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.

The enzymatic, chemical, and thermal breakdown pathways of glucobrassicin, the major indolylmethyl glucosinolate of cruciferous vegetables, have been studied using synthetic 3H-labeled glucobrassicin (GBS). Radio-HPLC was used to analyze qualitatively and quantitatively the resulting products as well as their kinetics of formation. Enzymatic breakdown of GBS under myrosinase action gave rise to different indole compounds [indole-3-carbinol (I3C), indole-3-acetonitrile (IAN), and 3,3‘-diindolylmethane (DIM)]. At neutral pH, GBS degradation was almost complete after 1 h, and the major breakdown product was I3C, which could be converted to DIM. The formation of this self-condensation product was observed as photosensitive. In acidic conditions, enzymatic degradation of GBS was a slower phenomenon, requiring 24 h to be nearly complete. IAN and I3C were the only two products occurring, and it was observed that the light had no effect either on the rate of formation or on the relative proportions of the breakdown products observed. GBS appeared as a very stable compound since no chemical degradation could be observed after 2 h in different aqueous media with pH in the 2−11 range. Moreover, after exposure to heat treatment, GBS was weakly degraded (10% in 1 h), giving rise to a new minor indole condensation product corresponding to a 3-(indolylmethyl)glucobrassicin (IM-GBS). Keywords: Glucosinolates; glucobrassicin; indole derivatives; anticarcinogenic substances; enzymatic breakdown; chemical breakdown; thermal breakdown