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

Cato, Anita R.; Celada, Lindsay J.; Kibakaya, Esther Caroline; Simmons, Nadia; Whalen, Margaret M.

doi:10.1007/s10565-014-9289-y

Cited by 21 publications

(19 citation statements)

References 48 publications

(82 reference statements)

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“…Both compounds are able to decrease the lytic function and cell surface protein expression of human NK cells (Hinkson & Whalen, 2009; Hinkson & Whalen, 2010; Kibakaya et al, 2009; Hurd & Whalen, 2011). This inhibition of NK lytic function may be due to their ability to induce activation/phosphorylation of MAPKs and MAP2Ks (Cato et al, 2014). Other environmental contaminants such as tributyltin (TBT) and dibutyltin (DBT) (Kimbrough, 1976) that decrease NK lytic function (Dudimah et al, 2007a,b), while activating the MAPK pathway (Aluoch et al, 2006; Odman- Ghazi et al, 2010), have been shown to alter IFNγ secretion from human immune cells (Lawrence et al, 2015).…”

Section: Discussionmentioning

confidence: 99%

“…Interestingly, HBCD and TBPA also differ in their capacity to activate MAPKs. HBCD is able to activate p44/42 while TBBPA activates both p44/42 and p38 (Cato et al, 2014). Thus, at least part of the difference in the effects of these 2 compounds on IFNγ secretion may be due to their ability to differentially activate MAPKs.…”

Section: Discussionmentioning

confidence: 99%

“…Human NK cells exposed to HBCD show decreased ability to lyse their target cells (cytolytic function) (Hinkson & Whalen, 2009). Additionally, they show decreases in cell surface proteins needed for cytolysis and activation of the mitogen activated protein kinase (MAPK), p44/42 (ERK1/2) (Cato et al, 2014; Hinkson &Whalen, 2010). …”

Section: Introductionmentioning

confidence: 99%

“…TBBPA was able to compete with thyroid hormone, T4, for binding to human transthyretin (thyroid hormone transport protein) in vitro (Meerts et al, 2000). TBBPA, like HBCD, decreases the cytolytic function of human NK cells while decreasing cell surface proteins and activating p44/42 (Cato et al, 2014; Kibakaya et al, 2009)…”

Section: Introductionmentioning

confidence: 99%

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Hexabromocyclododecane and tetrabromobisphenol A alter secretion of interferon gamma (IFN-γ) from human immune cells

Almughamsi

Whalen

2015

Arch Toxicol

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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 (IFNγ) 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 IFNγ 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 0.05–5 μM. HBCD generally caused increases in IFNγ 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 IFNγ from NK cells, MD-PBMCs and PBMCs. Thus, exposure to these compounds may potentially disrupt the immune regulation mediated by IFNγ. Signaling pathways that have the capacity to regulate IFNγ production (nuclear factor kappa B (NFκB), p44/42, p38, JNK) were examined for their role in the HBCD-induced increases in IFNγ. Results showed that the p44/42 (ERK1/2) MAPK pathway appears to be important in HBCD-induced increases in IFNγ secretion from human immune cells.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Hexabromocyclododecane and tetrabromobisphenol A alter secretion of interferon gamma (IFN-γ) from human immune cells

Almughamsi

Whalen

2015

Arch Toxicol

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“…Additionally, TBBPA and HBCD decreased key cell surface proteins and activated MAPKs in NK cells (Hinkson and Whalen, 2010; Hurd and Whalen, 2011; Cato et al, 2014). Additionally, alterations of interferon (IFN)-γ secretion from increasingly re-constituted immune cell preparations such as NK cells, peripheral blood mononuclear cells (PMBC), and monocyte-depleted (MD) peripheral blood mononuclear cells (MD-PBMC) were seen after exposure to TBBPA and HBCD (Almughamsi and Whalen, 2015).…”

Section: Introductionmentioning

confidence: 99%

Tetrabromobisphenol A and hexabromocyclododecane alter secretion of IL-1βfrom human immune cells

Anisuzzaman

Whalen

2015

Journal of Immunotoxicology

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Tetrabromobisphenol A (TBBPA) and hexabromocyclododecane (HBCD), flame retardant compounds used in epoxy resin circuit boards and upholstery, contaminate the environment and are found in human serum. Lymphocytes and monocytes are immune cells that among other functions secrete pro-inflammatory cytokines such as interleukin (IL)-1β, an important regulator of immune responsiveness and tissue growth and repair. Thus, if its levels are dysregulated, loss of proper immune function and increased invasiveness of tumors could ensue. This study examines whether exposures to varying concentrations (0.05-5.0 μM) of TBBPA and HBCD for 24 hr, 48 hr, and 6 d interfere with the ability of immune cells to secrete IL-1β. The immune cell preparations examined were human natural killer (NK) cells, monocyte-depleted (MD) peripheral blood mononuclear cells (MD-PBMC) and PBMC. Both increased and decreased secretion of IL-1β from all three types of cell preparation was seen with TBBPA exposures and was dependent on concentration and length of exposure. TBBPA induced changes varied considerably from donor to donor. Exposure to HBCD from 0.5-5.0 μM caused increases in IL-1β secretion after all lengths of exposures in all cell preparations. The specific HBCD levels at which increases occurred varied among donors. Examinations of the signaling pathway(s) responsible for the elevated secretion of IL-1β after HBCD exposure were carried out in MD-PBMC cells. Results revealed that MAPK pathways (ERK1/2 and p38) appear to be the targets of HBCD that lead to increased IL-1β secretion from immune cells.

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Flame retardant, hexabromocyclododecane, increases production of pro‐inflammatory cytokines, interleukin 1‐beta and interleukin 6, in human immune cells

Falconer‐Turner,

Brooks,

Ogaga

et al. 2024

J of Applied Toxicology

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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.

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

Cited by 21 publications

References 48 publications

Hexabromocyclododecane and tetrabromobisphenol A alter secretion of interferon gamma (IFN-γ) from human immune cells

Hexabromocyclododecane and tetrabromobisphenol A alter secretion of interferon gamma (IFN-γ) from human immune cells

Tetrabromobisphenol A and hexabromocyclododecane alter secretion of IL-1βfrom human immune cells

Flame retardant, hexabromocyclododecane, increases production of pro‐inflammatory cytokines, interleukin 1‐beta and interleukin 6, in human immune cells

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