Elsevier

Environmental Research

Volume 169, February 2019, Pages 62-71
Environmental Research

Decarbromodiphenyl ether (BDE-209) promotes monocyte–endothelial adhesion in cultured human aortic endothelial cells through upregulating intercellular adhesion molecule-1

https://doi.org/10.1016/j.envres.2018.10.035Get rights and content

Highlights

  • BDE-209 promotes monocyte–endothelial adhesion in cultured human endothelial cells.

  • BDE-209 increased the expression of ICAM-1.

  • BDE-209 decreased the expression of microRNA-141.

  • Few of the reports on the potential cardiovascular toxicity of POPs.

Abstract

There is growing evidence that exposure to persistent organic pollutants (POPs) is statistically associated with incidence of cardiovascular disease (CVD) or its risk factors. Decarbromodiphenyl ether (BDE-209) is a new POP which exists extensively in human tissues, but its potential effects on CVD have so far received less focus. The adhesion of circulating monocytes to endothelial cells is one of the critical underlying steps in the initiation and development of CVD. In the present study, we investigated the effect of BDE-209 on the adhesion of THP-1 monocytes to human aortic endothelial cells (HAECs) and identified the molecular mechanisms involved. Our results showed that 6.25, 12.5 and 25 µM of BDE-209 exposures caused significant increases in monocyte–endothelial cell adhesion, in a dose-dependent manner. Mechanistically, BDE-209 exposure increased the expression of intercellular adhesion molecule-1 (ICAM-1). Moreover, the up-regulation of ICAM-1 was accompanied by a decrease in the expression of microRNA-141 (miR-141). Furthermore, the up-regulation of ICAM-1 and the increased adhesion induced by BDE-209 could be reversed by miR-141 supplement. Taken together, our results show that BDE-209 potentiates monocyte–endothelial cell interaction via miR-141/ICAM-1 pathway in HAECs.

Introduction

Polybrominated diphenyl ethers (PBDEs) are flame-retardant chemicals that have been among the most abundantly used flame retardants (Rahman et al., 2001). They had been added in a variety of consumer products to decrease flammability, at levels up to 30% of overall material weight (Rahman et al., 2001, de Wit, 2002). These chemicals can be released to the environment during the use and disposal of the PBDE-containing products, and can be subsequently accumulated in biota including humans (Alaee et al., 2003, de Wit, 2002, Fang et al., 2015).

Decarbromodiphenyl ether (BDE-209) is the major component of c-decaBDE, a widely used commercial PBDE mixture (de Wit, 2002). Due to its environmental and human health concerns, c-decaBDE was recently included in the Stockholm Convention list of persistent organic pollutants (POPs) (Stockholm Convention, 2017). Historically, human exposure to BDE-209 was either occupational or accidental; however, the most relevant route of BDE-209 exposure today is through a combination of diet, ingestion of dust and inhalation of air (Domingo, 2012, Bramwell et al., 2016, He et al., 2018). Recent studies revealed that BDE-209 still are present widely in the human bodies of the general population, at levels of ng/g lipid weight (Fromme et al., 2016, Goodyer et al., 2017, Jeong et al., 2018). In human tissues, BDE-209 has a relative short half-life (~15 days) (Thuresson et al., 2006). The presence of BDE-209 in human tissues suggests that humans must be more continuously exposed to this chemical to sustain the tissue concentrations observed. In stark contrast to this widespread and continuous exposure, there is limited data on human health effects associated with BDE-209 (Darnerud, 2003, Hardy et al., 2009, Costa and Giordano, 2011, Czerska et al., 2013).

Cardiovascular diseases (CVD) have become the leading cause of death and disability in developed countries and are increasing in prevalence worldwide (Pagidipati and Gaziano, 2013). Genetic and behavioral factors are considered key causes of CVD, but there is emerging evidence that exposure to POPs may be also an important contributor (Perkins et al., 2016, Gupta et al., 2018, Barrett, 2012, Lind and Lind, 2012, Henriquez-Hernandez et al., 2017, Singh and Chan, 2018). Although the relationships between BDE-209 exposure and CVD or its risk factors have not been reported so far, previous studies indicated that some lower brominated PBDE congeners, e.g., BDEs-28, −47, −99 and −100, were statistically associated with certain markers of CVD or its risk factors (Lind and Lind, 2012, Gump et al., 2014, Penell et al., 2014). Moreover, epidemiological studies revealed that circulating levels of a polychlorinated biphenyl (PCB) congener, CB-209, were statistically associated with incidence of CVD risk factors (Lind and Lind, 2012, Penell et al., 2014). BDE-209 is structurally similar to CB-209 and the aforementioned lower brominated PBDE congeners, and usually presents in human bodies at higher levels than these chemicals (Fromme et al., 2016). However, whether BDE-209 can also contribute to the initiation and development of CVD remains unclear.

The activation of endothelial cells following circulating monocyte/macrophage adhesion to the intimal endothelial cells is considered to be one of the critical underlying steps in the initiation and development of CVD (Sima et al., 2009). Under normal physiological conditions, the monocyte keeps freely circulating in the blood vessels. In various vascular diseases, however, the adhesive property of the vasculature is altered due to a complex cascade of interactions between the monocyte and the endothelial layer. These processes are mediated primarily by cell adhesion molecules, e.g., vascular adhesion molecule-1 (VCAM-1), intracellular adhesion molecule-1 (ICAM-1), P-selectin and E-selectin, and some members of metalloproteinases such as matrix metalloproteinase 2 (MMP-2) and 9 (MMP-9) (Sima et al., 2009). Evidence suggests that exposure to POPs, e.g., PCBs and endosulfan, can up-regulate the expressions of some of these adhesion molecules in endothelial cells, leading to endothelial dysfunction (Han et al., 2010, Liu et al., 2015a, Zhang et al., 2017).

There is emerging evidence that cellular homeostasis of the CVD-related genes is regulated by specific mircroRNAs (miRNAs) (Small et al., 2010), which are endogenous, short noncoding RNAs that regulate gene expressions at the posttranscriptional level (Bartel, 2004). Both in vivo and in vitro data indicated that some endothelial function-related CVD were associated with distinct miRNA signatures (Fang et al., 2010, Zhou et al., 2011, Fang and Davies, 2012). Specifically, recent studies demonstrated that the ICAM-1 expression is related to some miRNA species such as miRs-22, −141, −155, miR-221, −222 and −296-3p (Jansen et al., 2015; Liu et al., 2017, Liu et al., 2015b). Furthermore, recent advances in human population-based studies suggested a possible response of specific miRNAs to environmental exposure, resulting from the combined effect of genes and environmental contaminants and the interactions between them (Vrijens et al., 2015). There are also some reports on the linkage between BDE-209 exposure and specific miRNA expression. A birth cohort study showed a positive association between BDE-209 concentrations in placentas and placental level of miRNA-188 (Li et al., 2015). Another research assessing the effects of BDE-209 on the early human embryonic development showed that the levels of miRs-145 and −335 were increased after BDE-209 exposure in human embryonic stem cell lines (Du et al., 2016). These results suggest that BDE-209 exposure may activate specific miRNA programs in pathophysiological processes.

Given the still prevalent exposure of BDE-209 in the blood of the general population and the lack of information regarding the vascular toxicity of this new POP, the aims of this study were to evaluate the effects of BDE-209 exposure on the monocyte-endothelial cell adhesion and to identify the underlying mechanism(s) involved, using the interaction between THP-1 cells and human aortic endothelial cells (HAECs) as a model. Our data indicate that BDE-209 can dose-dependently increase the adhesion of THP-1 to HAECs through up-regulation of the expression of ICAM-1, which is regulated by a decreased expression of miR-141 following BDE-209 exposure. Thus, the present study provides new insights into potential cardiovascular toxicity of BDE-209.

Section snippets

Chemicals and reagents

BDE-209 (CAS No. 1163–19-5, 95.9% purity) and dimethyl sulfoxide (DSMO) were obtained from Dr. Ehrenstorfer GmbH (Germany) and Sigma-Aldrich (USA), respectively. BDE-209 was dissolved in 100% of DMSO to make a stock solution of 2 mM. The stock was further diluted for testing.

Cell culture and BDE-209 treatment

HAECs and human monocytes (THP-1) were obtained from the American Type Culture Collection (ATCC; USA). HAECs were cultured in endothelial growth medium (EGM; PromoCell, Heigelberg) supplemented with 2% fetal calf serum

Cell viability

BDE-209 reduced viability of HAECs in a concentration-dependent manner (Fig. S1). The no observed effect concentration (NOEC), defined as the BDE-209 concentration that did not cause significant difference in the cell viability compared with the control, was 3.12 μM. The half maximal inhibitory concentration (IC50) and 20-percent inhibitory concentration (IC20) for BDE-209 were also calculated using the equation representing the relationship between the observed values of cell viability and the

Discussion

Over the past few decades, the numbers of individuals worldwide with CVD and the associated deaths and disability have increased substantially (Pagidipati and Gaziano, 2013). Therefore, increased knowledge of suspected risk factors of CVD is imperative from a public health perspective. Emerging evidence suggests a statistical association between incidence of CVD and the exposure to legacy POPs such as PCBs (Perkins et al., 2016, Gupta et al., 2018). BDE-209, a new POP recently listed in the

Conclusions

Herein, we provide evidence that BDE-209 stimulates monocyte adhesion to human vascular endothelial cells via up-regulation of the adhesion molecule ICAM-1. Furthermore, BDE-209 induces ICAM-1 expression by decreasing expression of miR-141. This study reveals a novel molecular mechanism of POPs action and how they potentially contribute to CVD. Further research on the possible effects of BDE-209 exposure on other pathogenesis of CVD or its risk factors is needed, to thoroughly identify the

Acknowledgments

Dr. Qing Wang from the First Affiliated Hospital, Sun Yat-sen University is kindly acknowledged for her assistance in qPCR analysis. This work was financially supported by the Natural Science Foundation of the Anhui Higher Education Institutions of China (Grant KJ2018A0258), the National Natural Science Foundation of China (Grant 41373105) and the Strategic Priority Research Program of the Chinese Academy of Sciences (Grant XDB14020301). Bi-Xian Mai is grateful to the Local Innovative and

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