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Receptor-Bound Perfluoroalkyl Carboxylic Acids Dictate Their Activity on Human and Mouse Peroxisome Proliferator-Activated Receptor γ.
Li, Chuan-Hai; Shi, Ya-Li; Li, Minjie; Guo, Liang-Hong; Cai, Ya-Qi.
Afiliação
  • Li CH; State Key Laboratory of Environmental Chemistry and Eco-toxicology, Research Center for Eco-environmental Sciences, Chinese Academy of Sciences, 18 Shuangqing Road, Beijing 100085, China.
  • Shi YL; School of Public Health, Qingdao University, 308 Ningxia Street, Qingdao, Shandong 266071, China.
  • Li M; State Key Laboratory of Environmental Chemistry and Eco-toxicology, Research Center for Eco-environmental Sciences, Chinese Academy of Sciences, 18 Shuangqing Road, Beijing 100085, China.
  • Guo LH; College of Quality & Safety Engineering, China Jiliang University, 258 Xueyuan Street, Hangzhou, Zhejiang 310018, China.
  • Cai YQ; Institute of Environmental and Health Sciences, China Jiliang University, 168 Xueyuan Street, Hangzhou, Zhejiang 310018, China.
Environ Sci Technol ; 54(15): 9529-9536, 2020 08 04.
Article em En | MEDLINE | ID: mdl-32639727
In in vitro cell assays, nominal concentrations of a test chemical are most frequently used in the description of its dose-response curves. Although the biologically effective concentration (BEC) is considered as the most relevant dose metric, in practice, it is very difficult to measure. In this work, we attempted to determine the BEC of long-chain perfluoroalkyl carboxylic acids (PFCAs) in peroxisome proliferator-activated receptor γ (PPARγ) activity assays. In both adipogenesis and transcriptional activity assays with human and mouse cells, PPARγ activity of 7 PFCAs first increased and then decreased with their carbon chain length. The binding affinity of these PFCAs with the ligand-binding domain of PPARγ was measured by fluorescence competitive binding assay and showed very poor correlation with their receptor activity (r2 = 0.002-0.047). Internal concentrations of the PFCAs in the cells were measured by LC-MS/MS. Although their correlation with the receptor activity increased significantly, it is still low (r2 = 0.41-0.82). Using the binding affinity constant, internal concentration, and PPARγ concentration measured by immunoassays, concentrations of receptor-bound PFCAs in cells were calculated, which exhibited excellent correlation with PPARγ activity in both adipogenesis and transcriptional activity assays (r2 = 0.91-0.93). These results demonstrate that the concentration of receptor-bound PFCA is the BEC that dictates its activity on human and mouse PPARγ in cell assays. In the absence of any direct detection method, our approach can be used to calculate the target-site concentration of other ligands.
Assuntos

Texto completo: 1 Base de dados: MEDLINE Assunto principal: PPAR gama / Fluorocarbonos Limite: Animals / Humans Idioma: En Revista: Environ Sci Technol Ano de publicação: 2020 Tipo de documento: Article País de afiliação: China

Texto completo: 1 Base de dados: MEDLINE Assunto principal: PPAR gama / Fluorocarbonos Limite: Animals / Humans Idioma: En Revista: Environ Sci Technol Ano de publicação: 2020 Tipo de documento: Article País de afiliação: China