Cross-sectional and Longitudinal Associations Between Metal Mixtures and Serum C3, C4: Result from the Manganese‑exposed 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.