Tetrabromobisphenol A has immunosuppressive effects on human natural killer cells

Kibakaya, Esther Caroline; Stephen, K. Anderson; Whalen, Margaret M.

doi:10.3109/15476910903258260

Cited by 54 publications

(53 citation statements)

References 30 publications

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“…HBCD and TBPPA are used as flame retardants and significantly contaminate the environment, with detectable levels being found in human tissues (Covaci et al, 2006; Knutsen et al, 2008; Hagmar et al, 2000; Nagayama et al, 2001; Thomsen et al, 2002). 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).…”

Section: Discussionmentioning

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%

“…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%

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

Almughamsi

Whalen

2015

Arch Toxicol

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“…TBBPA was an immunosuppressant in in vitro cell systems including suppression of NK cell activity (Hurd and Whalen, 2011; Kibakaya et al, 2009). Mice treated with TBBPA were less able to mount a defense against viral infection (Watanabe et al, 2010).…”

Section: Discussionmentioning

confidence: 99%

Tetrabromobisphenol A activates the hepatic interferon pathway in rats

et al. 2017

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Tetrabromobisphenol A (TBBPA) is a widely used flame retardant in printed circuit boards, paper, and textiles. In a two-year study, TBBPA showed evidence of uterine tumors in female Wistar-Han rats and liver and colon tumors in B6C3F1 mice. In order to gain further insight into early gene and pathway changes leading to cancer, we exposed female Wistar Han rats to TBBPA at 0, 25, 250, or 1000 mg/kg (oral gavage in corn oil, 5×/week) for 13 weeks. Because at the end of the TBBPA exposure period, there were no treatment-related effects on body weights, liver or uterus lesions, and liver and uterine organ weights were within 10% of controls, only the high dose animals were analyzed. Analysis of the hepatic and uterine transcriptomes showed TBBPA-induced changes primarily in the liver (1000 mg/kg), with 159 transcripts corresponding to 132 genes differentially expressed compared to controls (FDR = 0.05). Pathway analysis showed activation of interferon (IFN) and metabolic networks. TBBPA induced few molecular changes in the uterus. Activation of the interferon pathway in the liver occurred after 13-weeks of TBBPA exposure, and with longer term TBBPA exposure this may lead to immunomodulatory changes that contribute to carcinogenic processes.

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“…Previous studies in our laboratory have shown that human NK cells exposed to HBCD or TPBPA exhibit significantly decreased lytic function and cell surface protein expression (Hinkson and Whalen, 2009; Hinkson and Whalen, 2010; Kibakaya et al, 2009; Hurd and Whalen, 2011). In the current study, we examine the activation states of the MAPK pathway in NK cells.…”

Section: Introductionmentioning

confidence: 88%

“…There are limited studies on the toxicological effects of HBCD and TBBPA on humans (Hinkson and Whalen, 2009; Hinkson and Whalen, 2010; Kibakaya et al, 2009). However there have been studies on lab animals.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2014

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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.

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Tetrabromobisphenol A has immunosuppressive effects on human natural killer cells

Cited by 54 publications

References 30 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 activates the hepatic interferon pathway in rats

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

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