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Cornelia Schmutzler,¹ Inka Gotthardt,¹ Peter J. Hofmann,¹ Branislav Radovic,¹ Gabor Kovacs,¹ Luise Stemmler,¹ Inga Nobis,¹ Anja Bacinski,¹ Birgit Mentrup,¹ Petra Ambrugger,² Annette Grüters,² Ludwik K. Malendowicz,³ Julie Christoffel,⁴ Hubertus Jarry,⁴ Dana Seidlovà-Wuttke,⁴ Wolfgang Wuttke,⁴ and Josef Köhrle¹

¹Institut für Experimentelle Endokrinologie, Charité - Universitätsmedizin Berlin, Berlin, Germany; ²Institut für Experimentelle Pädiatrische Endokrinologie, Charité - Universitätsmedizin Berlin, Berlin, Germany; ³Department of Histology and Embryology, School of Medicine, Poznan, Poland; ⁴Klinische und Experimentelle Endokrinologie, Universitäts-Frauenklinik Göttingen, Göttingen, Germany

Abstract
Background: There is growing evidence that, in addition to the reproductive system, the hypothalamic–pituitary–thyroid axis is a target of endocrine-disrupting compounds (EDCs) . However, this is not reflected adequately in current screening and assessment procedures for endocrine activity that to date determine only general parameters of thyroid function.

Objective and Methods: We used several in vitro and ex vivo assays in an attempt to identify suitable biomarkers for antithyroid action testing a selected panel of putative EDCs.

Results: In vitro we detected stimulation or inhibition of iodide uptake into FRTL-5 rat thyroid cells, inhibition of thyroid hormone binding to transthyretin, agonistic or antagonistic effects in a thyroid hormone receptor–dependent reporter assay, and inhibition of thyroid peroxidase using a novel assay system based on human recombinant thyroperoxidase that might be suitable for routine screening for potential EDCs. Inrats, chronic application of several EDCs led to changes in thyroid morphology, alterations of thyrotropin and thyroid hormone serum levels as well as alterations in peripheral thyroid hormone–regulated end points such as malic enzyme and type I 5´-deiodinase activity.

Conclusions: As the effects of EDCs do not reflect classic mechanisms of hormone-dependent regulation and feedback, we believe multitarget and multimodal actions of EDCs affect the hypothalamic–pituitary–thyroid axis. These complex effects require a diverse approach for screening, evaluation, and risk assessment of potential antithyroid compounds. This approach involves novel in vitro or cell-based screening assays in order to assess thyroid hormone synthesis, transport, metabolism, and action as well as in vivo assays to measure thyroid hormone–regulated tissue-specific and developmental end points in animals.

Key words: deiodinase, flavonoids, malic enzyme, pituitary, sodium iodide symporter, thyroid gland, thyroid peroxidase, transthyretin, UV filters. Environ Health Perspect 115(suppl 1) :77–83 (2007) . doi:10.1289/ehp.9369 available via http://dx.doi.org/ [Online 8 June 2007]

Address correspondence to C. Schmutzler, Institut für Experimentelle Endokrinologie, Charité – Universitätsmedizin Berlin, Campus Charité Mitte, Charitéplatz 1, 10117 Berlin, Germany. Telephone: 0049 30 450 524 080. Fax: 0049 30 450 524 922. E-mail: cornelia.schmutzler@charite.de

This article is part of the monograph "Endocrine Disruptors—Exposure Assessment, Novel End Points, and Low-Dose and Mixture Effects."

This work was supported by European Union grant EKV1-CT-2002-00128 and Deutsche Forschungsgemeinschaft (DFG) grant KO 922/12-1 and -2.

We acknowledge the excellent technical assistance by K. Huhne and M. Topp.

The author declares he has no competing financial interests.

Received 22 May 2006 ; accepted 23 October 2006.