An Analysis of the Structural Relationship between Thyroid Hormone-Signaling Disruption and Polybrominated Diphenyl Ethers: Potential Implications for Male Infertility

Abstract

Polybrominated diphenyl ethers (PBDEs) are a common class of anthropogenic organobromine chemicals with fire-retardant properties and are extensively used in consumer products, such as electrical and electronic equipment, furniture, textiles, and foams. Due to their extensive use, PBDEs have wide eco-chemical dissemination and tend to bioaccumulate in wildlife and humans with many potential adverse health effects in humans, such as neurodevelopmental deficits, cancer, thyroid hormone disruption, dysfunction of reproductive system, and infertility. Many PBDEs have been listed as chemicals of international concern under the Stockholm Convention on Persistent Organic Pollutants. In this study, the aim was to investigate the structural interactions of PBDEs against thyroid hormone receptor (TRα) with potential implications in reproductive function. Structural binding of four PBDEs, i.e., BDE-28, BDE-100, BDE-153 and BDE-154 was investigated against the ligand binding pocket of TRα using Schrodinger’s induced fit docking, followed by molecular interaction analysis and the binding energy estimation. The results indicated the stable and tight binding of all four PDBE ligands and similarity in the binding interaction pattern to that of TRα native ligand, triiodothyronine (T3). The estimated binding energy value for BDE-153 was the highest among four PBDEs and was more than that of T3. This was followed by BDE-154, which is approximately the same as that of TRα native ligand, T3. Furthermore, the value estimated for BDE-28 was the lowest; however, the binding energy value for BDE-100 was more than BDE-28 and close to that of TRα native ligand, T3. In conclusion, the results of our study suggested the thyroid signaling disruption potential of indicated ligands according to their binding energy order, which can possibly lead to disruption of reproductive function and infertility.

Thyroid Hormone Biomonitoring: A Review on Their Metabolism and Machine-Learning Based Analysis on Effects of Endocrine Disrupting Chemicals

“…Another potential disruptive mechanism is competitive binding of PBDEs with TRs, as demonstrated in cell and animal experiments. In vitro cell studies have shown that PBDEs have an affinity similar to FT3 for binding with TRs (TRα and TRβ), thereby hindering FT3 activation in tissues. − Electrostatic interaction and hydrophobic interactions significantly contribute to the interference with TH-protein binding . Molecular dynamics simulations estimates on 18 OH-PBDEs reveals that the presence of more Br atom in OH-PBDEs results in stronger binding potential with THRβ-LBD .…”

A Review of the Association between Exposure to Flame Retardants and Thyroid Function

“…Zhang et al found that BTBPE levels reduced protein levels of PAX8, TTF1, and TTF2, inhibiting thyroglobulin and NIS [ 25 ]. More recent studies have begun analyzing the molecular relationships between specific flame retardants and thyroid hormones, including analysis of binding energies [ 13 ]. Sheikh et al analyzed the structural binding of PBDEs against the ligand binding pocket of thyroid receptor alpha and identified the specific amino acid residues and quantified the interactions in the binding pocket [ 13 ].…”

“…More recent studies have begun analyzing the molecular relationships between specific flame retardants and thyroid hormones, including analysis of binding energies [ 13 ]. Sheikh et al analyzed the structural binding of PBDEs against the ligand binding pocket of thyroid receptor alpha and identified the specific amino acid residues and quantified the interactions in the binding pocket [ 13 ]. Within human hepatic tissue, PBDEs are converted into their more active metabolite, OH-PBDEs, a chemical with even greater structural similarity to thyroid hormones.…”

“…The United States Consumer Product Safety Commission has also banned the sales of certain products that contain PBDEs for similar reasons as prior legislation with a particular emphasis on vulnerable populations including infants and children [ 12 ]. Many flame retardants, including tetrabrominated diphenyl ethers, hexabrominated diphenyl ethers, decabromodiphenyl ether, and hexabromocyclododecane, have been listed under several legislations, including the Stockholm Convention on Persistent Organic Pollutants [ 13 ]. Several states within the United States, including New York and California, have begun passing bills against products containing these molecules [ 14 ].…”