Abstract
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.
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References
Su F, Zeeshan M, Xiong LH, Lv JY, Wu Y, Tang XJ et al (2022) Co-exposure to perfluoroalkyl acids and heavy metals mixtures associated with impaired kidney function in adults: a community-based population study in China. Sci Total Environ 839:156299. https://doi.org/10.1016/j.scitotenv.2022.156299
Park SJ, Lee JH, Woo SJ, Kang SW, Park KH (2015) Five heavy metallic elements and age-related macular degeneration: Korean National Health and Nutrition Examination Survey, 2008–2011. Ophthalmology 122(1):129–137. https://doi.org/10.1016/j.ophtha.2014.07.039
Renu K, Chakraborty R, Myakala H, Koti R, Famurewa AC, Madhyastha H et al (2021) Molecular mechanism of heavy metals (lead, chromium, arsenic, mercury, nickel and cadmium) - induced hepatotoxicity - a review. Chemosphere 271:129735. https://doi.org/10.1016/j.chemosphere.2021.129735
Wen Y, Huang S, Zhang Y, Zhang H, Zhou L, Li D et al (2019) Associations of multiple plasma metals with the risk of ischemic stroke: a case-control study. Environ Int 125:125–134. https://doi.org/10.1016/j.envint.2018.12.037
Wang C, Zhang R, Wei X, Lv M, Jiang Z (2020) Metalloimmunology: the metal ion-controlled immunity. Adv Immunol 145:187–241. https://doi.org/10.1016/bs.ai.2019.11.007
Murdoch CC, Skaar EP (2022) Nutritional immunity: the battle for nutrient metals at the host-pathogen interface. Nat Rev Microbiol 20(11):657–670. https://doi.org/10.1038/s41579-022-00745-6
Suzuki T, Hidaka T, Kumagai Y, Yamamoto M (2020) Environmental pollutants and the immune response. Nat Immunol 21(12):1486–1495. https://doi.org/10.1038/s41590-020-0802-6
Ganguly K, Levanen B, Palmberg L, Akesson A, Linden A (2018) Cadmium in tobacco smokers: a neglected link to lung disease? Eur Respir Rev 27(147). https://doi.org/10.1183/16000617.0122-2017
Eggers S, Safdar N, Malecki KM (2018) Heavy metal exposure and nasal Staphylococcus aureus colonization: analysis of the National Health and Nutrition Examination Survey (NHANES). Environ Health 17(1):2. https://doi.org/10.1186/s12940-017-0349-7
Wang X, Bin W, Zhou M, Xiao L, Xu T, Yang S et al (2021) Systemic inflammation mediates the association of heavy metal exposures with liver injury: a study in general Chinese urban adults. J Hazard Mater 419:126497. https://doi.org/10.1016/j.jhazmat.2021.126497
Zhong Q, Wu HB, Niu QS, Jia PP, Qin QR, Wang XD et al (2021) Exposure to multiple metals and the risk of hypertension in adults: a prospective cohort study in a local area on the Yangtze River. China Environ Int 153:106538. https://doi.org/10.1016/j.envint.2021.106538
Ricklin D, Hajishengallis G, Yang K, Lambris JD (2010) Complement: a key system for immune surveillance and homeostasis. Nat Immunol 11(9):785–797. https://doi.org/10.1038/ni.1923
Ricklin D, Reis ES, Lambris JD (2016) Complement in disease: a defence system turning offensive. Nat Rev Nephrol 12(7):383–401. https://doi.org/10.1038/nrneph.2016.70
Conigliaro P, Triggianese P, Ballanti E, Perricone C, Perricone R, Chimenti MS (2019) Complement, infection, and autoimmunity. Curr Opin Rheumatol 31(5):532–541. https://doi.org/10.1097/BOR.0000000000000633
Yang X, Sun J, Gao Y, Tan A, Zhang H, Hu Y et al (2012) Genome-wide association study for serum complement C3 and C4 levels in healthy Chinese subjects. PLoS Genet 8(9):e1002916. https://doi.org/10.1371/journal.pgen.1002916
Reis ES, Mastellos DC, Hajishengallis G, Lambris JD (2019) New insights into the immune functions of complement. Nat Rev Immunol 19(8):503–516. https://doi.org/10.1038/s41577-019-0168-x
Li L, Huang L, Yang A, Feng X, Mo Z, Zhang H et al (2021) Causal relationship between complement C3, C4, and nonalcoholic fatty liver disease: bidirectional mendelian randomization analysis. Phenomics 1(5):211–221. https://doi.org/10.1007/s43657-021-00023-0
Jiang J, Wang H, Liu K, He S, Li Z, Yuan Y et al (2023) Association of complement C3 with incident type 2 diabetes and the mediating role of BMI: a 10-year follow-up study. J Clin Endocrinol Metab 108(3):736–744. https://doi.org/10.1210/clinem/dgac586
Wang H, Liu M (2021) Complement C4, infections, and autoimmune diseases. Front Immunol 12:694928. https://doi.org/10.3389/fimmu.2021.694928
Yammani RD, Leyva MA, Jennings RN, Haas KM (2014) C4 Deficiency is a predisposing factor for Streptococcus pneumoniae-induced autoantibody production. J Immunol 193(11):5434–5443. https://doi.org/10.4049/jimmunol.1401462
Acevedo F, Vesterberg O (2003) Nickel and cobalt activate complement factor C3 faster than magnesium. Toxicology 185(1–2):9–16. https://doi.org/10.1016/s0300-483x(02)00590-5
Jiang J, He S, Liu K, Yu K, Long P, Xiao Y et al (2022) Multiple plasma metals, genetic risk and serum complement C3, C4: a gene-metal interaction study. Chemosphere 291(Pt 1):132801. https://doi.org/10.1016/j.chemosphere.2021.132801
Li G, Liang L, Yang J, Zeng L, Xie Z, Zhong Y et al (2018) Pulmonary hypofunction due to calcium carbonate nanomaterial exposure in occupational workers: a cross-sectional study. Nanotoxicology 12(6):571–585. https://doi.org/10.1080/17435390.2018.1465606
Hu G, Long C, Hu L, Zhang Y, Hong S, Zhang Q et al (2022) Blood chromium exposure, immune inflammation and genetic damage: exploring associations and mediation effects in chromate exposed population. J Hazard Mater 425:127769. https://doi.org/10.1016/j.jhazmat.2021.127769
Li Y, Song D, Song Y, Zhao L, Wolkow N, Tobias JW et al (2015) Iron-induced local complement component 3 (C3) up-regulation via non-canonical transforming growth factor (TGF)-beta signaling in the retinal pigment epithelium. J Biol Chem 290(19):11918–11934. https://doi.org/10.1074/jbc.M115.645903
Puchau B, Zulet MA, Gonzalez de Echavarri A, Navarro-Blasco I, Martinez JA (2009) Selenium intake reduces serum C3, an early marker of metabolic syndrome manifestations, in healthy young adults. Eur J Clin Nutr 63(7):858–864. https://doi.org/10.1038/ejcn.2008.48
Wen B, Jin SR, Chen ZZ, Gao JZ, Liu YN, Liu JH et al (2018) Single and combined effects of microplastics and cadmium on the cadmium accumulation, antioxidant defence and innate immunity of the discus fish (Symphysodon aequifasciatus). Environ Pollut 243(Pt A):462–471. https://doi.org/10.1016/j.envpol.2018.09.029
Başaran N, Undeğer U (2000) Effects of lead on immune parameters in occupationally exposed workers. Am J Ind Med 38(3):349–354
Jannetto PJ, Cowl CT (2023) Elementary overview of heavy metals. Clin Chem 69(4):336–349. https://doi.org/10.1093/clinchem/hvad022
Lv Y, Zou Y, Liu J, Chen K, Huang D, Shen Y et al (2014) Rationale, design and baseline results of the Guangxi manganese-exposed workers healthy cohort (GXMEWHC) study. BMJ Open 4(7):e005070. https://doi.org/10.1136/bmjopen-2014-005070
Zhou Y, Ge X, Shen Y, Qin L, Zhong Y, Jiang C et al (2018) Follow-up of the manganese-exposed workers healthy cohort (MEWHC) and biobank management from 2011 to 2017 in China. BMC Public Health 18(1):944. https://doi.org/10.1186/s12889-018-5880-0
Bao Y, Ge X, Li L, He J, Huang S, Luo X et al (2021) The impacts of different anticoagulants and long-term frozen storage on multiple metal concentrations in peripheral blood: a comparative study. Biometals 34(5):1191–1205. https://doi.org/10.1007/s10534-021-00336-7
He J, Ge X, Cheng H, Bao Y, Feng X, Zan G et al (2022) Sex-specific associations of exposure to metal mixtures with telomere length change: results from an 8-year longitudinal study. Sci Total Environ 811:151327. https://doi.org/10.1016/j.scitotenv.2021.151327
Tibshirani R (1996) Regression shrinkage and selection via the lasso. J Roy Stat Soc: Ser B (Methodol) 58(1):267–288. https://doi.org/10.1111/j.2517-6161.1996.tb02080.x
Liu J, Tao L, Zhao Z, Mu Y, Zou D, Zhang J et al (2018) Two-year changes in hyperuricemia and risk of diabetes: a five-year prospective cohort study. J Diabetes Res 2018:6905720. https://doi.org/10.1155/2018/6905720
Beasley TM, Allison EDB (2009) Rank-Based Inverse Normal Transformations are Increasingly Used, But are They Merited? Behav Genet 39:580–595. https://doi.org/10.1007/s10519-009-9281-0
Feng X, Yang W, Huang L, Cheng H, Ge X, Zan G et al (2022) Causal effect of genetically determined blood copper concentrations on multiple diseases: a mendelian randomization and phenome-wide association study. Phenomics 2(4):242–253. https://doi.org/10.1007/s43657-022-00052-3
Percival SS (1998) Copper and immunity. Am J Clin Nutr 67(5 Suppl):1064s–1068s. https://doi.org/10.1093/ajcn/67.5.1064S
Al-Sagheer AA, Abdel-Rahman G, Elsisi GF, Ayyat MS (2022) Comparative effects of supplementary different copper forms on performance, protein efficiency, digestibility of nutrients, immune function and architecture of liver and kidney in growing rabbits. Anim Biotechnol:1–11. https://doi.org/10.1080/10495398.2022.2084746
Wang C, Wang MQ, Ye SS, Tao WJ, Du YJ (2011) Effects of copper-loaded chitosan nanoparticles on growth and immunity in broilers. Poult Sci 90(10):2223–2228. https://doi.org/10.3382/ps.2011-01511
Lu J, Liu X, Li X, Li H, Shi L, Xia X et al (2024) Copper regulates the host innate immune response against bacterial infection via activation of ALPK1 kinase. Proc Natl Acad Sci U S A 121(4):e2311630121. https://doi.org/10.1073/pnas.2311630121
Reichhardt MP, Meri S (2018) Intracellular complement activation-an alarm raising mechanism? Semin Immunol 38:54–62. https://doi.org/10.1016/j.smim.2018.03.003
Roberts EA, Sarkar B (2008) Liver as a key organ in the supply, storage, and excretion of copper. Am J Clin Nutr 88(3):851s–854s. https://doi.org/10.1093/ajcn/88.3.851S
Li Q, Wang S, Guo P, Feng Y, Yu W, Zhang H et al (2023) Mitochondrial DNA release mediated by TFAM deficiency promotes copper-induced mitochondrial innate immune response via cGAS-STING signalling in chicken hepatocytes. Sci Total Environ 905:167315. https://doi.org/10.1016/j.scitotenv.2023.167315
Tsvetkov P, Coy S, Petrova B, Dreishpoon M, Verma A, Abdusamad M et al (2022) Copper induces cell death by targeting lipoylated TCA cycle proteins. Science 375(6586):1254–1261. https://doi.org/10.1126/science.abf0529
Kahlson MA, Dixon SJ (2022) Copper-induced cell death. Science 375(6586):1231–1232. https://doi.org/10.1126/science.abo3959
Cheng F, Peng G, Lu Y, Wang K, Ju Q, Ju Y et al (2022) Relationship between copper and immunity: the potential role of copper in tumor immunity. Front Oncol 12:1019153. https://doi.org/10.3389/fonc.2022.1019153
Liu J, Wang Y, Zhao H, Mu M, Guo M, Nie X et al (2020) Arsenic (III) or/and copper (II) exposure induce immunotoxicity through trigger oxidative stress, inflammation and immune imbalance in the bursa of chicken. Ecotoxicol Environ Saf 190:110127. https://doi.org/10.1016/j.ecoenv.2019.110127
Guo H, Wang Y, Cui H, Ouyang Y, Yang T, Liu C et al (2022) Copper induces spleen damage through modulation of oxidative stress, apoptosis, DNA damage, and inflammation. Biol Trace Elem Res 200(2):669–677. https://doi.org/10.1007/s12011-021-02672-8
Gundacker C, Forsthuber M, Szigeti T, Kakucs R, Mustieles V, Fernandez MF et al (2021) Lead (Pb) and neurodevelopment: a review on exposure and biomarkers of effect (BDNF, HDL) and susceptibility. Int J Hyg Environ Health 238:113855. https://doi.org/10.1016/j.ijheh.2021.113855
Zhang H, Yan J, Niu J, Wang H, Li X (2022) Association between lead and cadmium co-exposure and systemic immune inflammation in residents living near a mining and smelting area in NW China. Chemosphere 287(Pt 3):132190. https://doi.org/10.1016/j.chemosphere.2021.132190
Undeger U, Başaran N, Canpinar H, Kansu E (1996) Immune alterations in lead-exposed workers. Toxicology 109(2–3):167–172. https://doi.org/10.1016/0300-483x(96)03333-1
Ewers U, Stiller-Winkler R, Idel H (1982) Serum immunoglobulin, complement C3, and salivary IgA levels in lead workers. Environ Res 29(2):351–357. https://doi.org/10.1016/0013-9351(82)90036-6
Guo J, Pu Y, Zhong L, Wang K, Duan X, Chen D (2021) Lead impaired immune function and tissue integrity in yellow catfish (Peltobargus fulvidraco) by mediating oxidative stress, inflammatory response and apoptosis. Ecotoxicol Environ Saf 226:112857. https://doi.org/10.1016/j.ecoenv.2021.112857
Wang L, Zheng Y, Zhang G, Han X, Li S, Zhao H (2021) Lead exposure induced inflammation in bursa of Fabricius of Japanese quail (C. japonica) via NF-kappaB pathway activation and Wnt/beta-catenin signaling inhibition. J Inorg Biochem 224:111587. https://doi.org/10.1016/j.jinorgbio.2021.111587
Yin K, Cui Y, Sun T, Qi X, Zhang Y, Lin H (2020) Antagonistic effect of selenium on lead-induced neutrophil apoptosis in chickens via miR-16-5p targeting of PiK3R1 and IGF1R. Chemosphere 246:125794. https://doi.org/10.1016/j.chemosphere.2019.125794
Dai Y, Huo X, Zhang Y, Yang T, Li M, Xu X (2017) Elevated lead levels and changes in blood morphology and erythrocyte CR1 in preschool children from an e-waste area. Sci Total Environ 592:51–59. https://doi.org/10.1016/j.scitotenv.2017.03.080
Nanda KP, Kumari C, Dubey M, Firdaus H (2019) Chronic lead (Pb) exposure results in diminished hemocyte count and increased susceptibility to bacterial infection in Drosophila melanogaster. Chemosphere 236:124349. https://doi.org/10.1016/j.chemosphere.2019.124349
Cestonaro LV, Garcia SC, Nascimento S, Gauer B, Sauer E, Goethel G et al (2020) Biochemical, hematological and immunological parameters and relationship with occupational exposure to pesticides and metals. Environ Sci Pollut Res Int 27(23):29291–29302. https://doi.org/10.1007/s11356-020-09203-3
Agathokleous E, Kitao M, Calabrese EJ (2018) Environmental hormesis and its fundamental biological basis: rewriting the history of toxicology. Environ Res 165:274–278. https://doi.org/10.1016/j.envres.2018.04.034
Lv M, Chen M, Zhang R, Zhang W, Wang C, Zhang Y et al (2020) Manganese is critical for antitumor immune responses via cGAS-STING and improves the efficacy of clinical immunotherapy. Cell Res 30(11):966–979. https://doi.org/10.1038/s41422-020-00395-4
Babaei MJ, Fakhraei J, MansooriYarahmadi H, Gomarian M (2021) Effect of different levels of bioplex manganese along with probiotics and multi-enzymes on performance and immune system indices of broilers. Vet Med Sci 7(4):1379–1390. https://doi.org/10.1002/vms3.479
Wu Q, Mu Q, Xia Z, Min J, Wang F (2021) Manganese homeostasis at the host-pathogen interface and in the host immune system. Semin Cell Dev Biol 115:45–53. https://doi.org/10.1016/j.semcdb.2020.12.006
Chen X, Liu Z, Ge X, Luo X, Huang S, Zhou Y et al (2020) Associations between manganese exposure and multiple immunological parameters in manganese-exposed workers healthy cohort. J Trace Elem Med Biol 59:126454. https://doi.org/10.1016/j.jtemb.2020.126454
Jiang WD, Tang RJ, Liu Y, Kuang SY, Jiang J, Wu P et al (2015) Manganese deficiency or excess caused the depression of intestinal immunity, induction of inflammation and dysfunction of the intestinal physical barrier, as regulated by NF-kappaB, TOR and Nrf2 signalling, in grass carp (Ctenopharyngodon idella). Fish Shellfish Immunol 46(2):406–416. https://doi.org/10.1016/j.fsi.2015.06.007
Weyh C, Krüger K, Peeling P, Castell L (2022) The role of minerals in the optimal functioning of the immune system. Nutrients 14(3). https://doi.org/10.3390/nu14030644
Minton K (2013) Immunodeficiency: magnesium regulates antiviral immunity. Nat Rev Immunol 13(8):548–549. https://doi.org/10.1038/nri3501
Schick V, Scheiber JA, Mooren FC, Turi S, Ceyhan GO, Schnekenburger J et al (2014) Effect of magnesium supplementation and depletion on the onset and course of acute experimental pancreatitis. Gut 63(9):1469–1480. https://doi.org/10.1136/gutjnl-2012-304274
Roth A, Kornowski R, Agmon Y, Vardinon N, Sheps D, Graph E et al (1996) High-dose intravenous magnesium attenuates complement consumption after acute myocardial infarction treated by streptokinase. Eur Heart J 17(5):709–714. https://doi.org/10.1093/oxfordjournals.eurheartj.a014937
Maier JA, Castiglioni S, Locatelli L, Zocchi M, Mazur A (2021) Magnesium and inflammation: advances and perspectives. Semin Cell Dev Biol 115:37–44. https://doi.org/10.1016/j.semcdb.2020.11.002
Blankstein R, Osborne M, Naya M, Waller A, Kim CK, Murthy VL et al (2014) Cardiac positron emission tomography enhances prognostic assessments of patients with suspected cardiac sarcoidosis. J Am Coll Cardiol 63(4):329–336. https://doi.org/10.1016/j.jacc.2013.09.022
Jones JM, Yeralan O, Hines G, Maher M, Roberts DW, Benson RW (1990) Effects of lithium and rubidium on immune responses of rats. Toxicol Lett 52(2):163–168. https://doi.org/10.1016/0378-4274(90)90150-k
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We thank all participants and researchers who took part in this study.
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This work was supported by the National Natural Science Foundation of China (No. U21A20340, 82073504) and the innovation and entrepreneurship training program for college students (202310594033).
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Sencai Lin: Writing - original draft, Writing - review & editing. Junxiu He: Writing - original draft, Writing - review & editing. Yinghua Zhou: Investigation, Data curation. Yu Bao: Investigation, Data curation. Xiuming Feng: Investigation, Data curation. Hong Cheng: Investigation, Data curation. Haiqing Cai: Investigation, Data curation. Sihan Hu: Investigation, Data curation. Lin Wang: Investigation, Data curation. Yuan Zheng: Investigation, Data curation. Mengdi Zhang: Investigation, Data curation. Qinghua Fan: Investigation, Data curation. Shifeng Wen: Investigation, Data curation. Yuanxin Lin: Investigation, Data curation. Chaoqun Liu: Conceptualization. Xing Chen: Conceptualization. Fei Wang: Conceptualization. Xiaoting Ge: Writing - review & editing, Conceptualization. Xiaobo Yang: Supervision, Project administration.
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Lin, S., He, J., Zhou, Y. et al. Cross-sectional and Longitudinal Associations Between Metal Mixtures and Serum C3, C4: Result from the Manganese‑exposed Workers Healthy Cohort. Biol Trace Elem Res (2024). https://doi.org/10.1007/s12011-024-04143-2
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DOI: https://doi.org/10.1007/s12011-024-04143-2