Search

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 (Dios) 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 necessary for substrates to undergo dehalogenation, suggesting they may behave as competitive inhibitors to 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.

Polybrominated diphenyl ethers (PBDEs) increase flame resistance in consumer goods, but these compounds and their hydroxylated derivatives (OH-BDEs) impair normal thyroid function. Halogen bonding (XB) of PBDEs to an active site selenocysteine may prevent iodothyronine deiodinase(Dio)-catalyzed activation/deactivation of thyroid hormone (TH) derivatives. In this study, we compare the strength of the XB interactions of TH derivatives, iodine-based contrast agents and PBDEs/OH-BDEs with a methylselenolate model of the Dio active site using density functional theory calculations. The strength of the XB interaction depends upon the acceptor halide, the position of the halide, the number of ring substituents, and the proximity of hydroxyl groups to the XB site. The weaker Se⋅⋅⋅Br interactions relative to Se⋅⋅⋅I interactions are consistent with a model of competitive inhibition that blocks binding of THs at elevated PBDE/OH-BDE concentrations. XB interactions were generally more favorable at ortho and meta positions and in substrates with more electron-withdrawing substituents. PBDEs/OH-BDEs that mimic the binding behavior of THs, that is, containing ortho and meta bromides and adjacent hydroxyl groups, may be the most effective inhibitors. Highly-brominated PBDEs/OH-BDEs have comparable interaction energies to THs and may undergo debromination. These results may also suggest that XB strength must exceed a threshold value in order for PBDEs/OH-BDEs to undergo nucleophilic attack by Dio.