Biological Trace Element Research

, Volume 183, Issue 1, pp 49–57 | Cite as

The Inflammatory Potential of Dietary Manganese in a Cohort of Elderly Men

  • Jacob K. Kresovich
  • Catherine M. Bulka
  • Brian T. Joyce
  • Pantel S. Vokonas
  • Joel Schwartz
  • Andrea A. Baccarelli
  • Elizabeth A. Hibler
  • Lifang Hou


Manganese is an essential nutrient that may play a role in the production of inflammatory biomarkers. We examined associations between estimated dietary manganese intake from food/beverages and supplements with circulating biomarkers of inflammation. We further explored whether estimated dietary manganese intake affects DNA methylation of selected genes involved in the production of these biomarkers. We analyzed 1023 repeated measures of estimated dietary manganese intakes and circulating blood inflammatory biomarkers from 633 participants in the Normative Aging Study. Using mixed-effect linear regression models adjusted for covariates, we observed positive linear trends between estimated dietary manganese intakes and three circulating interleukin proteins. Relative to the lowest quartile of estimated intake, concentrations of IL-1β were 46% greater (95% CI − 5, 126), IL-6 52% greater (95% CI − 9, 156). and IL-8 32% greater (95% CI 2, 71) in the highest quartiles of estimated intake. Estimated dietary manganese intake was additionally associated with changes in DNA methylation of inflammatory biomarker-producing genes. Higher estimated intake was associated with higher methylation of NF-κβ member activator NKAP (Q4 vs Q1: β = 3.32, 95% CI − 0.6, 7.3). When stratified by regulatory function, higher manganese intake was associated with higher gene body methylation of NF-κβ member activators NKAP (Q4 vs Q1: β = 10.10, 95% CI − 0.8, 21) and NKAPP1 (Q4 vs Q1: β = 8.14, 95% CI 1.1, 15). While needed at trace amounts for various physiologic functions, our results suggest estimated dietary intakes of manganese at levels slightly above nutritional adequacy contribute to inflammatory biomarker production.


Manganese Dietary manganese DNA methylation Inflammation Cytokines 



Body mass index


Confidence intervals


C-reactive protein


False discovery rate


Food Frequency Questionnaire


Intercellular adhesion molecule 1






Normative aging study


Nuclear factor kappa B subunit 1


Nuclear factor kappa B subunit 2


Nuclear factor kappa B P65 subunit


Nuclear factor kappa-light-chain-enhancer of Active B Cells


NF-κβ inhibitor alpha


NF-κβ inhibitor beta


NF-κβ Repressing factor


NF-κβ inhibitor interacting Ras-Like 1


NF-κβ inhibitor interacting Ras Like 2


NF-κβ activating protein


NF-κβ activating protein like


NF-κβ activating protein pseudogene 1


Proto-oncogene c-REL


RELB proto-oncogene NF-κβ subunit


Tolerable upper intake level


Tumor necrosis factor alpha


Tumor necrosis factor receptor, superfamily member 1B


Vascular cell adhesion protein 1


Vascular endothelial growth factor


Author Contributions

JKK, EAH, and LH designed the study. PSV, JS, and AAB supervised study operations. JKK performed the statistical analysis. JKK and CMB drafted the manuscript. BTJ, AAB, EAH, and LH provided critical revisions to the manuscript. All authors read and approved the final manuscript.

Funding Information

The Epidemiology Research and Information Center of US Department of Veterans Affairs (NIEHS R01-ES015172) support the Normative Aging Study. L. Hou received additional support from the Northwestern University Robert H. Lurie Comprehensive Cancer Center Rosenberg Research Fund. A. Baccarelli and J. Schwartz received additional support from the National Institute of Environmental Health Sciences (NIEHS R01-ES021733, NIEHS R01-ES015172, and NIEHS P30-ES00002). J. Kresovich received additional support from the National Cancer Institute Cancer Education and Career Development Program (NIH R25 CA057699).

Compliance with Ethical Standards

Conflicts of Interest

The authors declare that they have no conflicts of interest.

Supplementary material

12011_2017_1127_MOESM1_ESM.docx (14 kb)
Supplemental Table 1 (DOCX 13 kb)
12011_2017_1127_MOESM2_ESM.docx (18 kb)
Supplemental Table 2 (DOCX 18 kb)
12011_2017_1127_MOESM3_ESM.docx (18 kb)
Supplemental Table 3 (DOCX 18 kb)
12011_2017_1127_MOESM4_ESM.png (29 kb)
Supplemental Figure 1 Flow diagram of participant inclusion. (PNG 28 kb)


  1. 1.
    Takser L, Mergler D, Hellier G, Sahuquillo J, Huel G (2003) Manganese, monoamine metabolite levels at birth, and child psychomotor development. Neurotoxicology 24(4–5):667–674CrossRefPubMedGoogle Scholar
  2. 2.
    Leach RM, Lilburn MS (1978) Manganese metabolism and its function. World Rev Nutr Diet 32:123–134CrossRefPubMedGoogle Scholar
  3. 3.
    United States. Agency for toxic substances and disease registry: draft toxicological profile for manganese. In., Draft. edn. Atlanta, Ga.: U.S. Dept. of Health and Human Services, Public Health Service, Agency for Toxic Substances and Disease Registry,; 2008: 1 online resource ( 539 p.)Google Scholar
  4. 4.
    Aguirre JD, Culotta VC (2012) Battles with iron: manganese in oxidative stress protection. J Biol Chem 287(17):13541–13548CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Trumbo P, Yates AA, Schlicker S, Poos M (2001) Dietary reference intakes: vitamin a, vitamin K, arsenic, boron, chromium, copper, iodine, iron, manganese, molybdenum, nickel, silicon, vanadium, and zinc. J Am Diet Assoc 101(3):294–301CrossRefPubMedGoogle Scholar
  6. 6.
    Finley JW, Davis CD (1999) Manganese deficiency and toxicity: are high or low dietary amounts of manganese cause for concern? Biofactors 10(1):15–24CrossRefPubMedGoogle Scholar
  7. 7.
    Institute of Medicine (IOM), Food and Nutrition Board: dietary reference intakes for vitamin A, vitamin K, arsenic, boron, chromium, copper, iodine, iron, manganese, molybdenum, nickel, silicon, vanadium, and zinc: a Report of the Panel on Micronutrients. In (2001) Washington. National Academy Press, D.C.Google Scholar
  8. 8.
    Santos D, Dinamene S, Batoréu MC, Camila BM, Tavares de Almeida I, Davis Randall L, Mateus ML, Luisa MM, Andrade V, Vanda A et al (2013) Evaluation of neurobehavioral and neuroinflammatory end-points in the post-exposure period in rats sub-acutely exposed to manganese. Toxicology 314(1):95–99CrossRefPubMedGoogle Scholar
  9. 9.
    Kobayashi K, Kuroda J, Shibata N, Hasegawa T, Seko Y, Satoh M, Tohyama C, Takano H, Imura N, Sakabe K et al (2007) Induction of metallothionein by manganese is completely dependent on interleukin-6 production. J Pharmacol Exp Ther 320(2):721–727CrossRefPubMedGoogle Scholar
  10. 10.
    Zhao F, Cai T, Liu M, Zheng G, Luo W, Chen J (2009) Manganese induces dopaminergic neurodegeneration via microglial activation in a rat model of manganism. Toxicol Sci 107(1):156–164CrossRefPubMedGoogle Scholar
  11. 11.
    Liu M, Cai T, Zhao F, Zheng G, Wang Q, Chen Y, Huang C, Luo W, Chen J (2009) Effect of microglia activation on dopaminergic neuronal injury induced by manganese, and its possible mechanism. Neurotox Res 16(1):42–49CrossRefPubMedGoogle Scholar
  12. 12.
    Pascal LE, Tessier DM (2004) Cytotoxicity of chromium and manganese to lung epithelial cells in vitro. Toxicol Lett 147(2):143–151CrossRefPubMedGoogle Scholar
  13. 13.
    Jiang WD, Tang RJ, Liu Y, Kuang SY, Jiang J, Wu P, Zhao J, Zhang YA, Tang L, Tang WN 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-κB, TOR and Nrf2 signalling, in grass carp (Ctenopharyngodon idella). Fish Shellfish Immunol 46(2):406–416CrossRefPubMedGoogle Scholar
  14. 14.
    Tak PP, Firestein GS (2001) NF-kappaB: a key role in inflammatory diseases. J Clin Invest 107(1):7–11CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Du Y, Zhu Y, Teng X, Zhang K, Li S (2015) Toxicological effect of manganese on NF-κB/iNOS-COX-2 signaling pathway in chicken testes. Biol Trace Elem Res 168(1):227–234CrossRefPubMedGoogle Scholar
  16. 16.
    Maccani JZ, Koestler DC, Houseman EA, Armstrong DA, Marsit CJ, Kelsey KT (2015) DNA methylation changes in the placenta are associated with fetal manganese exposure. Reprod Toxicol 57:43–49CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Searles Nielsen S, Checkoway H, Criswell SR, Farin FM, Stapleton PL, Sheppard L, Racette BA (2015) Inducible nitric oxide synthase gene methylation and parkinsonism in manganese-exposed welders. Parkinsonism Relat Disord 21(4):355–360CrossRefPubMedGoogle Scholar
  18. 18.
    Bell B, Rose C, Damon A (1972) The normative aging study: an interdisciplinary and longitudinal study of health and aging. Int J Aging Hum Dev 3(1):5–17CrossRefGoogle Scholar
  19. 19.
    Willett WC, Sampson L, Stampfer MJ, Rosner B, Bain C, Witschi J, Hennekens CH, Speizer FE (1985) Reproducibility and validity of a semiquantitative food frequency questionnaire. Am J Epidemiol 122(1):51–65CrossRefPubMedGoogle Scholar
  20. 20.
    Willett WC, Sampson L, Browne ML, Stampfer MJ, Rosner B, Hennekens CH, Speizer FE (1988) The use of a self-administered questionnaire to assess diet four years in the past. Am J Epidemiol 127(1):188–199CrossRefPubMedGoogle Scholar
  21. 21.
    Roberts WL, Moulton L, Law TC, Farrow G, Cooper-Anderson M, Savory J, Rifai N (2001) Evaluation of nine automated high-sensitivity C-reactive protein methods: implications for clinical and epidemiological applications. Part 2. Clin Chem 47(3):418–425PubMedGoogle Scholar
  22. 22.
    Du P, Zhang X, Huang CC, Jafari N, Kibbe WA, Hou L, Lin SM (2010) Comparison of beta-value and M-value methods for quantifying methylation levels by microarray analysis. BMC Bioinformatics 11:587CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Fang SC, Mehta AJ, Alexeeff SE, Gryparis A, Coull B, Vokonas P, Christiani DC, Schwartz J (2012) Residential black carbon exposure and circulating markers of systemic inflammation in elderly males: the normative aging study. Environ Health Perspect 120(5):674–680CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Rodríguez-Matas MC, Campos MS, López-Aliaga I, Gómez-Ayala AE, Lisbona F (1998) Iron-manganese interactions in the evolution of iron deficiency. Ann Nutr Metab 42(2):96–109CrossRefPubMedGoogle Scholar
  25. 25.
    Finley JW, Davis CD (2001) Manganese absorption and retention in rats is affected by the type of dietary fat. Biol Trace Elem Res 82(1–3):143–158CrossRefPubMedGoogle Scholar
  26. 26.
    Benjamini Y, Hochberg Y (1995) Controlling the false discovery rate: a practical and powerful approach to multiple testing. J R Stat Soc Ser B Methodol 57:289–300Google Scholar
  27. 27.
    Hou L, Zhang X, Tarantini L, Nordio F, Bonzini M, Angelici L, Marinelli B, Rizzo G, Cantone L, Apostoli P et al (2011) Ambient PM exposure and DNA methylation in tumor suppressor genes: a cross-sectional study. Part Fibre Toxicol 8:25CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Wolf SF, Jolly DJ, Lunnen KD, Friedmann T, Migeon BR (1984) Methylation of the hypoxanthine phosphoribosyltransferase locus on the human X chromosome: implications for X-chromosome inactivation. Proc Natl Acad Sci U S A 81(9):2806–2810CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Jones PA (1999) The DNA methylation paradox. Trends Genet 15(1):34–37CrossRefPubMedGoogle Scholar
  30. 30.
    Rauscher GH, Kresovich JK, Poulin M, Yan L, Macias V, Mahmoud AM, Al-Alem U, Kajdacsy-Balla A, Wiley EL, Tonetti D et al (2015) Exploring DNA methylation changes in promoter, intragenic, and intergenic regions as early and late events in breast cancer formation. BMC Cancer 15:816CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Bai Y, Wang W, Sun G, Zhang M, Dong J (2016) Curcumin inhibits angiogenesis by up-regulation of microRNA-1275 and microRNA-1246: a promising therapy for treatment of corneal neovascularization. Cell ProlifGoogle Scholar
  32. 32.
    Filipov NM, Seegal RF, Lawrence DA (2005) Manganese potentiates in vitro production of proinflammatory cytokines and nitric oxide by microglia through a nuclear factor kappa B-dependent mechanism. Toxicol Sci 84(1):139–148CrossRefPubMedGoogle Scholar
  33. 33.
    Ramesh GT, Ghosh D, Gunasekar PG (2002) Activation of early signaling transcription factor, NF-kappaB following low-level manganese exposure. Toxicol Lett 136(2):151–158CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Eigenbrod T, Bode KA, Dalpke AH (2013) Early inhibition of IL-1β expression by IFN-γ is mediated by impaired binding of NF-κB to the IL-1β promoter but is independent of nitric oxide. J Immunol 190(12):6533–6541CrossRefPubMedGoogle Scholar
  35. 35.
    Matsusaka T, Fujikawa K, Nishio Y, Mukaida N, Matsushima K, Kishimoto T, Akira S (1993) Transcription factors NF-IL6 and NF-kappa B synergistically activate transcription of the inflammatory cytokines, interleukin 6 and interleukin 8. Proc Natl Acad Sci U S A 90(21):10193–10197CrossRefPubMedPubMedCentralGoogle Scholar
  36. 36.
    Kunsch C, Lang RK, Rosen CA, Shannon MF (1994) Synergistic transcriptional activation of the IL-8 gene by NF-kappa B p65 (RelA) and NF-IL-6. J Immunol 153(1):153–164PubMedGoogle Scholar
  37. 37.
    Kunsch C, Rosen CA (1993) NF-kappa B subunit-specific regulation of the interleukin-8 promoter. Mol Cell Biol 13(10):6137–6146CrossRefPubMedPubMedCentralGoogle Scholar
  38. 38.
    Cybulsky MI, Fries JW, Williams AJ, Sultan P, Eddy R, Byers M, Shows T, Gimbrone MA, Collins T (1991) Gene structure, chromosomal location, and basis for alternative mRNA splicing of the human VCAM1 gene. Proc Natl Acad Sci U S A 88(17):7859–7863CrossRefPubMedPubMedCentralGoogle Scholar
  39. 39.
    Arbibe L, Kim DW, Batsche E, Pedron T, Mateescu B, Muchardt C, Parsot C, Sansonetti PJ (2007) An injected bacterial effector targets chromatin access for transcription factor NF-kappaB to alter transcription of host genes involved in immune responses. Nat Immunol 8(1):47–56CrossRefPubMedGoogle Scholar
  40. 40.
    Ho TT, You JO (2016) Auguste DT: siRNA delivery impedes the temporal expression of cytokine-activated VCAM1 on endothelial cells. Ann Biomed Eng 44(4):895–902CrossRefPubMedGoogle Scholar
  41. 41.
    Gao JJ, Hu YW, Wang YC, Sha YH, Ma X, Li SF, Zhao JY, Lu JB, Huang C, Zhao JJ et al (2015) ApoM suppresses TNF-α-induced expression of ICAM-1 and VCAM-1 through inhibiting the activity of NF-κB. DNA Cell Biol 34(8):550–556CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2017

Authors and Affiliations

  • Jacob K. Kresovich
    • 1
    • 2
  • Catherine M. Bulka
    • 2
  • Brian T. Joyce
    • 1
    • 2
  • Pantel S. Vokonas
    • 3
  • Joel Schwartz
    • 4
  • Andrea A. Baccarelli
    • 5
  • Elizabeth A. Hibler
    • 1
  • Lifang Hou
    • 1
  1. 1.Center for Population Epigenetics, Robert H. Lurie Comprehensive Cancer Center and Department of Preventive MedicineNorthwestern University Feinberg School of MedicineChicagoUSA
  2. 2.Division of Epidemiology and BiostatisiticsUniversity of Illinois at Chicago School of Public HealthChicagoUSA
  3. 3.VA Normative Aging Study, Veterans Affairs Boston Healthcare System and the Department of MedicineBoston University School of MedicineBostonUSA
  4. 4.Department of Environmental Health and Program in Quantitative GenomicsHarvard T.H. Chan School of Public HealthBostonUSA
  5. 5.Departments of Epidemiology and Environmental Health SciencesColumbia University Mailman School of Public HealthNew York CityUSA

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