title: Effect on metabolic enzymes and thyroid receptors induced by BDE-47 by activation the pregnane X receptor in HepG2, a human hepatoma cell line.
abstract: 2,2',4,4'-Tetra-bromodiphenyl ether (BDE-47), an important congener among polybrominated diphenyl ether (PBDE) compounds, has been predominantly in environmental samples and human tissue. Thyroid disruption is the most sensitive endpoint effect among a number of health effects of exposure to BDE-47 in animals and humans. However, the detailed underlying mechanisms in humans are not well understood. In the present study, human pregnane X receptor (hPXR)-overexpressing HepG2 cell model and a dual-luciferase reporter assay system were constructed to investigate the role of hPXR in BDE-47-induced alterations of expression of metabolic enzymes and TR in vitro. The results showed that hPXR was significantly activated by BDE-47, and expression levels of both mRNA and protein of the thyroid receptor (TR) isoforms TRα1 and TRβ1 were decreased in hPXR-overexpressing HepG2 cells after BDE-47 treatment. However, the increased expression of hepatic microsomal phase I enzyme CYP3A4 and phase II enzymes, UGT1A3 and SULT2A1 were also found. Taken together, the results indicated that BDE-47 was a strong hPXR activator, activation of hPXR played an important role in BDE-47-induced down-regulation of TR, and up-regulations of CYP3A4, UGT1A3, and SULT2A1 participated in the process, which may provide more toxicological evidence on mechanisms of disruption of thyroid hormone induced by BDE-47.
authors: Shenzhen Center for Disease Control and Prevention, Shenzhen 518055, PR China; School of Public Health, Guangzhou Medical University, Guangzhou 510182, PR China.
authors: XinNan
authors: X
authors: Hu
authors: Shenzhen Center for Disease Control and Prevention, Shenzhen 518055, PR China. Electronic address: zhjianqing95@gmail.com.
authors: JianQing
authors: J
authors: Zhang
authors: Shenzhen Center for Disease Control and Prevention, Shenzhen 518055, PR China.
authors: YouSheng
authors: Y
authors: Jiang
authors: School of Public Health, Guangzhou Medical University, Guangzhou 510182, PR China. Electronic address: gz-leizeng@163.com.
authors: YiXiong
authors: Y
authors: Lei
authors: Department of Chronic Disease Epidemiology, Yale School of Medicine and School of Medicine, Yale University, New Haven, CT 06520-8034, USA.
authors: LinGeng
authors: L
authors: Lu
authors: Shenzhen Center for Disease Control and Prevention, Shenzhen 518055, PR China.
authors: Jian
authors: J
authors: Zhou
authors: Shenzhen Center for Disease Control and Prevention, Shenzhen 518055, PR China.
authors: HaiYan
authors: H
authors: Huang
authors: Shenzhen Center for Disease Control and Prevention, Shenzhen 518055, PR China.
authors: Daokui
authors: D
authors: Fang
authors: Shanghai Center for Disease Control & Prevention, 200336, PR China.
authors: GongHua
authors: G
authors: Tao
mesh_terms: D002470:Cell Survival / Q000187:drug effects; D051544:Cytochrome P-450 CYP3A / Q000096:biosynthesis; D004790:Enzyme Induction / Q000187:drug effects; D014453:Glucuronosyltransferase / Q000096:biosynthesis; D055768:Halogenated Diphenyl Ethers / Q000633:toxicity*; D056945:Hep G2 Cells; D006801:Humans; D008156:Luciferases / Q000235:genetics; D000077297:Pregnane X Receptor; D011987:Receptors, Steroid / Q000187:drug effects* / Q000502:physiology; D015238:Sulfotransferases / Q000096:biosynthesis; D037021:Thyroid Hormone Receptors alpha / Q000187:drug effects* / Q000235:genetics; D037042:Thyroid Hormone Receptors beta / Q000187:drug effects* / Q000235:genetics
chemical_list: D055768:Halogenated Diphenyl Ethers; D000077297:Pregnane X Receptor; D011987:Receptors, Steroid; D037021:Thyroid Hormone Receptors alpha; D037042:Thyroid Hormone Receptors beta; C511295:2,2',4,4'-tetrabromodiphenyl ether; D008156:Luciferases; D051544:Cytochrome P-450 CYP3A; C122075:UDP-glucuronosyltransferase, UGT1A3; D014453:Glucuronosyltransferase; D015238:Sulfotransferases; C028152:alcohol sulfotransferase
keywords: 2,2′,4,4′-Tetra-bromodiphenyl ether (BDE-47); Cytochrome P450 3A4 (CYP3A4); Pregnane X receptor (hPXR); Sulfotransferases (SULTs); Thyroid receptors (TRs); Uridine diphospho-glucuronosyltransferases (UGTs)