Human natural killer (NK) cells are lymphocytes that destroy tumor cells, virally infected cells, and antibody-coated cells. Tetrabromobisphenol A (TBBPA) is used both as a reactive and an additive flame retardant in a variety of materials and appears to contaminate the environment. TBBPA has been found in human blood samples and if it interferes with NK cell function, this could increase risk of tumor development and/or viral infection. This study examines the effects of exposure to various concentrations of TBBPA for 24 hr, 48 hr, and 6 d on the lytic function, tumor-target-binding function, and ATP levels of NK cells. These same parameters were also monitored in NK cells that were exposed to TBBPA for 1 hr followed by 24 hr, 48 hr, and 6 d in TBBPA-free media. A 24 hr exposure of NK cells to 5 μM TBBPA caused a greater than 95% decrease in NK lytic function, a 70% decrease in binding function, and a 34% decrease in ATP levels in NK cells. Exposure to 2.5 μM TBBPA for 24 hr decreased lytic function by 76%, binding function by 20%, and had no effect on ATP levels. Exposure of NK cells to 5 μM TBBPA for 1 hr followed by 24 hr in TBBPA-free media caused a progressive and persistent loss of lytic function (41%) while not affecting either binding ability or ATP levels. The results indicate that TBBPA exposures decrease the lytic function of human NK cells and that an initial brief (1 hr) exposure can cause a progressive loss of function. Additionally, the data also indicate that TBBPA-induced loss of NK lytic function can occur at concentration of TBBPA that do not affect target-binding ability and ATP levels of NK cells.

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.