title: Analysis of Ah receptor pathway activation by brominated flame retardants.
abstract: Brominated flame-retardants (BFRs) are used as additives in plastics to decrease the rate of combustion of these materials, leading to greater consumer safety. As the use of plastics has increased, the production and use of flame-retardants has also grown. Many BFRs are persistent and have been detected in environmental samples, raising concerns about the biological/toxicological risk associated with their use. Most BFRs appear to be non-toxic, however there is still some concern that these compounds, or possible contaminants in BFRs mixtures could interact with cellular receptors. In this study we have examined the interaction of decabromodiphenyl ether, Firemaster BP4A (tetrabromobisphenol A), Firemaster PHT4 (tetrabromophthalic anhydride), hexabromobenzene, pentabromotoluene, decabromobiphenyl, Firemaster BP-6 (2,2',4,4',5,5'-hexabromobiphenyl) and possible contaminants of BFR mixtures with the Ah receptor. Receptor binding and activation was examined using the Gel Retardation Assay and increased expression of dioxin responsive genes was detected using the reporter gene based CALUX assay. The results demonstrate the ability of BFRs to activate the AhR signal transduction pathway at moderate to high concentrations as assessed using both assays. AhR-dependent activation by BFRs may be due in part to contaminants present in commercial/technical mixtures. This was suggested by our comparative analysis of Firemaster BP-6 versus its primary component 2,2',4,4',5,5'-hexabromobiphenyl. Some technical mixtures of brominated flame-retardants contain brominated biphenyls, dioxins or dibenzofurans as contaminants. When tested in the CALUX assay these compounds were found to be equivalent to, or more active than their chlorinated analogues. Relative effective potency values were determined from dose response curves for these brominated HAHs.
authors.affiliation: Xenobiotic Detection Systems Inc., 1601 East Geer Street, Suite S, Durham, NC 27704, USA. davidbrown@dioxins.com
authors.forename: David J
authors.initials: DJ
authors.lastname: Brown
authors.forename: Ilse
authors.initials: I
authors.lastname: Van Overmeire
authors.forename: Leo
authors.initials: L
authors.lastname: Goeyens
authors.forename: Michael S
authors.initials: MS
authors.lastname: Denison
authors.forename: Michael J
authors.initials: MJ
authors.lastname: De Vito
authors.forename: George C
authors.initials: GC
authors.lastname: Clark
mesh_terms: D000818:Animals; D001572:Benzofurans / Q000032:analysis; D017605:Bromine Compounds / Q000378:metabolism* / Q000633:toxicity; D003600:Cytosol / Q000378:metabolism*; D004147:Dioxins / Q000032:analysis; D004305:Dose-Response Relationship, Drug; D024202:Electrophoretic Mobility Shift Assay; D005411:Flame Retardants / Q000378:metabolism* / Q000633:toxicity; D006168:Guinea Pigs; D008099:Liver / Q000378:metabolism*; D008156:Luciferases; D009841:Oligonucleotides; D010761:Phosphorus Radioisotopes; D011075:Polybrominated Biphenyls / Q000737:chemistry; D018336:Receptors, Aryl Hydrocarbon / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*
chemical_list: D001572:Benzofurans; D017605:Bromine Compounds; D004147:Dioxins; D005411:Flame Retardants; D009841:Oligonucleotides; D010761:Phosphorus Radioisotopes; D011075:Polybrominated Biphenyls; D018336:Receptors, Aryl Hydrocarbon; C018566:2,4,5,2',4',5'-hexabromobiphenyl; D008156:Luciferases