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.

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.

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.

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.