mixtures are extremely complex and rarely studied. Zinc (Zn) homeostasis plays an integral role in neural function, but the role of Zn homeostasis in the toxicity of metal mixtures is not well understood. Here, we investigated the combined effects of manganese (Mn), lead (Pb) and arsenic (As) on nerves and the effect of Zn homeostasis on metal toxicity. Caenorhabditis elegans (Maupas, 1900) were exposed to single and multiple metals for 8 days, their movement, behavior, neurons and metal concentration were detected to evaluate the combined effect of metal mixtures. After nematodes were co-treated with metal mixtures and Zn, the nerve function, Zn concentration and redox balance were detected to evaluate the effect of Zn homeostasis on metal toxicity. The results showed that Mn + Pb and Pb + As mixtures induced synergistic toxicity for nematode nerves, which damaged movement, behavior and neurons, and decreased Zn concentration. While Zn supplementation recovered Zn homeostasis and promoted redox balance on nematodes, and then improved the nerve function. Our study demonstrated the combined effects of metal mixtures and the neuroprotective effect of Zn homeostasis. Therefore, assessment of metal mixtures toxicity should consider their interaction and the impacts of essential metals homeostasis.

Relationship of multiple metals mixture and osteoporosis in older Chinese women: An aging and longevity study.

Osteoporosis has become a major health problem in older women. Previous studies have linked individual metals exposure with osteoporosis, but combined effects remain inconclusive. We aimed to explore the individual and combined association between multiple metals mixture and osteoporosis risk in older Chinese women. A total of 2297 older women (aged ≥60) from the Hongshuihe region of Guangxi, southern China included. We measured 22 blood metal levels through inductively coupled plasma mass spectrometry. And osteoporosis was defined as a T score ≤ -2.5. The least absolute shrinkage and selection operator (LASSO) penalized regression, and Bayesian kernel machine regression (BKMR) models were performed to explore the association between blood metals and osteoporosis risk. Of 2297 older women, there were 829 osteoporosis and 1468 non-osteoporosis participants. The median age was 71 and 68 years old in the osteoporosis and the non-osteoporosis group, respectively. In the single-metal model, rubidium and vanadium were negatively associated with osteoporosis (P for trend = 0.02 and 0.002, respectively), and lead presented the reverse trend (P for trend = 0.01). The LASSO penalized regression model selected nine metals (calcium, cadmium, cobalt, lead, magnesium, rubidium, strontium, vanadium and zinc), which were included in the subsequent analysis. And the multiple-metal model presented a consistent trend with the single-metal model using the selected metals. Furthermore, we performed BKMR to explore the combined effect, and found an overall negative effect between metals mixture and osteoporosis risk when all the metals were fixed at 50th, and rubidium and vanadium were the main contributors. In addition, blood Rb and V were significantly negatively related to OP risk with other metals at different levels (25th, 50th and 75th percentiles). The study suggests metal mixture exposure and osteoporosis risk in older Chinese women, and further studies need to be conducted.

Metal mixtures with longitudinal changes in lipid profiles: findings from the manganese-exposed workers healthy cohort.

The majority of epidemiological investigations on metal exposures and lipid metabolism employed cross-sectional designs and focused on individual metal. We explored the associations between metal mixture exposures and longitudinal changes in lipid profiles and potential sexual heterogeneity. We recruited 250 men and 73 women, aged 40 years at baseline (2012), and followed them up in 2020, from the manganese-exposed workers healthy cohort. We detected metal concentrations of blood cells at baseline with inductively coupled plasma mass spectrometry. Lipid profiles were repeatedly measured over 8 years of follow-up. We performed sparse partial least squares (sPLS) model to evaluate multi-pollutant associations. Bayesian kernel machine regression was utilized for metal mixtures as well as evaluating their joint impacts on lipid changes. In sPLS models, a positive association was found between manganese and change in total cholesterol (TC) (beta = 0.169), while a negative association was observed between cobalt (beta = - 0.134) and change in low density lipoprotein cholesterol (LDL-C) (beta = - 0.178) among overall participants, which were consistent in men. Interestingly, rubidium was positively associated with change in LDL-C (beta = 0.273) in women, while copper was negatively associated with change in TC (beta = - 0.359) and LDL-C (beta = - 0.267). Magnesium was negatively associated with change in TC (beta = - 0.327). We did not observe the significantly cumulative effect of metal mixtures on lipid changes. In comparison to other metals, manganese had a more significant influence on lipid change [group PIP (0.579) and conditional PIP (0.556) for TC change in men]. Furthermore, male rats exposed to manganese (20 mg/kg) had higher levels of LDL-C in plasma and more apparent inflammatory infiltration, vacuolation of liver cells, nuclear pyknosis, and fatty change than the controls. These findings highlight the potential role of metal mixtures in lipid metabolism with sex-dependent heterogeneity. More researches are needed to explore the underlying mechanisms.

Genome-wide association and Mendelian randomization study of blood copper levels and 213 deep phenotypes in humans.

Metal elements are present in the human body, and their levels in the blood have important impacts on health. In this study, 2488 Chinese individuals were included in a genome-wide association study of 21 serum metal levels, with approximately 179,000 East Asian individuals in a bidirectional two-sample Mendelian randomization (MR) analysis, and 628,000 Europeans in a two-sample MR analysis. We identified two single nucleotide polymorphisms (SNPs) rs35691438 and rs671 that were significantly associated with serum copper levels (SCLs). The bidirectional two-sample MR analysis in the East Asian population showed that gamma-glutamyl transpeptidase levels have a causal effect on SCLs. SCLs have causal effects on six outcomes, namely risks of esophageal varix, glaucoma, sleep apnea syndrome, and systemic lupus erythematosus, white blood cell count, and usage of drugs affecting bone structure and mineralization. The two-sample MR analyses in the European population showed causal effects of erythrocyte copper levels on risks of carpal tunnel syndrome and compression fracture. Our results provide original insights into the causal relationship between blood metal levels and multiple human phenotypes.

Causal relationships between blood calcium, iron, magnesium, zinc, selenium, phosphorus, copper, and lead levels and multisystem disease outcomes in over 400,000 Caucasian participants.

BACKGROUND & AIMS: Metal elements have been associated with a wide range of clinical outcomes. The available epidemiological evidence for these associations is often inconsistent and suffers from confounding and reverse causation. We aimed to explore the broad clinical effects of varying blood metal element levels and possible underlying mechanisms. METHODS: We performed a two-sample Mendelian randomization (MR) analysis by using metal element-associated genetic loci as instrumental variable to evaluate the causal associations between blood metal element levels and 1050 disease outcomes in a UK Biobank cohort. A total of 408,910 White British participants were enrolled in the analysis. We further used the metal element-related genes and disease-related genes to construct a protein-protein interaction (PPI) network. RESULTS: Eight metal elements were associated with 63 diseases in total. Notably, we found nine pairs of suggestive evidence between two different metal elements for the same disease. Selenium and lead share some of the associated clinical outcomes, including diabetes mellitus, type 2 diabetes, lymphoid leukemia, and acute pharyngitis. Lead and zinc share the associated disease of acquired hypothyroidism. Iron and copper share the associated disease of arthropathies. Copper and zinc share the associated disease of occlusion of cerebral arteries. Calcium and zinc share the associated disease of arthropathies. In addition, the PPI network provided potential links between metal elements and disease outcomes at the genetic level. CONCLUSIONS: Our MR study of eight metal elements comprehensively characterized their shared and unique clinical effects, highlighting their potential causal roles in multiple diseases. Given the modifiable nature of blood metal elements and the potential for clinical interventions, these findings warrant further investigation.

Causal Effect of Genetically Determined Blood Copper Concentrations on Multiple Diseases: A Mendelian Randomization and Phenome-Wide Association Study.

Exposures to copper have become a health concern. We aim to explore the broad clinical effects of blood copper concentrations. A total of 376,346 Caucasian subjects were enrolled. We performed a Mendelian randomization and phenome-wide association study (MR-PheWAS) to evaluate the causal association between copper and a wide range of outcomes in UK Biobank, and we constructed a protein-protein interaction network. We found association between blood copper concentrations and five diseases in the overall population and nine diseases in male. MR analysis implicated a causal role of blood copper in five diseases (overall population), including prostate cancer (OR = 0.87, 95% CI 0.77-0.98), malignant and unknown neoplasms of the brain and nervous system (OR = 0.58, 95% CI 0.38-0.89), and hypertension (OR = 0.94, 95% CI 0.90-0.98), essential hypertension (OR = 0.94, 95% CI 0.90-0.98) and cancer of brain and nervous system (OR = 0.63, 95% CI 0.41-0.98). For male, except for dysphagia being newly associated with blood copper (OR = 1.39, 95% CI 1.18-1.63), other MR results were consistent with the overall population. In addition, the PPI network showed possible relationship between blood copper and four outcomes, namely brain cancer, prostate cancer, hypertension, and dysphagia. Blood copper may have causal association with prostate cancer, malignant and unknown neoplasms of the brain and nervous system, hypertension, and dysphagia. Considering that copper is modifiable, exploring whether regulation of copper levels can be used to optimize health outcomes might have public health importance. Supplementary Information: The online version contains supplementary material available at 10.1007/s43657-022-00052-3.

Sex-specific associations of exposure to metal mixtures with telomere length change: Results from an 8-year longitudinal study.

Studies on the relationships between exposure to metal mixtures and telomere length (TL) are limited, particularly longitudinal studies. Few studies are available on the potential sex-specific associations between metal exposures and TL change. We examined blood metal concentrations and TL at baseline (August 2012) and follow-up (June 2020) among 316 participants in a ferro-manganese refinery. The least absolute shrinkage and selection operator (LASSO) followed by the generalized linear model (GLM) was applied to evaluate the associations between multiple-metal exposures and TL change (TL in 2012 minus TL in 2020). Bayesian kernel machine regression (BKMR) was applied to cope with metal mixtures and evaluate their joint effects on TL change. Among men, three statistical methods consistently showed rubidium was negatively associated with TL change (ß [95% CI] = -2.755 [-5.119, -0.391] in the GLM) and dominated the negative overall effects of 10 metal mixtures (magnesium, manganese, iron, cobalt, copper, zinc, selenium, rubidium, cadmium, and lead) on TL change (posterior inclusion probabilities = 0.816). Among women, the GLM (ß [95% CI] = 4.463 [0.943, 7.983]) and LASSO (ß = 4.289) showed rubidium was positively associated with TL change. Interestingly, no significant association was observed between exposure to metal mixtures and TL change in overall participants (P > 0.05). Furthermore, stratified analysis showed significant relationships between rubidium and TL change in men (ß = -2.744), women (ß = 3.624), and current smokers (ß = -3.266) (both P interaction <0.05). In summary, our findings underlined the steady and negative association between rubidium and TL change among men with potential sex-dependent heterogeneities. Further experimental studies are required to expound the underlying mechanisms.

MR-PheWAS for the causal effects of serum magnesium on multiple disease outcomes in Caucasian descent.

Magnesium is integral to many physiological processes, whereas variations in its levels, even within the normal range, can have critical implications for health. To explore the broad clinical effects of varying serum magnesium levels, we performed a two-sample Mendelian randomization and phenome-wide association study (MR-PheWAS) in the UK Biobank cohort. In total, MR-PheWAS analysis implicated a causal role of serum magnesium levels in five disease groups and six disease outcomes. In addition, our study indicated the gender-specific effects of nine disease groups/outcomes in MR estimated effects. The protein-protein interaction network demonstrated an interaction between the serum magnesium-associated gene DCDC1 and the cataract- associated gene PAX6. The present study verified several previously reported disease outcomes and identified novel potential disease outcomes for serum magnesium levels. The DCDC1 gene and the PAX6 gene may be the new targets for promoting the treatments of cataracts using magnesium intervention.

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.

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.

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.

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.

Association between long-term occupational manganese exposure and bone quality among retired workers.

Despite well documents for manganese-induced neurological deficits, limited researches are available for effects of manganese (Mn) exposure on the bone. Here we aimed to explore the associations between long-term occupational Mn exposure and bone quality among retired workers. We conducted a cross-sectional study of 304 exposed subjects (n, male = 161 and female = 143) and 277 control retired workers (n, male = 65 and female = 212) recruited from a ferromanganese refinery. Self-reported occupation types were used as exposure classification confirmed by expert consultation. Bone quality was measured by quantitative ultrasound (QUS). In sex-stratified analyses throughout, stiffness index (SI) and T-score levels of the participants in the highest exposed group [tertile 3 of Mn cumulative exposure index (Mn-CEI)] were significantly lower as compared with the control group among female workers (SI, mean, 61.60 vs. 68.17; T-score, mean, -3.01 vs. -2.34, both P < 0.05). In addition, SI and T-score were found to be negatively associated with Mn-CEI only in the highest exposure group as compared with the female controls (both P = 0.01). However, we did not find the significant difference for SI or T-score among the male subjects in exposure models and the male controls (P > 0.05). Our results suggest that female retired workers in the highest Mn-exposed model (tertile 3 of Mn-CEI) potentially experience a higher risk of developing osteoporosis compared with the female controls. Further investigations on possible mechanisms on bone quality alteration are needed in the future.

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.