In Silico Investigation of the Thyroid Hormone Activity of Hydroxylated Polybrominated Diphenyl Ethers

Abstract

Polybrominated diphenyl ethers (PBDEs) have been shown to have a disruptive effect on the thyroid hormone system, and one possible mechanism is the direct binding of their hydroxylated metabolites (HO-PBDEs) to thyroid hormone receptors (TRs). However, the experimental data on the thyroid hormone activity of HO-PBDEs are limited, and the molecular interaction mechanism remains unclear, impeding the ecological risk assessment for these widespread contaminants. In the present research, a quantum chemical approach was developed to predict the thyroid hormone activity of HO-PBDEs using the electronic structure parameters of neutral molecules. The ab initio HF/6-31G** algorithm was employed to optimize the molecular geometry and to calculate local molecular parameters regarding effective energy and electron transfer amount. The mechanistic analysis shows that the ability of the hydroxyl oxygen and hydrogen atom to donate or accept additional electron charges is an important property affecting the chemical activity of the thyroid hormone. The derived regression model was shown to have a good statistical performance and could be used to predict the thyroid hormone activity of other HO-PBDE congeners for which experimental measurements are not possible or are restricted. Therefore, the model has the potential to be a useful tool in the application of integrated testing strategies.

Halogen‐Bonding Interactions of Polybrominated Diphenyl Ethers and Thyroid Hormone Derivatives: A Potential Mechanism for the Inhibition of Iodothyronine Deiodinase

“…However, its C−Br bonds are less activated than expected compared to the penta‐ and hexabrominated compounds, considering its more favorable Δ E +ZPE, because the C−Br* character is delocalized over all C−Br bonds in the LUMO. In addition, for a study of THRβ (which is involved in binding T 3 ), increasingly brominated PBDEs/OH‐BDEs caused a steady increase in overall inhibition, a trend similar to our computational results albeit for different types of XB interactions …”

“…Br···Se XB interactions with MeSe À were modeled foras et of four PBDEs used by Roberts et al [10] and 18 OH-BDEs in Yu et al (Figure 5). [28] XB complexes are designated by the ring position at which XB takes place (o, m,o rp)u sing ap rime for interactions to the ring opposite the hydroxyl group. For example,f or XB-o'À À3a-HO-BDE-7,X Bo ccurs at the ortho position of 3a-HO-BDE-7 on the ring opposite the hydroxyl group.…”

“…and 18 OH‐BDEs in Yu et al. (Figure ) . XB complexes are designated by the ring position at which XB takes place ( o , m , or p ) using a prime for interactions to the ring opposite the hydroxyl group.…”

“…[29] However,i ts CÀBr bonds are less activated than expectedc ompared to the penta-and hexabrominated compounds,c onsidering its more favorable DE + ZPE, because the CÀBr* character is delocalized over all CÀBr bonds in the LUMO.I na ddition, for as tudy of THRb (which is involved in binding T 3 ), increasingly brominated PBDEs/OH-BDEs causedasteady increase in overall inhibition, at rend similart o our computational resultsa lbeit for different types of XB interactions. [28] The addition of hydroxyl groups of OH-BDEs may enhance their affinity for Dio. [10] XB strength and activation of CÀBr bond for OH-BDEs varies depending on the proximity of the hydroxyl group to the site of XB and the identity of the compound.…”

Binding of hydroxylated polybrominated diphenyl ethers with human serum albumin: Spectroscopic characterization and molecular modeling

“…For example, five monohydroxy tetra‐BDE metabolites of BDE‐47 were identified in rodents (rat and mouse) . Many studies have shown that OH‐PBDEs altered or enhanced toxicological effects compared with PBDEs, such as the ability to disrupt thyroid hormone homeostasis and sex hormone steroidogenesis as well as neurotoxicity . At present, the toxicity of pollutants such as PBDEs introduced into the blood stream during environmental exposure to industrial pollutants is a real concern.…”