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Hexabromocyclododecane (HBCD) is an environmental contaminant due to its use as a flame retardant in a variety of applications ranging from building insulation, furniture upholstery, and housing for appliances and electronics. HBCD is found in wildlife, human breastmilk, and serum. Interleukin 1-beta (IL-1β) and interleukin 6 (IL-6) are pro-inflammatory cytokines, whose dysregulation is associated with chronic inflammation and the pathologies that result, such as tumor growth, rheumatoid arthritis, Crohn's disease, and multiple sclerosis. HBCD has been shown to increase the secretion of both IL-1β and IL-6 from human immune cells. However, it is not clear if these increases are due solely to HBCD effects on the secretory process or whether it is stimulating cellular production of IL-1β and IL-6. This study examines if HBCD can increase the production of IL-1β and IL-6 by immune cells by simultaneously assessing secreted levels and cellular levels of these cytokines. Additionally, the mechanisms for any observed changes in production are investigated. Peripheral blood mononuclear cells were exposed to HBCD over a range of concentrations and lengths of exposure. HBCD was found to stimulate IL-1β and IL-6 production after 6 hrs. of exposure and production was sustained and intensified at 24 hrs. This increase in IL-1β and IL-6 production appears to, in part, be a result of increased mRNA expression. Additionally, the MAPK pathways, specifically the p38 and p44/42 pathways, appear to be required for HBCD-induced increases in IL-1β and IL-6 production., (© 2024 John Wiley & Sons Ltd.)

Hexabromocyclododecane (HBCD) and tetrabromobisphenol A (TBBPA) are brominated flame-retardant compounds used in a variety of applications including insulation, upholstery, and epoxy resin circuit boards. Interferon gamma (IFN-γ) is an inflammatory cytokine produced by activated T and NK cells that regulates immune responsiveness. HBCD and TBBPA are found in human blood, and previous studies have shown that they alter the ability of human natural killer (NK) lymphocytes to destroy tumor cells. This study examines whether HBCD and TBBPA affect the secretion of IFN-γ from increasingly complex preparations of human immune cells-purified NK cells, monocyte-depleted (MD) peripheral blood mononuclear cells (PBMCs), and PBMCs. Both HBCD and TBBPA were tested at concentrations ranging from 0.05 to 5 µM. HBCD generally caused increases in IFN-γ secretion after 24-h, 48-h, and 6-day exposures in each of the different cell preparations. The specific concentration of HBCD that caused increases as well as the magnitude of the increase varied from donor to donor. In contrast, TBBPA tended to decrease secretion of IFN-γ from NK cells, MD-PBMCs, and PBMCs. Thus, exposure to these compounds may potentially disrupt the immune regulation mediated by IFN-γ. Signaling pathways that have the capacity to regulate IFN-γ production (nuclear factor kappa B (NF-κB), p44/42, p38, JNK) were examined for their role in the HBCD-induced increases in IFN-γ. Results showed that the p44/42 (ERK1/2) MAPK pathway appears to be important in HBCD-induced increases in IFN-γ secretion from human immune cells.

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.

Human natural killer (NK) lymphocytes are able to destroy tumor cells and virally-infected cells. Interference with their function can leave an individual with increased susceptibility to cancer development and/or viral infection. We have shown that the tumor-destroying (lytic) function of NK cells can be dramatically decreased by exposure to the environmental contaminant tetrabromobisphenol A (TBBPA). TBBPA is a flame retardant used in a variety of materials including circuit boards, carpeting, and upholstery and has been found in human blood samples. TBBPA interferes with NK cell lytic function, in part, by decreasing the ability of NK cells to bind to target cells. This study examines the effects of exposures to concentrations of TBBPA (i.e., that were able to decrease the binding capacity of NK cells) on the expression of cell-surface proteins (CD2, CD11a, CD16, CD18, and CD56) that are needed for NK cells to bind target cells. NK cells were exposed to TBBPA for 24 h, 48 h, and 6 days or for 1 h followed by 24 h, 48 h, and 6 days in TBBPA-free media. Twenty-four-hour exposures to 5 µM TBBPA caused decreases in four of the cell-surface proteins examined. CD16 was decreased by >35%. The decreases in cell-surface proteins after a 48-h exposure were similar to those seen after 24 h. The results indicate that TBBPA exposures that decrease the binding function of human NK cells do so by decreasing the expression of cell-surface proteins needed for attachment of NK cells to targets cells.

Hexabromocyclododecane (HBCD) is a flame retardant that decreases the lytic function of human natural killer (NK) cells. NK cells defend against tumor cells and virally infected cells. Thus, HBCD has the potential to increase cancer incidence and viral infections. NK cells must bind to their targets for lysis to occur. Thus, concentrations of HBCD that decrease lytic function were examined for their ability to alter NK binding to tumor targets. Levels of HBCD that caused a loss of binding function were examined for effects on expression of cell surface proteins needed for binding. NK cells exposed to HBCD for 24 h, 48 h or 6 days or to HBCD for 1 h followed by 24 h, 48 h or 6 days in HBCD-free media were examined for binding function and cell surface protein expression. The results indicated that exposure of NK cells to 10 microM HBCD for 24 h (which caused a greater than 90% loss of lytic function) caused a very significant decrease in NK cell binding function (70.9%), and in CD16 and CD56 cell-surface protein expression (57.8 and 24.6% respectively). NK cells exposed to 10 microM HBCD for 1 h followed by 24 h in HBCD-free media (which caused a 89.3% loss of lytic function) showed decreased binding function (79.2%), and CD 16 expression (48.1%). Results indicate that HBCD exposures decreased binding function as well as cell-surface marker expression in NK cells and that these changes may explain the losses of lytic function induced by certain HBCD exposures., (2009 John Wiley & Sons, Ltd.)

This study investigates the effect of hexabromocyclododecane (HBCD) on the lytic function of human natural killer (NK) cells and on ATP levels in NK cells. NK cells are capable of lysing tumor cells, virally infected cells, and antibody-coated cells. HBCD is a brominated cyclic alkane used primarily as an additive flame retardant. If HBCD interferes with NK cell function, this could increase risk of tumor development and/or viral infection. NK cells were exposed to various concentrations of HBCD for 24 and 48 h and 6 days before determining lytic function and ATP levels. ATP levels and lytic function were also determined in NK cells that were exposed to HBCD for 1 h followed by 24 and 48 h, and 6 days in HBCD-free media. The results indicated that exposure of NK cells to 10 microm HBCD for 24 h causes a very significant decrease in both NK cell lytic function and ATP levels (93.5 and 90.5%, respectively). Exposure of NK cells to 10 microm HBCD for 1 h followed by 24 h in HBCD-free media showed a progressive and persistent loss of lytic function (89.3%) as well as a decrease in ATP levels (46.1%). The results indicate that HBCD exposures decreased lytic function as well as ATP levels. However, a decrease in lytic function was not necessarily accompanied by a similar decrease in ATP. Importantly, these results also indicate that a brief (1 h) exposure to HBCD causes a progressive loss of lytic function over a 6 day period.