期刊
ARCHIVES OF TOXICOLOGY
卷 89, 期 2, 页码 233-242出版社
SPRINGER HEIDELBERG
DOI: 10.1007/s00204-014-1258-y
关键词
Perfluoroalkyl compounds; Thyroid hormone receptor; Agonistic activity; Gene expression; Molecular docking
类别
资金
- National Basic Research Program of China [2011CB936001]
- National Natural Science Foundation of China [21077125]
- Research Center of Eco-environmental Sciences [YSW2013A01]
- Young Scientists Fund of RCEES [RCEES-QN-20130004F]
Perfluoroalkyl compounds (PFCs) have been shown to disrupt thyroid functions through thyroid hormone receptor (TR)-mediated pathways, but direct binding of PFCs with TR has not been demonstrated. We investigated the binding interactions of 16 structurally diverse PFCs with human TR, their activities on TR in cells, and the activity of perfluorooctane sulfonate (PFOS) in vivo. In fluorescence competitive binding assays, most of the 16 PFCs were found to bind to TR with relative binding potency in the range of 0.0003-0.05 compared with triiodothyronine (T3). A structure-binding relationship for PFCs was observed, where fluorinated alkyl chain length longer than ten, and an acid end group were optimal for TR binding. In thyroid hormone (TH)-responsive cell proliferation assays, PFOS, perfluorohexadecanoic acid, and perfluorooctadecanoic acid exhibited agonistic activity by promoting cell growth. Furthermore, similar to T3, PFOS exposure promoted expression of three TH upregulated genes and inhibited three TH downregulated genes in amphibians. Molecular docking analysis revealed that most of the tested PFCs efficiently fit into the T3-binding pocket in TR and formed a hydrogen bond with arginine 228 in a manner similar to T3. The combined in vitro, in vivo, and computational data strongly suggest that some PFCs disrupt the normal activity of TR pathways by directly binding to TR.
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