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Interpreting in vivo Effects of Thyroid Synthesis Inhibitors through the Lens of in vitro and ex vivo Assays
Citation:
HORNUNG, M. W., J. HASELMAN, G. W. HOLCOMBE, J. J. KORTE, L. KORTE, E. BURGESS, B. C. BUTTERWORTH, P. A. KOSIAN, J. A. SERRANO, J. E. TIETGE, AND S. J. DEGITZ. Interpreting in vivo Effects of Thyroid Synthesis Inhibitors through the Lens of in vitro and ex vivo Assays. Presented at 35th Annual Aquatic Toxicity Workshop, Saskatoon, SK, CANADA, October 05 - 08, 2008.
Impact/Purpose:
This presentation provides a brief overview of the amphibian thyroid toxicity research being conducted at MED under the Safe Pesticides/Safe Products research area. The research described herein is in response to the mandate to the Agency to develop a research program to evaluate the potential adverse effects of chemicals on vertebrate endocrine systems including thyroid hormones. The results are presented in the context of the development of shorter term in vitro and ex vivo assays that can be used to screen chemicals for thyroid activity which can then be prioritized for testing in vivo for verification of thyroid hormone axis disruption.
Description:
The US EPA has been charged to evaluate chemicals for their ability to disrupt endocrine pathways including estrogen, androgen, and thyroid hormone. Amphibian metamorphosis, which is regulated by thyroid hormone, is an ideal model system for investigating disruption of the thyroid-axis, and an in vivo metamorphosis assay has been developed for this purpose. In vivo tests that take several weeks to complete, however, are not an efficient or realistic mechanism for obtaining data on the full inventory of chemicals that are of concern to regulatory agencies. Advances in scientific knowledge and techniques at the molecular level of gene and protein expression provide promise for developing biomarkers using shorter term assays. Understanding the linkages between these early molecular events and organismal-level adverse effects is essential for ultimately utilizing short term assays as diagnostic tools. To this end, diagnostic markers of effects on thyroid hormone synthesis in the Xenopus laevis tadpole were developed using the model thyroid hormone synthesis inhibitors methimazole, propylthiouracil, and perchlorate. The effects of these chemicals were determined for inhibition of thyroid hormone synthesis in vitro, and on thyroid gland gene expression, and thyroid hormone synthesis and release in a thyroid gland explant culture system. These assays provided information on the proximal effects of the chemicals independent of the compensatory mechanisms in the developing organism. The insights gained regarding dose, time, and compensatory mechanisms for interpretation of in vivo gene expression, thyroid hormone measurements, and developmental sensitivity will be presented.