| Metabolism of Polybrominated Diphenyl Ethers (PBDEs) by Human Hepatocytes in Vitro Heather M. Stapleton,1 Shannon M. Kelly,1 Ruoting Pei,2 Robert J. Letcher,3 and Claudia Gunsch2 1Nicholas School of the Environment, Duke University, Durham, North Carolina, USA; 2Department of Civil and Environmental Engineering, Duke University, Durham, North Carolina, USA; 3Wildlife and Landscape Science Directorate, Science and Technology Branch, Environment Canada, National Wildlife Research Centre, Carleton University, Ottawa, Ontario, Canada Abstract
Background: Polybrominated diphenyl ethers (PBDEs) are flame-retardant chemicals that accumulate in human tissues and are potential toxicants. Concentrations of PBDEs in human tissues have increased recently, and body burdens in the U.S. and Canadian populations are higher than in any other region. Objectives: Although metabolism in animal laboratory studies has been examined, no studies have explored the metabolism of these contaminants in human tissues. We undertook this study to determine whether PBDEs could be metabolized by human liver cells in vitro and to identify what types of metabolites are formed. Methods: We exposed hepatocytes from three different donors (two cryopreserved batches and one fresh batch) to solutions containing 10 µM of either of two environmentally relevant and prominent PBDE congeners—BDE-99 or BDE-209—for periods of 24–72 hr. We also conducted gene expression analysis to provide information on potential induction of xenobiotic metabolizing enzymes. Results: Exposing hepatocytes to BDE-99 resulted in the formation of 2,4,5-tribromophenol, two monohydroxylated pentabrominated diphenyl ether metabolites, and a yet unidentified tetrabrominated metabolite. No hydroxylated or debrominated metabolites were observed in the cells exposed to BDE–209. This suggests that BDE-209 was not metabolized, that nonextractable, covalently protein-bound metabolites were formed, or that the exposure time was not long enough for BDE-209 to diffuse into the cell to be metabolized. However, we observed up-regulation of genes encoding for cytochrome P450 monooxygenase (CYP) 1A2, CYP3A4, deiodinase type 1, and glutathione S-transferase M1 in hepatocyes exposed to both BDE-99 and BDE–209. Conclusions: Our in vitro results suggest that the human liver will likely metabolize some BDE congeners (e.g., BDE-99) in vivo. These metabolites have been shown to elicit greater toxicity than the parent BDE congeners in laboratory bioassays ; thus, more research on body burdens and human health effects from these metabolites are warranted. Key words: brominated flame retardants, hepatocytes, metabolism, OH-PBDEs, polybrominated diphenyl ethers. Environ Health Perspect 117:197–202 (2009) . doi:10.1289/ehp.11807 available via http://dx.doi.org/ [Online 2 September 2008]
Address correspondence to H. Stapleton, Nicholas School of the Environment, Duke University, A220 LSRC, Box 90328, Durham, NC 27708 USA. Telephone: (919) 613-8717. Fax: (919) 684-8741. E-mail: heather.stapleton@duke.edu We thank T. Moeller (Celsis Inc.) for assistance and advice during these experiments, and S. Chu (National Wildlife Research Centre, Environment Canada, Carleton University) for expert liquid chromatography-mass spectrometry analysis for possible OH-containing metabolites from BDE-209. We also thank L. Birnbaum for assistance and advice in designing these experiments. The authors declare they have no competing financial interests. Received 16 June 2008 ; accepted 2 September 2008.
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