Elsevier

Toxicology in Vitro

Volume 32, April 2016, Pages 212-219
Toxicology in Vitro

Brominated flame retardants, hexabromocyclododecane and tetrabromobisphenol A, affect proinflammatory protein expression in human bronchial epithelial cells via disruption of intracellular signaling

https://doi.org/10.1016/j.tiv.2015.12.013Get rights and content

Highlights

  • HBCD and TBBPA affect the viability and proliferation in BEAS-2B cells.

  • HBCD and TBBPA affect the expression of proinflammatory proteins in BEAS-2B cells.

  • HBCD and TBBPA stimulate EGFR-related protein phosphorylation.

  • TBBPA may affect inflammatory response via disrupt nuclear receptor signaling pathways.

Abstract

Hexabromocyclododecane (HBCD) and tetrabromobisphenol A (TBBPA) are widely used as brominated flame retardants (BFRs) in consumer products. Because humans can be exposed to BFRs mainly through air or dust, the effects of the BFRs on the respiratory system and the underlying mechanisms were investigated. HBCD exposure significantly increased the expression of intercellular adhesion molecule (ICAM)-1 and the production of interleukin (IL)-6 and -8 in human bronchial epithelial cells (BEAS-2B). TBBPA exposure significantly increased the expression of ICAM-1 and IL-6, but not IL-8. HBCD and TBBPA stimulated epidermal growth factor (EGF) production and EGF receptor (EGFR) phosphorylation. Inhibitors of EGFR-selective tyrosine kinase and the subsequent mitogen-activated protein kinase effectively blocked the increase in the expression of proinflammatory proteins. The activation of nuclear factor-kappa B (p50, p65) and activator protein 1 (c-Jun) was also observed following HBCD exposure. Furthermore, the modulation for nuclear receptors was investigated. TBBPA but not HBCD showed ligand activity for thyroid hormone receptor (TR) and TR antagonist significantly suppressed the TBBPA-induced increase of the expression of ICAM-1 and IL-6. In conclusion, HBCD and TBBPA can disrupt the expression of proinflammatory proteins in bronchial epithelial cells, possibly via the modulation of EGFR-related pathways and/or nuclear receptors.

Introduction

Brominated flame retardants (BFRs) are used in industrial and consumer products, including electronic products, textiles, and building materials, for preventing fire-related injury and property damage (Birnbaum and Staskal, 2004). Decabromodiphenyl ether (decaBDE), hexabromocyclododecane (HBCD), and tetrabromobisphenol A (TBBPA) are currently the most widely used BFRs (Birnbaum and Staskal, 2004). On May 2013, the Stockholm Convention on Persistent Organic Pollutants decided to list HBCD as a persistent organic pollutant for elimination, with time-limited exemptions for production and use in expanded polystyrene, and extruded polystyrene insulation foams in buildings. In Japan, the import and production of HBCD were banned in May 2014. However, HBCD derived from consumer products still exists in the indoor environment.

HBCD is used as an additive BFR, which is simply blended with polymers and is easily leached out (Alaee et al., 2003). TBBPA is mainly used as a reactive BFR, which is chemically bonded into polymer products. However, the remaining TBBPA is used as an additive BFR. BFRs can be released into the environment through volatilization or dust formation from BFR-containing products in homes (Stapleton et al., 2008, Takigami et al., 2009), offices (Batterman et al., 2010, Destaillats et al., 2008), and car interiors (Abdallah and Harrad, 2010). In particular, polybromodiphenyl ethers (PBDEs) and HBCD at concentrations greater than parts per million have been observed with indoor dust in many countries (Abdallah et al., 2007, Batterman et al., 2010, Sjoin et al., 2008, Stapleton et al., 2005). Serum concentrations of HBCD were correlated with exposure to household dust (Roosens et al., 2009). HBCD and its degradation products were detected in human breast milk (Abdallah and Harrad, 2011, Shi et al., 2009). TBBPA has also been detected in air (Sjodin et al., 2001), dust (D'Hollander et al., 2010), and human breast milk and serum (Cariou et al., 2008, Shi et al., 2009).

Recent studies on the health effects of BFRs have demonstrated their potential endocrine-disrupting effects and developmental neurotoxicity (Costa et al., 2008, Talsness et al., 2009). Because humans can be exposed to BFRs by inhaling indoor air or dust, the respiratory system may be particularly vulnerable to indoor chemical pollutants, such as BFRs. However, the effects of BFRs on the respiratory and immune system are poorly understood.

We have demonstrated that PBDEs, HBCD, and TBBPA can aggravate immune responses by the activation of antigen-presenting cells such as dendritic cells and enhancement of interleukin (IL)-4 production in splenocytes from atopic prone NC/Nga mice (Koike et al., 2013). We have also demonstrated that penta- and octa-BDE, but not deca-BDE, promote the expression of proinflammatory proteins, such as IL-6 and -8, in bronchial epithelial cells and that the effects may occur partly by the EGFR-related signaling pathways (Koike et al., 2014b). These mediators play important roles in the immune system and in promoting respiratory diseases, such as asthma. IL-6 is involved in various physiological functions, such as promoting proliferation and expressing cell adhesion molecules. IL-8 is a chemokine that recruits inflammatory cells. In this study, we focused on the effects of HBCD and TBBPA on the inflammatory response in bronchial epithelial cells and attempted to understand the mechanisms by which BFRs affect these cells.

Section snippets

BFRs

1,2,5,6,9,10-HBCD (95%, MW 641.70; Sigma-Aldrich Co., St. Louis, MO) and TBBPA (> 98.0%, MW 543.87; Tokyo Chemical Industry Co., Ltd., Tokyo, Japan) were used. Fig. 1a shows the chemical structure of HBCD and TBBPA. HBCD and TBBPA were dissolved in dimethyl sulfoxide (DMSO; Sigma-Aldrich Co., St. Louis, MO, USA) and diluted with culture medium. The final concentration of DMSO was 0.1% in all experiments.

Cell culture and treatments

The normal human bronchial epithelial cell line, BEAS-2B, was obtained from the European

Effects of HBCD and TBBPA on cell viability/proliferation in BEAS-2B cells

We examined the viability and proliferation of BEAS-2B cells following a 24-h exposure to HBCD and TBBPA. Fig. 1b shows that a low concentration of HBCD and TBBPA increased cell proliferation compared with the control (HBCD: 1 μg/mL, p < 0.05; HBCD: 0.1, 3 μg/mL and TBBPA: 0.03, 0.1, 0.3, 1 μg/mL, p < 0.01). On the other hand, viable cells after exposure to 10 μg/mL of HBCD and 3 and 10 μg/mL of TBBPA decreased significantly compared with the control (p < 0.01).

Effects of HBCD and TBBPA on the expression of proinflammatory proteins in BEAS-2B cells

We examined the expression of ICAM-1 and

Discussion

In the present study, we found HBCD and TBBPA can affect the expression of proinflammatory proteins, possibly by modulating EGFR-related signaling pathways and/or nuclear receptors in bronchial epithelial cells.

Twenty-four hour exposure to HBCD (10 μg/mL) and TBBPA (3 and 10 μg/mL) decreased viable cells in BEAS-2B cells, although low concentrations of these BFRs stimulated cell proliferation (Fig. 1b). The cytotoxicity may be due to chemical-mediated oxidative capacity, like polycyclic aromatic

Conflict of interest

The authors declare that they have no conflict of interest.

Transparency Document

Transparency document.

Acknowledgments

This study was supported by grants from the National Institute for Environmental Studies (1115AA082), and in part by an Environment Research and Technology Development Fund (K2314) from the Ministry of the Environment. The authors would like to thank Ms. Satomi Abe for technical assistance and Enago (http://www.enago.jp) for the English language review.

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