title: Parallel biotransformation of tetrabromobisphenol A in Xenopus laevis and mammals: Xenopus as a model for endocrine perturbation studies.
abstract: The flame retardant tetrabromobisphenol A (TBBPA) is a high production flame retardant that interferes with thyroid hormone (TH) signaling. Despite its rapid metabolism in mammals, TBBPA is found in significant amounts in different tissues. Such findings highlight first a need to better understand the effects of TBBPA and its metabolites and second the need to develop models to address these questions experimentally. We used Xenopus laevis tadpoles to follow radiolabeled (14)C-TBBPA uptake and metabolism. Extensive and rapid uptake of radioactivity was observed, tadpoles metabolizing > 94% of (14)C-TBBPA within 8 h. Four metabolites were identified in water and tadpole extracts: TBBPA-glucuronide, TBBPA-glucuronide-sulfate, TBBPA-sulfate, and TBBPA-disulfate. These metabolites are identical to the TBBPA conjugates characterized in mammals, including humans. Most radioactivity (> 75%) was associated with sulfated conjugates. The antithyroid effects of TBBPA and the metabolites were compared using two in vivo measures: tadpole morphology and an in vivo tadpole TH reporter gene assay. Only TBBPA, and not the sulfated metabolites, disrupted thyroid signaling. Moreover, TBBPA treatment did not affect expression of phase II enzymes involved in TH metabolism, suggesting that the antithyroid effects of TBBPA are not due to indirect effects on TH metabolism. Finally, we show that only the parent TBBPA inhibits T3-induced transactivation in cells expressing human, zebrafish, or X. laevis TH receptor, TRα. We conclude, first, that perturbation of thyroid signaling by TBBPA is likely due to rapid direct action of the parent compound, and second, that Xenopus is an excellent vertebrate model for biotransformation studies, displaying homologous pathways to mammals.
authors.affiliation: UMR CNRS 7221, Evolution des Régulations Endocriniennes Department of Regulations, Development and Molecular Diversity, Muséum National d'Histoire Naturelle, 75231 Paris Cedex 05, France.
authors.forename: Jean-Baptiste
authors.initials: JB
authors.lastname: Fini
authors.forename: Anne
authors.initials: A
authors.lastname: Riu
authors.forename: Laurent
authors.initials: L
authors.lastname: Debrauwer
authors.forename: Anne
authors.initials: A
authors.lastname: Hillenweck
authors.forename: Sébastien
authors.initials: S
authors.lastname: Le Mével
authors.forename: Sylvie
authors.initials: S
authors.lastname: Chevolleau
authors.forename: Abdelaye
authors.initials: A
authors.lastname: Boulahtouf
authors.forename: Karima
authors.initials: K
authors.lastname: Palmier
authors.forename: Patrick
authors.initials: P
authors.lastname: Balaguer
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Cravedi
authors.forename: Barbara A
authors.initials: BA
authors.lastname: Demeneix
authors.forename: Daniel
authors.initials: D
authors.lastname: Zalko
mesh_terms: D000818:Animals; D013956:Antithyroid Agents / Q000378:metabolism* / Q000633:toxicity; D001667:Binding, Competitive; D001711:Biotransformation; D002853:Chromatography, Liquid; D004305:Dose-Response Relationship, Drug; D052244:Endocrine Disruptors / Q000378:metabolism* / Q000633:toxicity; D005411:Flame Retardants / Q000378:metabolism* / Q000633:toxicity; D017930:Genes, Reporter; D020719:Glucuronides / Q000378:metabolism; D006801:Humans; D007700:Kinetics; D007814:Larva / Q000187:drug effects / Q000378:metabolism; D011075:Polybrominated Biphenyls / Q000378:metabolism* / Q000633:toxicity; D021241:Spectrometry, Mass, Electrospray Ionization; D013431:Sulfates / Q000378:metabolism; D037021:Thyroid Hormone Receptors alpha / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D018675:Toxicity Tests / Q000379:methods*; D015533:Transcriptional Activation / Q000187:drug effects; D014162:Transfection; D014284:Triiodothyronine / Q000378:metabolism; D014982:Xenopus laevis / Q000196:embryology / Q000235:genetics / Q000378:metabolism*; D029961:Zebrafish Proteins / Q000187:drug effects / Q000235:genetics
chemical_list: D013956:Antithyroid Agents; D052244:Endocrine Disruptors; D005411:Flame Retardants; D020719:Glucuronides; D011075:Polybrominated Biphenyls; D013431:Sulfates; D037021:Thyroid Hormone Receptors alpha; D029961:Zebrafish Proteins; D014284:Triiodothyronine; C020806:tetrabromobisphenol A