Halogen Bonding Interactions of Polychlorinated Biphenyls and the Potential for Thyroid Disruption

Abstract

Polychlorinated biphenyl (PCB) flame retardants are persistent pollutants and inhibit neurodevelopment, particularly in the early stages of life. Halogen bonding (XB) to the iodothyronine deiodinases (Dio) that modulate thyroid hormones (THs) is a potential mechanism for endocrine disruption. Cl⋅⋅⋅Se XB interactions of PCBs with SeMe−, a small model of the Dio active site selenocysteine, are compared with previous results on polybrominated diphenylethers (PBDEs) and THs using density functional theory. PCBs generally display weaker XB interactions compared to PBDEs and THs, consistent with the dependence of XB strength on the size of the halogen (I>Br>Cl). PCBs also do not meet a proposed energy threshold for substrates to undergo dehalogenation, suggesting they may behave as competitive inhibitors of Dio in addition to other mechanisms of endocrine disruption. XB interactions in PCBs are position‐dependent, with ortho interactions slightly more favorable than meta and para interactions, suggesting that PCBs may have a greater effect on certain classes of Dio. Flexibility of PCBs around the biphenyl C−C bond is limited by ortho substitutions relative to the biphenyl linkage, which may contribute to the ability to inhibit Dio and other TH‐related proteins.

A Halogen Bonding Perspective on Iodothyronine Deiodinase Activity

“…Modeling of the Cl•••Se XB interactions for all possible 209 PCB congeners at each unique XB position found that PCBs have much weaker XB interactions than PBDEs and THs (Figure 9), as expected based on the trend of XB strength in the order of I > Br > Cl [73]. XB interactions for PCBs are more favorable at the ortho position, consistent with PBDE XB interactions.…”

“…These two conformations differ in terms of toxicity-non-dioxin-like PCBs are only toxic at higher concentrations (>1000 nM), while dioxin-like PCBs are highly toxic and mimic the structure of TCDD. Addition of halogens to ortho positions restrain the PCB to a noncoplanar conformation due to steric clashes, leading to lower flexibility around the central C-C bond [73]. Therefore, highly-ortho chlorinated species have much lower conformational flexibility, which may impact the ability of the PCB to adapt to the active site and inhibit the protein.…”

“…Meta and para XB interactions also generally have higher %X values compared to ortho XB interactions, consistent with their stronger ∆E D→A values. The slightly more favorable XB interactions for meta and para chlorides flanked by two halogens are attributed to the electron-withdrawing properties of the neighboring substituents, which stabilizes the σ C-Cl * acceptor MO [73].…”

“…Dios prefer the rare Sec residue due to its high nucleophilicity relative to Cys, which is enhanced by deprotonation at physiological conditions. Recent studies by our group explored the possibility that organohalogens like PCBs and PBDEs could inhibit Dio activity by blocking the active site through an X•••Se halogen bonding (XB) interaction [28,73]. PCBs, like PBDEs, are industrial flame retardants with high chemical stability (Figure 2b) [42,43].…”

Endocrine-disrupting pollutants properties affecting their bioactivity, remediation, and detection

“…The C-I bond in THs had the best orbital overlap with the Se donor, leading to high donor-acceptor energies and the greatest activation of the C-X bond. The higher orbital energy gaps of C-Br and C-Cl bonds in PBDEs and PCBs, respectively, resulted in weaker donor-acceptor complexes and weaker C-X activation [39]. Comparison of halogen•••selenium interactions suggested the existence of a threshold of noncovalent bonding strength required for dehalogenation.…”