{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,9]],"date-time":"2026-10-09T03:52:08Z","timestamp":1791517928126,"version":"4.3.4"},"reference-count":57,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2024,7,22]],"date-time":"2024-07-22T00:00:00Z","timestamp":1721606400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Public Health"],"abstract":"<jats:sec><jats:title>Introduction<\/jats:title><jats:p>Persistent infections caused by certain viruses and parasites have been associated with multiple diseases and substantial mortality. Heavy metals are ubiquitous environmental pollutants with immunosuppressive properties. This study aimed to determine whether heavy metals exposure suppress the immune system, thereby increasing the susceptibility to persistent infections.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Using data from NHANES 1999\u20132016, we explored the associations between heavy metals exposure and persistent infections: Cytomegalovirus (CMV), Epstein\u2013Barr Virus (EBV), Hepatitis C Virus (HCV), Herpes Simplex Virus Type\u20131 (HSV\u20131), <jats:italic>Toxoplasma gondii<\/jats:italic> (<jats:italic>T. gondii<\/jats:italic>), and <jats:italic>Toxocara canis<\/jats:italic> and <jats:italic>Toxocara cati<\/jats:italic> (<jats:italic>Toxocara<\/jats:italic> spp.) by performing logistic regression, weighted quantile sum (WQS) and Bayesian kernel machine regression (BKMR) models. Mediation analysis was used to determine the mediating role of host immune function in these associations.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Logistic regression analysis revealed positive associations between multiple heavy metals and the increased risk of persistent infections. In WQS models, the heavy metals mixture was associated with increased risks of several persistent infections: CMV (OR: 1.58; 95% CI: 1.17, 2.14), HCV (OR: 2.94; 95% CI: 1.68, 5.16), HSV\u20131 (OR: 1.25; 95% CI: 1.11, 1.42), <jats:italic>T. gondii<\/jats:italic> (OR: 1.97; 95% CI: 1.41, 2.76), and <jats:italic>Toxocara<\/jats:italic> spp. (OR: 1.76; 95% CI: 1.16, 2.66). BKMR models further confirmed the combined effects of heavy metals mixture and also identified the individual effect of arsenic, cadmium, and lead. On mediation analysis, the systemic immune inflammation index, which reflects the host\u2019s immune status, mediated 12.14% of the association of mixed heavy metals exposure with HSV\u20131 infection.<\/jats:p><\/jats:sec><jats:sec><jats:title>Discussion<\/jats:title><jats:p>The findings of this study revealed that heavy metals exposure may increase susceptibility to persistent infections, with the host\u2019s immune status potentially mediating this relationship. Reducing exposure to heavy metals may have preventive implications for persistent infections, and further prospective studies are needed to confirm these findings.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fpubh.2024.1367644","type":"journal-article","created":{"date-parts":[[2024,7,22]],"date-time":"2024-07-22T04:58:17Z","timestamp":1721624297000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":21,"title":["Association between heavy metals exposure and persistent infections: the mediating role of immune function"],"prefix":"10.3389","volume":"12","author":[{"given":"Huiling","family":"Zhang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juan","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kunlun","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jianyang","family":"Shi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yameng","family":"Gao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jingying","family":"Zheng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jingtong","family":"He","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jing","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yang","family":"Song","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ruifei","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xuening","family":"Shi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lina","family":"Jin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hui","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2024,7,22]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","first-page":"4103","DOI":"10.3390\/ijms21114103","article-title":"Editorial for special issue \u201cheavy metals accumulation, toxicity, and detoxification in plants\u201d","volume":"21","author":"Aprile","year":"2020","journal-title":"Int J Mol Sci"},{"key":"ref2","doi-asserted-by":"publisher","first-page":"167","DOI":"10.1093\/bmb\/ldg032","article-title":"Hazards of heavy metal contamination","volume":"68","author":"J\u00e4rup","year":"2003","journal-title":"Br Med Bull"},{"key":"ref3","doi-asserted-by":"publisher","first-page":"563","DOI":"10.1007\/s10534-019-00193-5","article-title":"Exposure routes and health effects of heavy metals on children","volume":"32","author":"Al Osman","year":"2019","journal-title":"Biometals"},{"key":"ref4","doi-asserted-by":"publisher","first-page":"206","DOI":"10.1080\/10937400902902062","article-title":"The effects of metals as endocrine disruptors","volume":"12","author":"Iavicoli","year":"2009","journal-title":"J Toxicol Environ Health B Crit Rev"},{"key":"ref5","doi-asserted-by":"publisher","first-page":"643972","DOI":"10.3389\/fphar.2021.643972","article-title":"Toxic mechanisms of five heavy metals: mercury, Lead, chromium, cadmium, and arsenic","volume":"12","author":"Balali-Mood","year":"2021","journal-title":"Front Pharmacol"},{"key":"ref6","doi-asserted-by":"publisher","first-page":"157","DOI":"10.1002\/jcb.26234","article-title":"Prevalence of exposure of heavy metals and their impact on health consequences","volume":"119","author":"Rehman","year":"2018","journal-title":"J Cell Biochem"},{"key":"ref7","doi-asserted-by":"publisher","first-page":"146654","DOI":"10.1016\/j.scitotenv.2021.146654","article-title":"Pre and postnatal exposure to mercury and respiratory health in preschool children from the Spanish INMA birth cohort study","volume":"782","author":"Carrasco","year":"2021","journal-title":"Sci Total Environ"},{"key":"ref8","doi-asserted-by":"publisher","first-page":"456","DOI":"10.1016\/j.fsi.2018.07.055","article-title":"The impact of ocean acidification and cadmium on the immune responses of Pacific oyster, Crassostrea gigas","volume":"81","author":"Cao","year":"2018","journal-title":"Fish Shellfish Immunol"},{"key":"ref9","doi-asserted-by":"publisher","first-page":"181","DOI":"10.1016\/j.taap.2012.10.009","article-title":"Prenatal cadmium exposure produces persistent changes to thymus and spleen cell phenotypic repertoire as well as the acquired immune response","volume":"265","author":"Hol\u00e1skov\u00e1","year":"2012","journal-title":"Toxicol Appl Pharmacol"},{"key":"ref10","doi-asserted-by":"publisher","first-page":"196","DOI":"10.1016\/j.taap.2012.04.002","article-title":"Prenatal cadmium exposure alters postnatal immune cell development and function","volume":"261","author":"Hanson","year":"2012","journal-title":"Toxicol Appl Pharmacol"},{"key":"ref11","doi-asserted-by":"publisher","first-page":"108794","DOI":"10.1016\/j.envres.2019.108794","article-title":"Exposure to lead and vaccine-specific IgG titers in south African children participating in the Venda health examination of mothers, babies and their environment (VHEMBE): a longitudinal study","volume":"180","author":"Di Lenardo","year":"2020","journal-title":"Environ Res"},{"key":"ref12","doi-asserted-by":"publisher","first-page":"354","DOI":"10.1016\/j.envpol.2016.09.071","article-title":"Decreased vaccine antibody titers following exposure to multiple metals and metalloids in e-waste-exposed preschool children","volume":"220","author":"Lin","year":"2017","journal-title":"Environ Pollut"},{"key":"ref13","doi-asserted-by":"publisher","first-page":"566","DOI":"10.3389\/fimmu.2017.00566","article-title":"Hepatitis C virus and human cytomegalovirus-natural killer cell subsets in persistent viral infections","volume":"8","author":"Pollmann","year":"2017","journal-title":"Front Immunol"},{"key":"ref14","doi-asserted-by":"publisher","first-page":"17096","DOI":"10.1038\/nmicrobiol.2017.96","article-title":"Toxoplasma depends on lysosomal consumption of autophagosomes for persistent infection","volume":"2","author":"Di Cristina","year":"2017","journal-title":"Nat Microbiol"},{"key":"ref15","doi-asserted-by":"publisher","first-page":"227","DOI":"10.1016\/j.coviro.2013.04.005","article-title":"The pathogenesis of Epstein-Barr virus persistent infection","volume":"3","author":"Thorley-Lawson","year":"2013","journal-title":"Curr Opin Virol"},{"key":"ref16","doi-asserted-by":"publisher","first-page":"371","DOI":"10.1007\/s00430-012-0247-0","article-title":"Herpes simplex virus type 1 induces simultaneous activation of toll-like receptors 2 and 4 and expression of the endogenous ligand serum amyloid a in astrocytes","volume":"201","author":"Villalba","year":"2012","journal-title":"Med Microbiol Immunol"},{"key":"ref17","doi-asserted-by":"publisher","first-page":"45","DOI":"10.1161\/01.cir.103.1.45","article-title":"Prospective study of pathogen burden and risk of myocardial infarction or death","volume":"103","author":"Zhu","year":"2001","journal-title":"Circulation"},{"key":"ref18","doi-asserted-by":"publisher","first-page":"97","DOI":"10.2147\/CIA.S285000","article-title":"Association between systemic immune-inflammation index and diabetic depression","volume":"16","author":"Wang","year":"2021","journal-title":"Clin Interv Aging"},{"key":"ref19","doi-asserted-by":"publisher","first-page":"20","DOI":"10.1016\/j.atherosclerosis.2021.02.012","article-title":"Systemic immune-inflammation index and incident cardiovascular diseases among middle-aged and elderly Chinese adults: the Dongfeng-Tongji cohort study","volume":"323","author":"Xu","year":"2021","journal-title":"Atherosclerosis"},{"key":"ref20","doi-asserted-by":"publisher","first-page":"699","DOI":"10.2147\/CIA.S357319","article-title":"The association between systemic immune-inflammation index and postoperative cognitive decline in elderly patients","volume":"17","author":"Lu","year":"2022","journal-title":"Clin Interv Aging"},{"key":"ref21","doi-asserted-by":"publisher","first-page":"896","DOI":"10.1097\/AOG.0000000000001978","article-title":"Emerging infectious diseases in pregnancy","volume":"129","author":"Beigi","year":"2017","journal-title":"Obstet Gynecol"},{"key":"ref22","doi-asserted-by":"publisher","first-page":"3507","DOI":"10.1093\/jn\/nxab253","article-title":"Intake of nuts and seeds is associated with a lower prevalence of non-alcoholic fatty liver disease in US adults: findings from 2005-2018 NHANES","volume":"151","author":"Cardoso","year":"2021","journal-title":"J Nutr"},{"key":"ref23","doi-asserted-by":"publisher","first-page":"965","DOI":"10.1289\/ehp.1408630","article-title":"Analysis of environmental chemical mixtures and non-Hodgkin lymphoma risk in the NCI-SEER NHL study","volume":"123","author":"Czarnota","year":"2015","journal-title":"Environ Health Perspect"},{"key":"ref24","doi-asserted-by":"publisher","first-page":"67","DOI":"10.1186\/s12940-018-0413-y","article-title":"Statistical software for analyzing the health effects of multiple concurrent exposures via Bayesian kernel machine regression","volume":"17","author":"Bobb","year":"2018","journal-title":"Environ Health"},{"key":"ref25","doi-asserted-by":"publisher","first-page":"122","DOI":"10.1016\/j.envint.2018.01.016","article-title":"Association between prenatal exposure to multiple insecticides and child body weight and body composition in the VHEMBE south African birth cohort","volume":"113","author":"Coker","year":"2018","journal-title":"Environ Int"},{"key":"ref26","doi-asserted-by":"publisher","first-page":"6261","DOI":"10.3748\/wjg.v23.i34.6261","article-title":"Systemic immune-inflammation index for predicting prognosis of colorectal cancer","volume":"23","author":"Chen","year":"2017","journal-title":"World J Gastroenterol"},{"key":"ref27","doi-asserted-by":"publisher","first-page":"4569","DOI":"10.3390\/ijerph19084569","article-title":"Association among Helicobacter pylori infection, tooth loss, and heavy medal exposure in a Chinese rural population","volume":"19","author":"Yan","year":"2022","journal-title":"Int J Environ Res Public Health"},{"key":"ref28","doi-asserted-by":"publisher","first-page":"21","DOI":"10.1016\/j.envres.2014.05.037","article-title":"Associations between blood lead level and substance use and sexually transmitted infection risk among adults in the United States","volume":"135","author":"Hu","year":"2014","journal-title":"Environ Res"},{"key":"ref29","doi-asserted-by":"publisher","first-page":"16","DOI":"10.1186\/s12940-016-0113-4","article-title":"Elevated blood lead and cadmium levels associated with chronic infections among non-smokers in a cross-sectional analysis of NHANES data","volume":"15","author":"Krueger","year":"2016","journal-title":"Environ Health"},{"key":"ref30","doi-asserted-by":"publisher","first-page":"1121","DOI":"10.1016\/j.envpol.2016.11.023","article-title":"Body burden of heavy metals among HIV high risk population in USA","volume":"220","author":"Xu","year":"2017","journal-title":"Environ Pollut"},{"key":"ref31","doi-asserted-by":"publisher","first-page":"24","DOI":"10.1016\/j.envres.2013.05.001","article-title":"In utero arsenic exposure and infant infection in a United States cohort: a prospective study","volume":"126","author":"Farzan","year":"2013","journal-title":"Environ Res"},{"key":"ref32","doi-asserted-by":"publisher","first-page":"197","DOI":"10.1111\/imr.12091","article-title":"Virus infection, antiviral immunity, and autoimmunity","volume":"255","author":"Getts","year":"2013","journal-title":"Immunol Rev"},{"key":"ref33","doi-asserted-by":"publisher","first-page":"2670","DOI":"10.1080\/21505594.2021.1982373","article-title":"Pathogenesis and virulence of herpes simplex virus","volume":"12","author":"Zhu","year":"2021","journal-title":"Virulence"},{"key":"ref34","doi-asserted-by":"publisher","first-page":"734471","DOI":"10.3389\/fimmu.2021.734471","article-title":"Epstein Barr virus: development of vaccines and immune cell therapy for EBV-associated diseases","volume":"12","author":"Cui","year":"2021","journal-title":"Front Immunol"},{"key":"ref35","doi-asserted-by":"publisher","first-page":"161691","DOI":"10.1016\/j.scitotenv.2023.161691","article-title":"Epidemiological evidence for the effect of environmental heavy metal exposure on the immune system in children","volume":"868","author":"Zheng","year":"2023","journal-title":"Sci Total Environ"},{"key":"ref36","doi-asserted-by":"publisher","first-page":"335","DOI":"10.1007\/s40201-020-00455-2","article-title":"Effects of lead and cadmium on the immune system and cancer progression","volume":"18","author":"Ebrahimi","year":"2020","journal-title":"J Environ Health Sci Eng"},{"key":"ref37","doi-asserted-by":"publisher","first-page":"695484","DOI":"10.3389\/fimmu.2021.695484","article-title":"Effects of cadmium exposure on the immune system and Immunoregulation","volume":"12","author":"Wang","year":"2021","journal-title":"Front Immunol"},{"key":"ref38","doi-asserted-by":"publisher","first-page":"515","DOI":"10.1016\/j.jaci.2013.07.020","article-title":"Natural killer cell deficiency","volume":"132","author":"Orange","year":"2013","journal-title":"J Allergy Clin Immunol"},{"key":"ref39","doi-asserted-by":"publisher","first-page":"673813","DOI":"10.3389\/fcell.2021.673813","article-title":"Recent advances in the roles of autophagy and autophagy proteins in host cells during toxoplasma gondii infection and potential therapeutic implications","volume":"9","author":"Subauste","year":"2021","journal-title":"Front Cell Dev Biol"},{"key":"ref40","doi-asserted-by":"publisher","first-page":"L754","DOI":"10.1152\/ajplung.00022.2016","article-title":"Cadmium attenuates the macrophage response to LPS through inhibition of the NF-\u03baB pathway","volume":"311","author":"Cox","year":"2016","journal-title":"Am J Physiol Lung Cell Mol Physiol"},{"key":"ref41","doi-asserted-by":"publisher","first-page":"7625","DOI":"10.3390\/ijerph17207625","article-title":"Environmental Lead exposure and influenza and respiratory syncytial virus diagnoses in young children: a test-negative case-control study","volume":"17","author":"Feiler","year":"2020","journal-title":"Int J Environ Res Public Health"},{"key":"ref42","doi-asserted-by":"publisher","first-page":"122","DOI":"10.1016\/j.jhazmat.2015.05.020","article-title":"Decreased blood hepatitis B surface antibody levels linked to e-waste lead exposure in preschool children","volume":"298","author":"Xu","year":"2015","journal-title":"J Hazard Mater"},{"key":"ref43","doi-asserted-by":"publisher","first-page":"e086","DOI":"10.1097\/EE9.0000000000000086","article-title":"A prospective cohort study of in utero and early childhood arsenic exposure and infectious disease in 4-to 5-year-old Bangladeshi children","volume":"4","author":"Ahmed","year":"2020","journal-title":"Environ Epidemiol"},{"key":"ref44","doi-asserted-by":"publisher","first-page":"1187","DOI":"10.1289\/ehp.1306748","article-title":"Early life arsenic exposure and acute and long-term responses to influenza a infection in mice","volume":"121","author":"Ramsey","year":"2013","journal-title":"Environ Health Perspect"},{"key":"ref45","doi-asserted-by":"publisher","first-page":"20221312","DOI":"10.1098\/rspb.2022.1312","article-title":"Avian influenza antibody prevalence increases with mercury contamination in wild waterfowl","volume":"289","author":"Teitelbaum","year":"2022","journal-title":"Proc Biol Sci"},{"key":"ref46","doi-asserted-by":"publisher","first-page":"3005","DOI":"10.1007\/s12011-023-03901-y","article-title":"Association of Exposure to heavy metal mixtures with systemic immune-inflammation index among US adults in NHANES 2011-2016","volume":"202","author":"Sun","year":"2024","journal-title":"Biol Trace Elem Res"},{"key":"ref47","doi-asserted-by":"publisher","first-page":"115863","DOI":"10.1016\/j.ecoenv.2023.115863","article-title":"Serum albumin mediates the associations between heavy metals and two novel systemic inflammation indexes among U.S. adults","volume":"270","author":"He","year":"2024","journal-title":"Ecotoxicol Environ Saf"},{"key":"ref48","doi-asserted-by":"publisher","first-page":"132190","DOI":"10.1016\/j.chemosphere.2021.132190","article-title":"Association between lead and cadmium co-exposure and systemic immune inflammation in residents living near a mining and smelting area in NW China","volume":"287","author":"Zhang","year":"2022","journal-title":"Chemosphere"},{"key":"ref49","doi-asserted-by":"publisher","first-page":"100","DOI":"10.1007\/s13253-014-0180-3","article-title":"Characterization of weighted quantile sum regression for highly correlated data in a risk analysis setting","volume":"20","author":"Carrico","year":"2015","journal-title":"J Agric Biol Environ Stat"},{"key":"ref50","doi-asserted-by":"publisher","first-page":"761","DOI":"10.1016\/j.scitotenv.2019.04.395","article-title":"Cadmium exposure in living organisms: a short review","volume":"678","author":"Zhang","year":"2019","journal-title":"Sci Total Environ"},{"key":"ref51","doi-asserted-by":"publisher","first-page":"545","DOI":"10.1016\/j.envres.2017.08.051","article-title":"The toxicology of mercury: current research and emerging trends","volume":"159","author":"Bj\u00f8rklund","year":"2017","journal-title":"Environ Res"},{"key":"ref52","doi-asserted-by":"publisher","first-page":"e00905","DOI":"10.1128\/mSphere.00905-19","article-title":"Microsphere-based IgM and IgG avidity assays for human parvovirus B19, human cytomegalovirus, and toxoplasma gondii","volume":"5","author":"Wang","year":"2020","journal-title":"mSphere"},{"key":"ref53","doi-asserted-by":"publisher","first-page":"3","DOI":"10.1128\/microbiolspec.DMIH2-0011-2015","article-title":"Epstein-Barr Virus","volume":"4","author":"Nowalk","year":"2016","journal-title":"Microbiol Spectr"},{"key":"ref54","doi-asserted-by":"publisher","first-page":"3786","DOI":"10.3748\/wjg.v21.i13.3786","article-title":"Hepatitis C virus and antiviral innate immunity: who wins at tug-of-war?","volume":"21","author":"Yang","year":"2015","journal-title":"World J Gastroenterol"},{"key":"ref55","doi-asserted-by":"publisher","first-page":"83","DOI":"10.1186\/1743-422X-11-83","article-title":"Diagnosis of genital herpes simplex virus infection in the clinical laboratory","volume":"11","author":"LeGoff","year":"2014","journal-title":"Virol J"},{"key":"ref56","doi-asserted-by":"publisher","first-page":"959","DOI":"10.1016\/j.pt.2020.08.005","article-title":"Toxoplasma gondii: an underestimated threat?","volume":"36","author":"Milne","year":"2020","journal-title":"Trends Parasitol"},{"key":"ref57","doi-asserted-by":"publisher","first-page":"204","DOI":"10.3389\/fcimb.2020.00204","article-title":"Review on the current trends of toxoplasmosis Serodiagnosis in humans","volume":"10","author":"Yba\u00f1ez","year":"2020","journal-title":"Front Cell Infect Microbiol"}],"container-title":["Frontiers in Public Health"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fpubh.2024.1367644\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,7,22]],"date-time":"2024-07-22T04:58:20Z","timestamp":1721624300000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fpubh.2024.1367644\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,7,22]]},"references-count":57,"alternative-id":["10.3389\/fpubh.2024.1367644"],"URL":"https:\/\/doi.org\/10.3389\/fpubh.2024.1367644","relation":{},"ISSN":["2296-2565"],"issn-type":[{"value":"2296-2565","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,7,22]]},"article-number":"1367644"}}