期刊
TOXICOLOGICAL SCIENCES
卷 110, 期 1, 页码 125-137出版社
OXFORD UNIV PRESS
DOI: 10.1093/toxsci/kfp086
关键词
flame retardant; luciferase; pesticide; plasticizer; reporter gene assay; UV-filter
类别
资金
- EU [EKV1-CT-2002-00128]
- Multi-Organic Risk Assessment of Selected Endocrine Disrupters (EURISKED)
- Charite-Universitatsmedizin Berlin
Thyroid hormones regulate critical developmental processes and key metabolic pathways. A number of natural and synthetic substances have been identified which adversely interfere with the endocrine system. These so-called endocrine disrupters (ED) have mainly been studied for their impact on the gonadal hormone axis. The aim of this work was to develop a novel sensitive and convenient in vitro screening assay for the detection and characterization of potential ED of thyroid hormone (TH)-dependent transactivation of gene transcription and to apply this tool to test relevant environmental and nutritive ED compounds. We constructed a TH-responsive luciferase-based reporter plasmid and established a reporter gene assay in a 96 well microplate format using the human hepatocarcinoma cell line HepG2 as host system. Both the synthetic TH receptor (TR) agonist GC-1 and the antagonist NH-3 were used to evaluate the assay. Concentration-response data of test compounds (food constituents, isoflavones, ultraviolet-absorbers, pesticides, industrial chemicals) were recorded in activation assays. In addition, interference with TH-mediated transactivation was tested by coincubation of the ED with triiodothyronine (T-3) in competition assays. Most ED tested affected T-3 reporter gene activity at concentrations of 1 mu M or higher and displayed either agonistic or mixed agonistic/antagonistic activities. Effects of relevant ED occurred only at relatively high concentrations compared with the endogenous TR ligand T-3. However, on basis of their high production volumes and potential bioaccumulation of some fat-soluble ED our data indicate the need to carefully monitor certain ED for potential disruption of the TH system in intact organisms and humans.
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