Skip to main content

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

Abstract

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.

This is a preview of subscription content, access via your institution.

Fig. 1
Fig. 2
Fig. 3

References

  • 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):459–464

    CAS  Article  Google Scholar 

  • Almughamsi H, Whalen M (2015). Hexabromocyclododecane and tetrabromobisphenol A alter secretion of interferon gamma (IFNγ) from human immune cells. Arch Toxicol, 90(7), 1695–707

    Google Scholar 

  • Anisuzzaman S, Whalen MM (2016) Tetrabromobisphenol A and hexabromocyclododecane alter secretion of IL-1β from human immune cells. J Immunotoxicol 13(3):403–416

    CAS  Article  PubMed  Google Scholar 

  • Balkwill F, Mantovani A (2001) Inflammation and cancer: back to Virchow? Lancet 357(9255):539–545

    CAS  Article  PubMed  Google Scholar 

  • 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):522–529

    Article  Google Scholar 

  • Birnbaum LS, Staskal DF (2004) Brominated flame retardants: cause for concern? Environ Health Perspect 112(1):9–17

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  • Chowers Y, Allez M (2010) Efficacy of anti-TNF in Crohn’s disease: how does it work? Curr Drug Targets 11(2):138–142

    CAS  Article  PubMed  Google Scholar 

  • 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):3679–3688

    CAS  Article  PubMed  Google Scholar 

  • de Wit CA (2002) An overview of brominated flame retardants in the environment. Chemosphere 46(5):583–624

    Article  PubMed  Google Scholar 

  • Gaestel M, Kotlyarov A, Kracht M (2009) Targeting innate immunity protein kinase signaling in inflammation. Nat Rev Drug Discovy 8(6):480–481

    CAS  Article  Google Scholar 

  • 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):229–236

    CAS  Article  PubMed  Google Scholar 

  • Goetz FW, Planas JV, MacKenzie S (2004) Tumor necrosis factors. Dev Comp Immunol 28(5):487–497

    CAS  Article  PubMed  Google Scholar 

  • Guicciardi ME, Gores GJ (2009) Life and death by death receptors. J Fed Am Soc Exp Biol 23(6):1625–1637

    CAS  Google Scholar 

  • Hale RC, La Guardia MJ, Harvey E, Gaylor MO, Mainor TM (2006) Brominated flame retardant concentrations and trends in abiotic media. Chemosphere 64(2):181–186

    CAS  Article  PubMed  Google Scholar 

  • Hinkson NC, Whalen MM (2009) Hexabromocyclododecane decreases the lytic function and ATP levels of human natural killer cells. J Appl Toxicol 29(8):656–661

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  • 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):302–309

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  • 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):219–227

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  • 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 33:503–510

    CAS  Article  PubMed  Google Scholar 

  • IPCS/WHO (International Program on Chemical Safety/World Health Organization) (1995). Environmental Health Criteria172: Tetrabromobisphenol A and Derivatives. Geneva: World Health Organization

    Google Scholar 

  • Kajiwara N, Seuoka M, Ohiwa T, Takigami H (2009) Determination of flame-retardant hexabromocyclododecane diastereomers in textiles. Chemosphere 74(11):1485–1489

    CAS  Article  PubMed  Google Scholar 

  • Kakimoto K, Akutsu K, Konishi Y, Tanaka Y (2008) Time trend of hexabromocyclododecanes in the breast milk of Japanese women. Chemosphere 71(6):1110–1114

    CAS  Article  PubMed  Google Scholar 

  • Khalil AA, Hall JC, Aziz FA, Price P (2006) Tumour necrosis factor: Implications for surgical patients. ANZ J Surg 76(11):8613–8623

    Article  Google Scholar 

  • Kibakaya HK, Stephen K, Whalen MM (2009) Tetrabromobisphenol A has immunosuppressive effects on human natural killer cells. J Immunotoxicol 6(4):285–292

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  • 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):217–227

    CAS  Article  PubMed  Google Scholar 

  • 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-G520

    Google Scholar 

  • 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):150–166

    CAS  Article  PubMed  Google Scholar 

  • 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):1208–1232

    CAS  Article  PubMed  Google Scholar 

  • 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, 218–221

    Google Scholar 

  • Parameswaran N, Patial S (2010) Tumor necrosis factor-α signaling in macrophages. Crit Rev Eukaryot Gene Expr 20(2):87–103

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  • 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):431–433

    CAS  Google Scholar 

  • 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):63–68

    Article  PubMed  Google Scholar 

  • Remberger M, Sternbeck J, Palm A, Kaj L, Strömberg K, Brorström-Lundén E (2004) The environmental occurrence of hexabromocyclododecane in Sweden. Chemosphere 54(1):9–21

    CAS  Article  PubMed  Google Scholar 

  • 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):229–245

    CAS  Article  PubMed  Google Scholar 

  • 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):1260–1264

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  • Sellström U, Jansson B (1995) Analysis of tetrabromobisphenol A in a product and environmental samples. Chemosphere 31(4):3085–3092

    Article  Google Scholar 

  • 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):427–438

    CAS  Article  PubMed  Google Scholar 

  • Silke J (2011) The regulation of TNF signaling: what a tangled web we weave. Curr Opin Immunol 23(5):620–626

    CAS  Article  PubMed  Google Scholar 

  • Stanley AC, Lacy P (2010) Pathways for cytokine secretion. Physiology 25:218–229

    CAS  Article  PubMed  Google Scholar 

  • Taylor PC, Feldmann M (2009) Anti-TNF biologic agents: still the therapy of choice for rheumatoid arthritis. Nat Rev Rheumatol 5(10):578–782

    CAS  Article  PubMed  Google Scholar 

  • 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):1414–1418

    CAS  Article  PubMed  Google Scholar 

  • Vajdic CM, van Leeuwen MT (2009) Cancer incidence and risk factors after solid organ transplantation. Int J Cancer 125(8):1747–1754

    CAS  Article  PubMed  Google Scholar 

  • 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):194–203

    Article  PubMed  Google Scholar 

  • 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):281–292

    Article  PubMed  Google Scholar 

  • Wajant H, Pfizenmaier K, Scheurich P (2003) Tumor necrosis factor signaling. Cell Death Differ 10(1):45–65

    CAS  Article  PubMed  Google Scholar 

Download references

Acknowledgements

Grant U54CA163066 from the National Institutes of Health.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Margaret Whalen.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Yasmin, S., Whalen, M. Flame retardants, hexabromocyclododecane (HCBD) and tetrabromobisphenol a (TBBPA), alter secretion of tumor necrosis factor alpha (TNFα) from human immune cells. Arch Toxicol 92, 1483–1494 (2018). https://doi.org/10.1007/s00204-018-2156-5

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00204-018-2156-5

Keywords

  • NK cells
  • PBMCs
  • Granulocytes
  • Hexabromocyclododecane
  • Tetrabromobisphenol A
  • TNFα