Parallel Biotransformation of Tetrabromobisphenol A in Xenopus laevis and Mammals: Xenopus as a Model for Endocrine Perturbation Studies

• Published in: Toxicological Sciences Vol. 125; no. 2; pp. 359 - 367
• Main Authors: Fini, Jean-Baptiste, Riu, Anne, Debrauwer, Laurent, Hillenweck, Anne, Le Mével, Sébastien, Chevolleau, Sylvie, Boulahtouf, Abdelaye, Palmier, Karima, Balaguer, Patrick, Cravedi, Jean-Pierre, Demeneix, Barbara A., Zalko, Daniel
• Format: Journal Article
• Language: English
• Published: United States Oxford University Press 01.02.2012; Oxford University Press (OUP)
• Subjects: Animals; Antithyroid Agents - metabolism; Antithyroid Agents - toxicity; Binding, Competitive; Biotransformation; Chromatography, Liquid; Dose-Response Relationship, Drug; Endocrine Disruptors - metabolism; Endocrine Disruptors - toxicity; Flame Retardants - metabolism; Flame Retardants - toxicity; Genes, Reporter; Glucuronides - metabolism; Humans; Kinetics; Larva - drug effects; Larva - metabolism; Life Sciences; Polybrominated Biphenyls - metabolism; Polybrominated Biphenyls - toxicity; Spectrometry, Mass, Electrospray Ionization; Sulfates - metabolism; Thyroid Hormone Receptors alpha - drug effects; Thyroid Hormone Receptors alpha - genetics; Thyroid Hormone Receptors alpha - metabolism; Toxicity Tests - methods; Transcriptional Activation - drug effects; Transfection; Triiodothyronine - metabolism; Xenopus laevis - embryology; Xenopus laevis - genetics; Xenopus laevis - metabolism; Zebrafish Proteins - drug effects; Zebrafish Proteins - genetics; biotransformation; thyroid hormone; vertebrate model; metabolism; TBBPA; endocrine disruption; phase II metabolism
• ISSN: 1096-6080; 1096-0929; 1096-0929; 1096-6099
• DOI: 10.1093/toxsci/kfr312

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 14C-TBBPA uptake and metabolism. Extensive and rapid uptake of radioactivity was observed, tadpoles metabolizing > 94% of 14C-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.