title: Identification of Thyroid Hormone Disruptors among HO-PBDEs: In Vitro Investigations and Coregulator Involved Simulations.
abstract: Some hydroxylated polybrominated diphenyl ethers (HO-PBDEs), that have been widely detected in the environment and tissues of humans and wildlife, bind to thyroid hormone (TH) receptor (TR) and can disrupt functioning of systems modulated by the TR. However, mechanisms of TH disrupting effects are still equivocal. Here, disruption of functions of TH modulated pathways by HO-PBDEs was evaluated by assays of competitive binding, coactivator recruitment, and proliferation of GH3 cells. In silico simulations considering effects of coregulators were carried out to investigate molecular mechanisms and to predict potencies for disrupting functions of the TH. Some HO-PBDEs were able to bind to TR with moderate affinities but were not agonists. In GH3 proliferation assays, 13 out of 16 HO-PBDEs were antagonists for the TH. In silico simulations of molecular dynamics revealed that coregulators were essential for identification of TH disruptors. Among HO-PBDEs, binding of passive antagonists induced repositioning of H12, blocking AF-2 (transactivation function 2) and preventing recruitment of the coactivator. Binding of active antagonists exposed the coregulator binding site, which tended to bind to the corepressor rather than the coactivator. By considering both passive and active antagonisms, anti-TH potencies of HO-PBDEs could be predicted from free energy of binding.
authors.affiliation: State Key Laboratory of Pollution Control and Resources Reuse, School of the Environment, Nanjing University , Nanjing 210023, PR China.
authors.forename: Qinchang
authors.initials: Q
authors.lastname: Chen
authors.affiliation: State Key Laboratory of Pollution Control and Resources Reuse, School of the Environment, Nanjing University , Nanjing 210023, PR China.|Multiphase Chemistry Department, Max Planck Institute for Chemistry , 55128 Mainz, Germany.
authors.forename: Xiaoxiang
authors.initials: X
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Pollution Control and Resources Reuse, School of the Environment, Nanjing University , Nanjing 210023, PR China.
authors.forename: Wei
authors.initials: W
authors.lastname: Shi
authors.affiliation: State Key Laboratory of Pollution Control and Resources Reuse, School of the Environment, Nanjing University , Nanjing 210023, PR China.
authors.forename: Hongxia
authors.initials: H
authors.lastname: Yu
authors.affiliation: State Key Laboratory of Pollution Control and Resources Reuse, School of the Environment, Nanjing University , Nanjing 210023, PR China.
authors.forename: Xiaowei
authors.initials: X
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Pollution Control and Resources Reuse, School of the Environment, Nanjing University , Nanjing 210023, PR China.|Department of Veterinary Biomedical Sciences and Toxicology Centre, University of Saskatchewan , Saskatoon, Saskatchewan S7N 5B4, Canada.|Department of Zoology and Center for Integrative Toxicology, Michigan State University , East Lansing, Michigan 48824, United States.|School of Biological Sciences, University of Hong Kong , Hong Kong, SAR, China.
authors.forename: John P
authors.initials: JP
authors.lastname: Giesy
mesh_terms: D001665:Binding Sites; D052244:Endocrine Disruptors; D055768:Halogenated Diphenyl Ethers / Q000737:chemistry*; D006801:Humans; D056004:Molecular Dynamics Simulation; D011988:Receptors, Thyroid Hormone / Q000378:metabolism; D013963:Thyroid Hormones / Q000378:metabolism*
chemical_list: D052244:Endocrine Disruptors; D055768:Halogenated Diphenyl Ethers; D011988:Receptors, Thyroid Hormone; D013963:Thyroid Hormones