Brominated flame retardants, tetrabromobisphenol A and hexabromocyclododecane, activate mitogen-activated protein kinases (MAPKs) in human natural killer cells

Cell Biol Toxicol. 2014 Dec;30(6):345-60. doi: 10.1007/s10565-014-9289-y. Epub 2014 Oct 24.


Natural killer (NK) cells provide a vital surveillance against virally infected cells, tumor cells, and antibody-coated cells through the release of cytolytic mediators and gamma interferon (IFN-γ). Hexabromocyclododecane (HBCD) is a brominated flame retardant used primarily in expanded (EPS) and extruded (XPS) polystyrene foams for thermal insulation in the building and construction industry. Tetrabromobisphenol A (TBBPA) is used both as a reactive and an additive flame retardant in a variety of materials. HBCD and TBBPA contaminate the environment and are found in human blood samples. In previous studies, we have shown that other environmental contaminants, such as the dibutyltin (DBT) and tributyltin (TBT), decrease NK lytic function by activating mitogen-activated protein kinases (MAPKs) in the NK cells. HBCD and TBBPA also interfere with NK cell(s) lytic function. The current study evaluates whether HBCD and/or TBBPA have the capacity to activate MAPKs and MAPK kinases (MAP2Ks). The effects of concentrations of HBCD and TBBPA that inhibited lytic function on the phosphorylation state and total levels of the MAPKs (p44/42, p38, and JNK) and the phosphorylation and total levels of the MAP2Ks (MEK1/2 and MKK3/6) were examined. Results indicate that exposure of human NK cells to 10-0.5 μM HBCD or TBBPA activate MAPKs and MAP2Ks. This HBCD and TBBPA-induced activation of MAPKs may leave them unavailable for activation by virally infected or tumor target cells and thus contributes to the observed decreases in lytic function seen in NK cells exposed to HBCD and TBBPA.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Dose-Response Relationship, Drug
  • Enzyme Activation / drug effects
  • Female
  • Flame Retardants / pharmacology*
  • Gene Expression Regulation / drug effects*
  • Humans
  • Hydrocarbons, Brominated / pharmacology*
  • Killer Cells, Natural / cytology
  • Killer Cells, Natural / drug effects*
  • Killer Cells, Natural / metabolism
  • MAP Kinase Kinase 1 / genetics
  • MAP Kinase Kinase 1 / metabolism
  • MAP Kinase Kinase 2 / genetics
  • MAP Kinase Kinase 2 / metabolism
  • MAP Kinase Kinase 4 / genetics
  • MAP Kinase Kinase 4 / metabolism
  • MAP Kinase Kinase Kinase 3 / genetics
  • MAP Kinase Kinase Kinase 3 / metabolism
  • MAP Kinase Kinase Kinases / genetics
  • MAP Kinase Kinase Kinases / metabolism
  • Male
  • Mitogen-Activated Protein Kinase 1 / genetics
  • Mitogen-Activated Protein Kinase 1 / metabolism
  • Mitogen-Activated Protein Kinase 3 / genetics
  • Mitogen-Activated Protein Kinase 3 / metabolism
  • Phosphorylation / drug effects
  • Polybrominated Biphenyls / pharmacology*
  • Primary Cell Culture
  • Signal Transduction
  • p38 Mitogen-Activated Protein Kinases / genetics
  • p38 Mitogen-Activated Protein Kinases / metabolism


  • Flame Retardants
  • Hydrocarbons, Brominated
  • Polybrominated Biphenyls
  • hexabromocyclododecane
  • MAP2K2 protein, human
  • Mitogen-Activated Protein Kinase 1
  • Mitogen-Activated Protein Kinase 3
  • p38 Mitogen-Activated Protein Kinases
  • MAP Kinase Kinase Kinase 3
  • MAP Kinase Kinase Kinases
  • MAP kinase kinase kinase 6
  • MAP3K3 protein, human
  • MAP Kinase Kinase 1
  • MAP Kinase Kinase 2
  • MAP Kinase Kinase 4
  • MAP2K1 protein, human
  • tetrabromobisphenol A