Metabolism of polybrominated diphenyl ethers (PBDEs) by human hepatocytes in vitro.

Polybrominated diphenyl ethers (PBDEs) are a class of flame-retardant chemicals frequently applied to textiles, furniture, and electronic and electrical items. Large amounts of PBDEs have been produced and applied over the past few decades, resulting in widespread contamination of the environment and accumulation in food webs. Furthermore, because of their physico-chemical properties, PBDEs are persistent in the environment and bioaccumulate in both aquatic and terrestrial food webs (Alaee et al. 2003; Christensen et al. 2005; de Wit et al. 2006; Law et al. 2006). A number of laboratory animal exposure studies have found significant species-specific differences in uptake kinetics, metabolism, and disposition of several different 14C-labeled and unlabeled PBDE congeners. For example, mice or rats exposed in vivo to 2,2′,4,4′,5-penta-bromodiphenyl ether (BDE-99) have been found to produce oxidative metabolites, such as hydroxylated BDE congeners (OH-BDE) (Chen et al. 2006; Hakk et al. 2002; Qiu et al. 2007). However, in vivo exposure of common carp (Cyprinus carpio) to BDE-99 resulted in significant formation and accumulation of a reductively debrominated metabolite, 2,2′,4,4′-tetrabromodiphenyl ether (BDE-47) (Stapleton et al. 2004). In addition, the extent of metabolism in these studies depends on the structure and bromine substitution of the BDE congener. BDE-99 appears to be metabolized to a greater extent than does BDE-47, 2,2′,4,4′,5,5′-hexabromodiphneyl ether (BDE-153), or 2,2′,3,3′,4,4′,5,5′,6,6′-deca-bromodiphenyl ether (BDE-209) (Chen et al. 2006; Morck et al. 2003; Staskal et al. 2006). Thus, these laboratory PBDE metabolism studies suggest that humans will accumulate and metabolize PBDEs; however, it is not clear how PBDEs are specifically metabolized in human tissues and what types of metabolites will be formed. Studies have documented measurements of PBDEs in several different human populations, and their presence in tissues appears to be ubiquitous (Hites 2004; Schecter et al. 2003; Sjodin et al. 2001). The primary congeners detected in human tissues include BDE congeners 47, 99, and 153, which are the primary congeners found in a commercial mixture referred to as pentaBDE. To our knowledge, no studies have investigated the metabolism of BDE congeners in human tissues. Analyses of human sera have identified multiple OH-BDE congeners, suggesting that metabolism does occur (Athanasiadou et al. 2008); however, natural sources of OH-BDEs have also been identified in marine environments (Malmvarn et al. 2005). The formation of OH-BDE metabolites is of concern because greater adverse effects have been documented for the OH-BDEs relative to the PBDEs in laboratory studies. For example, OH-BDEs have been shown to significantly affect aromatase activity in human adrenocortical carcinoma cells, whereas PBDEs had no effect (Canton et al. 2005). In addition, OH-BDEs have an order of magnitude higher potency than do PBDEs in their ability to compete with thyroid hormones for binding sites on serum transporters (Hamers et al. 2006; Meerts et al. 2000, 2001). We undertook the present study to determine whether PBDE metabolites could be detected after in vitro exposure to human hepatocytes. Our objective was to determine if reductively debrominated and/or OH metabolites of BDE congeners 99 and 209 (i.e., the primary congeners found in the pentaBDE and decaBDE commercial mixtures) would be produced by human hepatocytes. We also designed this study to examine the expression of genes coding for the enzymes potentially involved in the metabolism of PBDEs through oxidative and reductive pathways.