Penta- and octa-bromodiphenyl ethers promote proinflammatory protein expression in human bronchial epithelial cells in vitro

Highlights

• Penta- and octa-BDE increased ICAM-1, IL-6, and IL-8 expression in BEAS-2B.

• The increase could be partly mediated by EGFR-related signaling pathways.

• Less brominated PBDEs might affect respiratory and immune systems.

Abstract

Polybrominated diphenyl ethers (PBDEs) are widely used as flame retardants in consumer products. Humans can be exposed to PBDEs mainly through the inhalation of air or dust. Thus, PBDEs can affect respiratory and immune systems. In the present study, we investigated whether PBDEs stimulate bronchial epithelial cells. We examined commercial penta-BDE (DE-71), octa-BDE (DE-79), and deca-BDE (DE-83R). Human bronchial epithelial cells (BEAS-2B) were exposed to each PBDE for 24 h. Subsequently, the expression of intercellular adhesion molecule-1 (ICAM-1) and proinflammatory cytokines were investigated. DE-71 and DE-79, but not DE-83R, significantly increased the expression of ICAM-1, interleukin-6 (IL-6), and IL-8 in BEAS-2B. Because these remarkable effects were observed with DE-71, we further investigated the underlying intracellular mechanisms. DE-71 promoted epidermal growth factor receptor (EGFR) phosphorylation. Inhibitors of EGFR-selective tyrosine kinase and p38 mitogen-activated protein kinase effectively blocked the increase of IL-6 and IL-8. Furthermore, antagonists of thyroid hormone receptor and aryl hydrocarbon receptor significantly suppressed the increase in IL-6 and/or IL-8 production. In conclusion, penta- and octa-BDE, but not deca-BDE, might promote the expression of proinflammatory proteins in bronchial epithelial cells possibly by activating protein kinases and/or stimulating nuclear receptors related to subsequent activation of transcriptional factors.

Introduction

Brominated flame retardants (BFRs) are used in industrial and consumer products, including electronic products, textiles, and building materials, to prevent fire-related injury and property damage (Birnbaum and Staskal, 2004). Major BFRs are polybrominated diphenyl ethers (PBDEs), hexabromocyclododecane, and tetrabromobisphenol A (Birnbaum and Staskal, 2004). BFRs are used as additive or reactive components. Additive BFRs, including PBDEs, are simply blended with polymers and are not chemically bound to products; thus, additive BFRs can easily leach into the environment (Alaee et al., 2003). In particular, PBDEs have been observed in indoor dust in many countries (Abdallah et al., 2007, Batterman et al., 2010, Sjodin et al., 2008, Stapleton et al., 2005). A positive relationship was also found between PBDE concentrations in household dust and in human plasma (Karlsson et al., 2007) and breast milk (Wu et al., 2007).

Besides BFRs, other chemicals such as phthalate plasticizers are present in indoor air and dust and coexist with allergens such as house dust mites. Epidemiological studies have suggested associations between phthalate exposure at home and the risk of asthma and allergies (Jaakkola and Knight, 2008). Experimental studies have also shown that phthalates can aggravate allergic diseases and/or responses in animal models (Koike et al., 2010, Larsen and Nielsen, 2007, Takano et al., 2006) and in vitro (Koike et al., 2009, Koike et al., 2010, Rakkestad et al., 2010). Thus, individuals with respiratory and allergy-related diseases may have a high sensitivity for indoor chemical pollutants.

PBDEs include the commercial products of penta-, octa-, and deca-BDE. Each product is a mixture composed of several PBDE congeners. PBDEs are structurally similar to polychlorinated biphenyls and resist degradation in the environment. Because of their accumulation in human tissues (Hites, 2004, Inoue et al., 2006, Sjodin et al., 2003) and potential toxicity (Birnbaum and Staskal, 2004, Viberg et al., 2004), penta- and octa-BDE are banned in some countries or have been voluntarily withdrawn. However, their component congeners are still detected in humans and the environment.

Recent concerns regarding the possible adverse health effects of BFRs have focused on 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, it is important to determine the effects of BFRs on respiratory and immune systems. Recently, we examined the effects of BFRs, including PBDEs, on immune cells in atopic prone NC/Nga mice and demonstrated that these BFRs can aggravate immune/allergic responses by enhancing antigen presentation-related molecule expression and IL-4 production in splenocytes (Koike et al., 2013). However, the effects of BFRs on respiratory and immune systems have not been completely elucidated. Activated airway epithelial cells release hematopoietic and proinflammatory cytokines that initiate immune responses and, therefore, play an essential role in respiratory diseases such as asthma. For instance, air pollutants (particulate matters and organic chemicals) can aggravate respiratory diseases by proinflammatory cytokine secretion from airway epithelial cells (Dergham et al., 2012, Fischader et al., 2008, Ghio et al., 2009).

In this study, we investigated whether PBDEs affect the expression of proinflammatory proteins such as intercellular adhesion molecule-1 (ICAM-1), interleukin-6 (IL-6), and IL-8 in bronchial epithelial cells in vitro. In addition, we examined the effects of PBDEs on the signaling pathways such as activation of inflammatory-related protein kinase to evaluate the intracellular mechanisms.