Tetrabromobisphenol A Disrupts Vertebrate Development via Thyroid Hormone Signaling Pathway in a Developmental Stage-Dependent Manner

Abstract

Data concerning effects of tetrabromobisphenol A (TBBPA) on thyroid hormone (TH)-dependent vertebrate development have been limited, although TBBPA has been demonstrated in vitro to disrupt the TH signaling pathway at the transcriptional level. In this study, we investigated the effects of TBBPA on T3-induced and spontaneous Xenopus laevis metamorphosis, which share many similarities with TH-dependent development in higher vertebrates. In a 6-day T3-induced metamorphosis assay using premetamorphic tadpoles, 10-1000 nM TBBPA exhibited inhibitory effects on T3-induced expression of TH-response genes and morphological changes in a concentration-dependent manner, with a weak stimulatory action on tadpole development and TH-response gene expression in the absence of T3 induction. In a spontaneous metamorphosis assay, we further found that TBBPA promoted tadpole development from stage 51 to 56 (pre- and prometamorphic stages) but inhibited metamorphic development from stage 57 to 66 (metamorphic climax). These results strongly show that TBBPA, even at low concentrations, disrupts TH-dependent development in a developmental stage-dependent manner, i.e., TBBPA exhibits an antagonistic activity at the developmental stages when animals have high endogenous TH levels, whereas it acts as an agonist at the developmental stages when animals have low endogenous TH levels. Our study highlights the adverse influences of TBBPA on TH-dependent development in vertebrates.

A screening assay for thyroid hormone signaling disruption based on thyroid hormone-response gene expression analysis in the frog Pelophylax nigromaculatus

“…laevis has been most commonly used to study TH signaling disruption of chemicals (Crump et al, 2002;Fini et al, 2007;Zhang et al, 2014). However, it is necessary to develop some other assays using native species, considering species differences and the accessibility of test species.…”

“…Given that amphibian metamorphosis serves as an ideal model for studying TH actions (Laudet, 2011;Opitz et al, 2005;Tata, 1993), this model has begun to be used to investigate the TH signaling disruption of chemicals (Veldhoen et al, 2006(Veldhoen et al, , 2014bZhang et al, 2014). In this model, pre-metamorphic tadpoles, which can be induced by TH to metamorphose precociously, are treated with test chemicals in the presence or absence of TH for several days.…”

“…At the end of treatment, if a chemical inhibits TH-induced metamorphosis at morphological and transcriptional levels, this chemical will be determined to be a TH signaling antagonist. In contrast, if a chemical promotes metamorphosis at morphological and transcriptional levels in the presence or absence of TH, this chemical will be determined as TH signaling agonist (Heimeier et al, 2009;Zhang et al, 2014). So far, the model organism Xenopus laevis is the most commonly used species to study TH signaling disruption (Crump et al, 2002;Fini et al, 2007;Searcy et al, 2012;Zhang et al, 2014).…”

“…In contrast, if a chemical promotes metamorphosis at morphological and transcriptional levels in the presence or absence of TH, this chemical will be determined as TH signaling agonist (Heimeier et al, 2009;Zhang et al, 2014). So far, the model organism Xenopus laevis is the most commonly used species to study TH signaling disruption (Crump et al, 2002;Fini et al, 2007;Searcy et al, 2012;Zhang et al, 2014). Also, certain native amphibian species are promising as test species for TH signaling disruption research (Hammond et al, 2013;Helbing et al, 2006;Veldhoen et al, 2014a).…”

“…Furthermore, we applied this assay to detect the TH signaling disrupting action of the flame retardant tetrabromobisphenol A (TBBPA), a known TH signaling disruptor, to validate the screening assay established (Jagnytsch et al, 2006;Terasaki et al, 2011;Zhang et al, 2014).…”