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Molecular mechanism study on the toxicological effects of polybrominated diphenyl ethers and perfluoroalkyl acids
Author(s): REN Xiaomin, ZHANG Lianying, GUO Lianghong, State Key Laboratory of Environmental Chemistry and Eco-toxicology, Research Centre for Eco-environmental Sciences, Chinese Academy of Sciences
Pages: 1662-
1671
Year: 2014
Issue:
10
Journal: Environmental Chemistry
Keyword: persistent organic pollutants; PBDEs; PFAAs; molecular toxicological mechanism; hormone nuclear receptors; transport proteins.;
Abstract: Polybrominated diphenyl ethers( PBDEs) and perfluoroalkyl acids( PFAAs) are two groups of persistent organic pollutants( POPs) which are widely used,broadly existing in the environment,and frequently detected in humans. In 2009 they were added to the POPs list of the Stockholm Convention. However,the toxicological effects and mechanisms of PBDEs and PFAAs are still not well understood. This review summarizes our recent work on the studies of molecular toxicological mechanisms of PBDEs and PFAAs,focusing on their disruption effects on thyroid hormone system,estrogen system and hepatic fatty acid metabolism system. From the molecular,cellular and in vivo level,we investigated the direct binding interaction of these chemicals with hormone nuclear receptors,receptor conformational change after ligand binding,receptor mediated transcriptional activity in cells,and change of gene expression in experimental animals. Based on the results,we established a direct link between receptor binding and change of biological functions in cells and in vivo. Using molecular docking,we investigated the structural basis for the observed agonistic or antagonistic activity. It was found that their activity was determined by the bindinggeometry with the receptor,and their potency depended on the binding affinity with the protein,which were dominated by the hydrophobic and hydrogen-bond interactions. We also studied the binding interaction of these chemicals with transport proteins,and estimated their potential disruption effect on the in vivo transport of endogenous substances. Through these studies,we put forward a multi-level,multi-target strategy for the investigation of molecular toxicological mechanisms of POPs,established and introduced new methods for the study of POPs interactions with biological macromolecules,identified new binding modes of PBDEs and PFAAs with ER,TR and PPARγnuclear receptors. Our work has provides new information on the molecular toxicological mechanisms of PBDEs and PFAAs,and also new tools for the study of other POPs.
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