Thyroid Disruption by Bisphenol S Analogues via Thyroid Hormone Receptor β: in Vitro, in Vivo, and Molecular Dynamics Simulation Study

Abstract

Bisphenol S (4-hydroxyphenyl sulfone, BPS) is increasingly used as a bisphenol A (BPA) alternative. The global usage of BPS and its analogues (BPSs) resulted in the frequent detection of their residues in multiple environmental media. We investigated their potential endocrine-disrupting effects toward thyroid hormone receptor (TR) β. The molecular interaction of BPSs toward TRβ ligand binding domain (LBD) was probed by fluorescence spectroscopy and molecular dynamics (MD) simulations. BPSs caused the static fluorescence quenching of TRβ LBD. The 100 ns MD simulations revealed that the binding of BPSs caused significant changes in the distance between residue His435 at helix 11(H11) and residue Phe459 at H12 in comparison to no ligand-bound TRβ LBD, indicating relative repositioning of H12. The recombinant two-hybrid yeast assay showed that tetrabromobisphenol S (TBBPS) and tetrabromobisphenol A (TBBPA) have potent antagonistic activity toward TRβ, with an IC of 10.1 and 21.1 nM, respectively. BPS and BPA have the antagonistic activity with IC of 312 and 884 nM, respectively. BPSs significantly altered the expression level of mRNA of TRβ gene in zebrafish embryos. BPS and TBBPS at environmentally relevant concentrations have antagonistic activity toward TRβ, implying that BPSs are not safe BPA alternatives in many BPA-free products. Future health risk assessments for TR disruption and other adverse effects should focus more on the structure-activity relationship in the design of environmentally benign BPA alternatives.

Bisphenols and Thyroid Hormone

“…Like BPA, BPF and BPS can bind TRβ and exert antagonistic activity [4849]. In zebrafish, BPF exposure altered T 4 , T 3 , and TSH levels and changed the expression of genes including Tg , Ttr , and Ugt1ab [3350].…”

Multiplex Analysis Platform for Endocrine Disruption Prediction Using Zebrafish

“…However, since dilution factors for estrogens were optimized to detect effects on the parental pathway, it is possible that the lack of response may be due to the relatively low concentrations tested. It is interesting to note that BPA was recognized as a thyroid antagonist in cell-based assays [56] and described to alter some genes within the HPT axis in vivo [57,58]. However, results in vivo have to be taken cautiously since embryos were exposed from 0–72 hpf in both cases, an exposure window that may interfere with the development of the thyroid gland rather than affecting thyroid signaling.…”

Bisphenols as Environmental Triggers of Thyroid Dysfunction: Clues and Evidence

“…BPs mainly acts as TR antagonists, inhibiting crucial processes related to development [64][65][66][67]. The TH signaling interference can occur by a direct binding of BPs to the receptor due to the high degree of structural similarity with THs ( Figure 1) and preventing the binding of T3 [10,[68][69][70][71]. Inhibitory effects of BPs on T3 hormonal activity were reported in different cell lines at doses of 10 6 -10 −4 M [2,10,64,65,69,[72][73][74], with brominated bisphenols showing a much stronger anti-TH activity than BPA and BPS [68].…”

“…Similarly, BPs disrupting effects on thyroid gene expression vary according to the different experimental conditions, especially the duration of exposure [126]. Hence, transcription levels of genes implicated in thyroid cell function and proliferation (Tsh-r), TH activity (Trα, Trβ), and transport (Ttr) can be up- [37,68,126,130,132,133] or down-regulated [38,68,126,128,130,133]. The transcription of Hematopoietically expressed homeobox (Hhex) was up-regulated in larval fish following exposure to BPA or BPF, although it is important to note that the Hhex gene is expressed in early life, contributing to differentiation and development of the thyroid gland, as well as of other organs, such as the pancreas and liver [37].…”