TA2 Molecular Indicators for Ecological Exposure
255 Portland Ballroom
8:00 AM - 12:00 PM, Tuesday
() A Multi-Endpoint Strategy for Determining Mechanism of Action of Thyroid Active Chemicals.
Degitz, S1, Korte, J1, Serrano, J1, Batterman, S1, Holcombe, G1, Kosian, P1, Tietge, J1, 1 US EPA, Duluth, MN, USA
ABSTRACT- To facilitate the process of identifying the mechanisms by which xenobiotics perturb the thyroid pathway, we have adopted a multiple endpoint strategy using the amphibian model, Xenopus laevis. Theoretically, normal thyroid hormone homeostasis and action can be disrupted at several sites in the pathway, including: the hypothalamohyphophysial-thyroid axis, thyroid hormone synthesis, thyroid hormone transport, metabolic conversion of thyroid hormone to active and inactive forms, receptor-mediated transcriptional effects of T3, and nonspecific effects. Xenobiotic chemicals which are known to interfere with normal thyroid hormone homeostasis and action have been shown to act primarily by (1) up-regulation of catabolism of thyroid hormone, (2) inhibition of iodide uptake, (3) inhibition of T4 synthesis, or (4) inhibition and/or up-regulation of deiodinases. Several chemicals are also known to associate with the carrier protein, with affinities sufficiently high to competitively displace T4, thereby altering circulating T4 concentrations. To this point, the specific actions of xenobiotics have been identified on a case-by-case basis. Given the fact that the xenobotics may have their action at different points in the thyroid pathway, it is advantageous to develop a suite of endpoints that allows one to ascertain where in the pathway impact is occurring. Our strategy makes use of recently developed molecular approaches in combination with classical in vivo methods. These approaches include analysis of thyroid pathway specific gene expression, analysis of differential protein expression, and advanced biochemical analysis of the endogenous hormone, the related synthetic precursors and degradation products. These endpoints are being assessed following challenges with thyroid active chemicals with known mechanisms of action to determine if the responses have characteristic patterns which can be used as signatures of the given mechanism. We will report specific gene and protein patterns produced by a suite of model T4 synthesis inhibitors. (This abstract does not necessarily reflect U.S. EPA policy)
Key words: Xenopus, Amphibian, Thyroid, Gene