Academic journal article Environmental Health Perspectives

Hydroxylated Polybrominated Biphenyl Ethers Exert Estrogenic Effects Via Non-Genomic G Protein-Coupled Estrogen Receptor Mediated Pathways

Academic journal article Environmental Health Perspectives

Hydroxylated Polybrominated Biphenyl Ethers Exert Estrogenic Effects Via Non-Genomic G Protein-Coupled Estrogen Receptor Mediated Pathways

Article excerpt

Introduction

Polybrominated diphenyl ethers (PBDEs) have been and are currently used as flame retardant additives in a variety of industrial and consumer products such as plastic materials and textile fabrics (Li et al. 2017). As a result of such widespread use, PBDEs are thought to be ubiquitously present in human biological samples; in support of this theory, numerous studies from Europe, Asia, Australia, the United States, and Canada have detected measurable levels of various PBDEs in whole blood, plasma, and serum samples (Fromme et al. 2016). In addition, hydroxylated PBDEs (OH-PBDEs), which are metabolically biotransformed from PBDEs or of natural origin, were also found in the blood serum of children 11-15 yold residing in Nicaragua (Athanasiadou et al. 2008) and in the blood of pregnant women in the U.S. state of Indiana (Qiu et al. 2009). There is evidence that the toxicologic effects reported for PBDEs on the thyroid hormone receptor (Li et al. 2010) and the estrogen receptor (Mercado-Feliciano and Bigsby 2008a) might be enhanced by metabolism of the parent compounds to OH-PBDEs.

Specific PBDEs have been shown to disrupt thyroid function in various in vivo animal models, including birds, fish, and rodents (Jugan et al. 2010; Legler 2008) and were associated with changes in the thyroid hormone thyroxine in U.S. adult male sportfish consumers (Turyk et al. 2008). Moreover, PBDEs were shown to increase the migration and invasion of human colorectal carcinoma cells (Wang et al. 2015) and the viability and proliferation of human breast, ovarian, and cervical cancer cells (Li et al. 2012), supporting potential carcinogenic activity. Finally, PBDEs have been associated with neurodevelopmental deficits in rats and humans (Herbstman and Mall 2014). In recent years, there has been growing concern about the estrogen-disrupting activities of PBDEs. For example, in vivo studies showed that exposure of pregnant rats to PBDE-99 (1-10 mg/kg) resulted in changes in the regulation of estrogen target genes in the uterus of female offspring (Ceccatelli et al. 2006), decreases in sex steroid levels and disruption of sexual development in male and female offspring (Lilienthal et al. 2006), and exhibition of sexually dimorphic behavior in male offspring (Lilienthal et al. 2006). Using the ovariectomized (OVX) mouse as a model, Mercado-Feliciano and Bigsby (2008b) found that exposure to PBDE mixture DE-71 (50 mg/kg) led to changes in uterine weight, uterine epithelial height, and vaginal epithelial thickness. In addition, in vitro studies showed that some PBDEs and OH-PBDEs exerted estrogenic effects in Chinese hamster ovary (Kojima et al. 2009) and human breast cancer (Meerts et al. 2001) cell lines.

The mechanisms by which exogenous chemicals are thought to disrupt the estrogen system are numerous and complex (Shanle and Xu 2011). An exogenous chemical may exert estrogenic effects by both classical nuclear estrogen receptors (ERs) and non-genomic G protein-coupled estrogen receptor (GPER) pathways (Shanle and Xu 2011). Earlier mechanistic studies of the exogenous chemicals focused on their estrogenic effects through ER-mediated pathways (Li et al. 2013; Meerts et al. 2001; Mercado-Feliciano and Bigsby 2008a). In recent years, a growing body of evidence has shown that some exogenous chemicals, such as bisphenol A (BPA), atrazine, nonylphenol, kepone, and genistein, might exert their estrogenic effects by activating GPERmediated pathways (Albanito et al. 2015; Pupo et al. 2012; Thomas and Dong 2006). Understanding how estrogenic compounds activate GPER pathways is essential to thoroughly evaluating potential estrogenic effects. It has been shown that PBDEs and OH-PBDEs had weak activities towards ERs [with activities [10.sup.4]-to [10.sup.7]-fold less potent than 17[beta]-estradiol ([E.sub.2])] (Kojima et al. 2009; Li et al. 2013; Meerts et al. 2001; Mercado-Feliciano and Bigsby 2008a). Some OH-PBDEs bind to ERs directly with relatively low binding affinities (with binding potencies of 0. …

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