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ToxSci Advance Access published online on April 29, 2009
Toxicological Sciences, doi:10.1093/toxsci/kfp086
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© The Author 2009. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For permissions, please email: journals.permissions@oxfordjournals.org

Interference of endocrine disrupters with thyroid hormone receptor-dependent transactivation

Peter Josef Hofmann, Lutz Schomburg and Josef Köhrle

Institut für Experimentelle Endokrinologie, Charité – Universitätsmedizin Berlin, Südring 8-10, CVK, Campus Virchow-Klinikum, D-13353 Berlin, Germany (peter.hofmann{at}charite.de, lutz.schomburg{at}charite.de; josef.koehrle{at}charite.de)

Corresponding Author Dr. Peter Josef Hofmann, Institut für Experimentelle Endokrinologie, Charité – Universitätsmedizin Berlin, Charité Campus Virchow-Klinikum, Augustenburger Platz 1, D-13353 Berlin, Germany. Telephone: 0049-30-450 576 097, Fax: 0049-30-450 524 922, E-mail: peter.hofmann{at}charite.de

Received December 20, 2008; revision received March 22, 2009; accepted April 21, 2009


  Abstract

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, UV-absorbers, pesticides, industrial chemicals) were recorded in activation assays. In addition, interference with TH-mediated transactivation was tested by co-incubation of the ED with triiodothyronine (T3) in competition assays. Most ED tested affected T3 reporter gene activity at concentrations of 1 µM or higher and displayed either agonistic or mixed agonistic/antagonistic activities. Effects of relevant ED occurred only at relatively high concentrations compared to the endogenous TR ligand T3. 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.

Key Words: flame retardant; luciferase; pesticide; plasticizer; reporter gene assay; UV-filter.


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