Structural binding perspectives of common plasticizers and a flame retardant, BDE‐153, against thyroxine‐binding globulin: potential for endocrine disruption

Abstract

The human exposure to diverse endocrine‐disrupting chemicals (EDCs) has increased dramatically over several decades with very adverse health effects. Plasticizers and flame retardants constitute important classes of EDCs interfering in endocrine physiology including the thyroid function. Thyroxine (T4) is an important hormone regulating metabolism and playing key roles in developmental processes. In this study, six phthalate and nonphthalate plasticizers and one flame retardant (BDE‐153) were subjected to structural binding against thyroxine‐binding globulin (TBG). The aim was to understand their potential role in thyroid dysfunction using structural binding approach. The structural study was performed using Schrodinger's induced fit docking, followed by binding energy estimations of ligands and the molecular interaction analysis between the ligands and the amino acid residues in the TBG ligand‐binding pocket. The results indicated that all the compounds packed tightly into the TBG ligand‐binding pocket with similar binding pattern to that of TBG native ligand, T4. A high majority of TBG interacting amino acid residues for ligands showed commonality with native ligand, T4. The estimated binding energy values were highest for BDE‐153 followed by nonphthalate plasticizer, DINCH, with values comparable with native ligand, T4. The estimated binding energy values of other plasticizers DEHP, DEHT, DEHA, ATBC, and TOTM were less than DINCH. In conclusion, the tight docking conformations, amino acid interactions, and binding energy values of the most of the indicated ligands were comparable with TBG native ligand, T4, suggesting their potential for thyroid dysfunction. The results revealed highest potential thyroid disruptive action for BDE‐153 and DINCH.

Effects of Polybrominated Diphenyl Ethers on Hormonal and Reproductive Health in E-Waste-Exposed Population: A Systematic Review

“…PBDEs can also compete with T4 to bind with thyroxin-binding globulin and transthyretin, which transport thyroid hormones and prolong their half-life, and thyroid hormone receptor alpha and thyroid hormone receptor beta, which are thyroid hormone nuclear receptors responsible for the transcription of genes [66,70,71]. This will decrease T4 levels in the blood and cause thyroid gland hyperactivity as a feedback response [72], similar to our review's findings.…”

“…Thyroid hormones exert their influence in the body at extremely low doses and are maintained through complex feedback mechanisms such that interactions of even low doses of PBDEs can cause disruptions in homeostasis through multiple known pathways [63][64][65][66]. For example, PBDEs and their metabolites can alter thyroid hormones by their interaction with deiodinases, which are enzymes that help in the synthesis of T3 from T4, by competing with T4 to bind at the active site [67].…”

Insights into the Endocrine Disrupting Activity of Emerging Non-Phthalate Alternate Plasticizers against Thyroid Hormone Receptor: A Structural Perspective

“…Furthermore, metabolites of DEHA were shown to induce cytotoxicity in murine L929 Cell Line [ 35 ]. In our recent in silico study, we also reported potential thyroid dysregulation by non-phthalate alternate plasticizers, such as DINCH, DEHA, ATBC, etc., because of interactions with thyroxine-binding globulin [ 36 ]. All these above and other limited evidences point to the potential health risks of these emerging environmental contaminants, which is a serious cause of concern.…”

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

“…For example, Li et al reported the docking studies of PBDE structural analogues (hydroxylated PBDEs) with TR [ 63 ]. Similarly, in our previous study, we reported that BDE-153 structurally interacts with thyroxine binding globulin (TBG) [ 52 ]. In another study, we reported the binding of BDE-47, BDE-99, and their structural analogues with TBG [ 51 ].…”

“…PBDEs share their chemical structural resemblance with thyroid hormones, and hence have the potential to interfere with thyroid hormone action. The possible mechanisms include competitive binding with thyroid hormone receptors (TRα) and thyroid hormone transport proteins [ 49 , 50 , 51 , 52 ] and an increase in metabolism and clearance of T4 [ 53 ]. Numerous studies have reported that PBDEs interfere with T4 transport causing thyroid dysfunction [ 50 , 54 , 55 ].…”