Archives of Toxicology

, Volume 92, Issue 4, pp 1483–1494 | Cite as

Flame retardants, hexabromocyclododecane (HCBD) and tetrabromobisphenol a (TBBPA), alter secretion of tumor necrosis factor alpha (TNFα) from human immune cells

  • Sharia Yasmin
  • Margaret Whalen


Hexabromocyclododecane (HBCD) and tetrabromobisphenol A (TBBPA) are flame retardants, used in a variety of applications, which contaminate the environment and are found in human blood. HBCD and TBBPA have been shown to alter the tumor killing function of natural killer (NK) lymphocytes and the secretion of the inflammatory cytokines interferon gamma (IFNγ) and interleukin 1 beta (IL-1β). The current study examined the effects of HBCD and TBBPA on secretion of the critical pro-inflammatory cytokine tumor necrosis factor alpha (TNFα) from human immune cells. Preparations of human immune cells that ranged in complexity were studied to determine if the effects of the compounds were consistent as the composition of the cell preparation became more heterogeneous. Cell preparations studied were: NK cells, monocyte-depleted (MD) peripheral blood mononuclear cells (PBMCs), and PBMCs. Exposure of NK cells to higher concentrations of HBCD (5 and 2.5 µM) caused decreased secretion of TNFα. However, when the cell preparation contained T lymphocytes (MD-PBMCs and PBMCs) these same concentrations of HBCD increased TNFα secretion as did nearly all other concentrations. This suggests that HBCD’s ability to increase TNFα secretion from immune cells was dependent on the presence of T lymphocytes. In contrast, exposures to TBBPA decreased the secretion of TNFα from all immune cell preparations regardless of the composition of the cell preparation. Further, HBCD-induced increases in TNFα secretion utilized the p38 MARK pathway. Thus, both HBCD and TBBPA may have the capacity to disrupt the inflammatory response with HBCD having the potential to cause chronic inflammation.


NK cells PBMCs Granulocytes Hexabromocyclododecane Tetrabromobisphenol A TNFα 



Grant U54CA163066 from the National Institutes of Health.


  1. Abdallah MAE, Harrad S, Ibarra C, Diamond M, Melymuk L, Robson M, Covaci A (2008) Hexabromocyclododecanes in indoor dust from Canada, The United Kingdom, and the United States. Environ Sci Technol 42(2):459–464CrossRefGoogle Scholar
  2. Almughamsi H, Whalen M (2015). Hexabromocyclododecane and tetrabromobisphenol A alter secretion of interferon gamma (IFNγ) from human immune cells. Arch Toxicol, 90(7), 1695–707Google Scholar
  3. Anisuzzaman S, Whalen MM (2016) Tetrabromobisphenol A and hexabromocyclododecane alter secretion of IL-1β from human immune cells. J Immunotoxicol 13(3):403–416CrossRefPubMedGoogle Scholar
  4. Balkwill F, Mantovani A (2001) Inflammation and cancer: back to Virchow? Lancet 357(9255):539–545CrossRefPubMedGoogle Scholar
  5. Barnabe C, Martin B, Ghali WA (2011) Systemic review and meta-analysis: anti-tumor necrosis factor α therapy and cardiovascular events in rheumatoid arthritis. Arthritis Care Res 64(4):522–529CrossRefGoogle Scholar
  6. Birnbaum LS, Staskal DF (2004) Brominated flame retardants: cause for concern? Environ Health Perspect 112(1):9–17CrossRefPubMedPubMedCentralGoogle Scholar
  7. Chowers Y, Allez M (2010) Efficacy of anti-TNF in Crohn’s disease: how does it work? Curr Drug Targets 11(2):138–142CrossRefPubMedGoogle Scholar
  8. Covaci A, Gerecke AC, Law RJ, Voorspoels S, Kohler M, Heeb NV, Leslie H, Allchin CR, De Boer J (2006) Hexabromocyclododecanes (HBCDs) in the environment and humans: a review. Environ Sci Technol 40(12):3679–3688CrossRefPubMedGoogle Scholar
  9. de Wit CA (2002) An overview of brominated flame retardants in the environment. Chemosphere 46(5):583–624CrossRefPubMedGoogle Scholar
  10. Gaestel M, Kotlyarov A, Kracht M (2009) Targeting innate immunity protein kinase signaling in inflammation. Nat Rev Drug Discovy 8(6):480–481CrossRefGoogle Scholar
  11. Germer S, Piersma AH, van der Ven L, Kamyshnikow A, Fery Y, Schmitz HJ, Schrenk D (2006) Subacute effects of the brominated flame retardants hexabromocyclododecanes and tetrabromobisphenol A on hepatic cytochrome P450 levels in rats. Toxicology 218(2–3):229–236CrossRefPubMedGoogle Scholar
  12. Goetz FW, Planas JV, MacKenzie S (2004) Tumor necrosis factors. Dev Comp Immunol 28(5):487–497CrossRefPubMedGoogle Scholar
  13. Guicciardi ME, Gores GJ (2009) Life and death by death receptors. J Fed Am Soc Exp Biol 23(6):1625–1637Google Scholar
  14. Hale RC, La Guardia MJ, Harvey E, Gaylor MO, Mainor TM (2006) Brominated flame retardant concentrations and trends in abiotic media. Chemosphere 64(2):181–186CrossRefPubMedGoogle Scholar
  15. Hinkson NC, Whalen MM (2009) Hexabromocyclododecane decreases the lytic function and ATP levels of human natural killer cells. J Appl Toxicol 29(8):656–661CrossRefPubMedPubMedCentralGoogle Scholar
  16. Hinkson NC, Whalen MM (2010) Hexabromocyclododecane decreases the tumor-cell-binding capacity and cell-surface protein expression of human natural killer cells. J Appl Toxicol 30(4):302–309CrossRefPubMedPubMedCentralGoogle Scholar
  17. Hurd T, Whalen MM (2011) Tetrabromobisphenol A decreases cell surface proteins involved in human natural killer (NK) cell-dependent target cell lysis. J Immunotoxicol 8(3):219–227CrossRefPubMedPubMedCentralGoogle Scholar
  18. Hurt K, Hurd-Brown T, Whalen MM (2013) Tributyltin and dibutyltin alter secretion of tumor necrosis factor alpha from human natural killer (NK) cells and a mixture of T cells and NK cells. J Appl Toxicol 33:503–510CrossRefPubMedGoogle Scholar
  19. IPCS/WHO (International Program on Chemical Safety/World Health Organization) (1995). Environmental Health Criteria172: Tetrabromobisphenol A and Derivatives. Geneva: World Health OrganizationGoogle Scholar
  20. Kajiwara N, Seuoka M, Ohiwa T, Takigami H (2009) Determination of flame-retardant hexabromocyclododecane diastereomers in textiles. Chemosphere 74(11):1485–1489CrossRefPubMedGoogle Scholar
  21. Kakimoto K, Akutsu K, Konishi Y, Tanaka Y (2008) Time trend of hexabromocyclododecanes in the breast milk of Japanese women. Chemosphere 71(6):1110–1114CrossRefPubMedGoogle Scholar
  22. Khalil AA, Hall JC, Aziz FA, Price P (2006) Tumour necrosis factor: Implications for surgical patients. ANZ J Surg 76(11):8613–8623CrossRefGoogle Scholar
  23. Kibakaya HK, Stephen K, Whalen MM (2009) Tetrabromobisphenol A has immunosuppressive effects on human natural killer cells. J Immunotoxicol 6(4):285–292CrossRefPubMedPubMedCentralGoogle Scholar
  24. Knutsen HK, Kvalem HE, Thomsen C, Froshaug M, Haugen M, Becher G, Alexander J, Meltzer HM (2008) Dietary exposure to brominated flame retardants correlates with male blood levels in a selected group of Norwegians with a wide range of seafood consumption. Mol Nutr Food Res 52(2):217–227CrossRefPubMedGoogle Scholar
  25. Macarthur M, Hold GL, El-Omar EM (2004) Inflammation and cancer II. Role of chronic inflammation and cytokine gene polymorphisms in the pathogenesis of gastrointestinal malignancy. Am J Physiol: Gastrointest Liver Physiol 286(4):G515-G520Google Scholar
  26. Meyer TP, Zehnter I, Hofmann B, Zaisserer J, Burkhart J, Rapp S, Illert WE (2005) Filter buffy coast (FBC): a source of peripheral blood leukocytes recovered from leukocyte depletion filters. J Immunol Methods 307(1–2):150–166CrossRefPubMedGoogle Scholar
  27. Michaud TL, Rho YH, Shamliyan T, Kuntz KM, Choi HK (2014) The comparative safety of tumor necrosis factor inhibitors in rheumatoid arthritis: a meta-analysis update of 44 trials. Am J Med 127(12):1208–1232CrossRefPubMedGoogle Scholar
  28. Nagayama J, Takasuga T, Tsuji H, and editors (2001). Contamination levels of brominated flame retardants, dioxins, and organochlorine compounds in the blood of Japanese adults. Hum Levels Trends, 4, 218–221Google Scholar
  29. Parameswaran N, Patial S (2010) Tumor necrosis factor-α signaling in macrophages. Crit Rev Eukaryot Gene Expr 20(2):87–103CrossRefPubMedPubMedCentralGoogle Scholar
  30. Peterman PH, Orazio CE, Gale RW (2000) Detection of tetraboromobisphenol A and formation of brominated [13C]-bisphenol A’s in commercial drinking water stored in reusable polycarbonate containers. Am Chem Soc Div Environ Chem: Ext Abstr 40(1):431–433Google Scholar
  31. Pulkrabová J, Hrádková P, Hajslová J, Poustka J, Nápravníková M, Polácek V (2009) Brominated flame retardants and other organochlorine pollutants in human adipose tissue samples from Czech Republic. Environ Int 35(1):63–68CrossRefPubMedGoogle Scholar
  32. Remberger M, Sternbeck J, Palm A, Kaj L, Strömberg K, Brorström-Lundén E (2004) The environmental occurrence of hexabromocyclododecane in Sweden. Chemosphere 54(1):9–21CrossRefPubMedGoogle Scholar
  33. Ronisz D, Finne EF, Karlsson H, Förlin L (2004) Effects of the brominated flame retardants hexabromocyclododecane (HBCD) and tetrabromobisphenol A (TBBPA), on hepatic enzymes and other biomarkers in juvenile rainbow trout and feral eelpout. Aquat Toxicol 69(3):229–245CrossRefPubMedGoogle Scholar
  34. Schecter A, Szabo DT, Miller J, Gent TL, Malik-Bass N, Petersen M,.. . Birnbaum LS (2012) Hexabromocyclododecane (HBCD) stereoisomers in US food from Dallas, Texas. Environ Health Perspect 120(9):1260–1264CrossRefPubMedPubMedCentralGoogle Scholar
  35. Sellström U, Jansson B (1995) Analysis of tetrabromobisphenol A in a product and environmental samples. Chemosphere 31(4):3085–3092CrossRefGoogle Scholar
  36. Shurety W, Merino-Trigo A, Brown D, Hume DA, Stow JL (2000) Localization and post-golgi trafficking of tumor necrosis factor-alpha in macrophages. J Interferon Cytokine Res 20(4):427–438CrossRefPubMedGoogle Scholar
  37. Silke J (2011) The regulation of TNF signaling: what a tangled web we weave. Curr Opin Immunol 23(5):620–626CrossRefPubMedGoogle Scholar
  38. Stanley AC, Lacy P (2010) Pathways for cytokine secretion. Physiology 25:218–229CrossRefPubMedGoogle Scholar
  39. Taylor PC, Feldmann M (2009) Anti-TNF biologic agents: still the therapy of choice for rheumatoid arthritis. Nat Rev Rheumatol 5(10):578–782CrossRefPubMedGoogle Scholar
  40. Thomsen C, Lundanes E, Becher G (2002) Brominated flame retardants in archived serum samples from Norway: a study on temporal trends and the role of age. Environ Sci Technol 36(7):1414–1418CrossRefPubMedGoogle Scholar
  41. Vajdic CM, van Leeuwen MT (2009) Cancer incidence and risk factors after solid organ transplantation. Int J Cancer 125(8):1747–1754CrossRefPubMedGoogle Scholar
  42. van Leeuwen SP, Boer J (2008) Brominated flame retardants in fish and shellfish—levels and contribution of fish consumption to dietary exposure of Dutch citizens to HBCD. Mol Nutr Food Res 52(2):194–203CrossRefPubMedGoogle Scholar
  43. van der Ven LT, Verhoef A, van de Kuil T, Slob W, Leonards PE, Visser TJ, Vos JG (2006) A 28-day oral dose toxicity study enhanced to detect endocrine effects of hexabromocyclododecane in Wistar rats. Toxicol Sci 94(2):281–292CrossRefPubMedGoogle Scholar
  44. Wajant H, Pfizenmaier K, Scheurich P (2003) Tumor necrosis factor signaling. Cell Death Differ 10(1):45–65CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Departments of Biological SciencesTennessee State UniversityNashvilleUSA
  2. 2.Departments of ChemistryTennessee State UniversityNashvilleUSA

Personalised recommendations