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Develop a Systems Approach to Characterizing and Predicting Thyroid Toxicity using an Amphibian Model
Citation:
DEGITZ, S. J., M. HORNUNG, AND J. E. TIETGE. Develop a Systems Approach to Characterizing and Predicting Thyroid Toxicity using an Amphibian Model. Presented at EPA B.O.S.C. Computational Toxicology Subcommittee Meeting, Durham, NC, September 29 - 30, 2009.
Impact/Purpose:
This research makes use of in vitro and in vivo approaches to understand and discriminate the compensatory and toxicological responses of the highly regulated HPT system. Development of an initial systems model will be based on the current understanding of the HPT axis and the compensatory processes involved in thyroid hormone homeostasis. Experiments have been conducted to better understand the relationships of the critical sub-components of the system. Particular emphasis has been placed on understanding the relative importance of gene expression in the pituitary, thyroid, and peripheral tissues under normal conditions and following exposure to chemicals known to interfere with thyroid hormone (TH) synthesis. These molecular changes are being linked to functional measurements of key hormones and enzymes that are part of the HPT pathway, all of which are being interpreted in the context of organismal-Ievel effects. The primary goal of this work is to develop a sufficient understanding of the HPT so that predictive models can be developed, testing protocols can be abbreviated, and efforts in inter-species extrapolation can be improved. One of the most likely uses for a HPT systems model is to aid in the understanding and discrimination of different modes of action. As such, this work further enables the development of quantitative structure activity relationships (QSARs) by providing a basis for sorting chemicals by mode of action, a necessary step prior to quantifying features of chemical structure associated with a particular type of toxicity. If these relationships can ultimately be established, then predictive models can be developed to rank chemicals for future in vivo testing.
Description:
This research makes use of in vitro and in vivo approaches to understand and discriminate the compensatory and toxicological responses of the highly regulated HPT system. Development of an initial systems model will be based on the current understanding of the HPT axis and the compensatory processes involved in thyroid hormone homeostasis. Experiments have been conducted to better understand the relationships of the critical sub-components of the system. Particular emphasis has been placed on understanding the relative importance of gene expression in the pituitary, thyroid, and peripheral tissues under normal conditions and following exposure to chemicals known to interfere with thyroid hormone (TH) synthesis. These molecular changes are being linked to functional measurements of key hormones and enzymes that are part of the HPT pathway, all of which are being interpreted in the context of organismal-Ievel effects. The primary goal of this work is to develop a sufficient understanding of the HPT so that predictive models can be developed, testing protocols can be abbreviated, and efforts in inter-species extrapolation can be improved. One of the most likely uses for a HPT systems model is to aid in the understanding and discrimination of different modes of action. As such, this work further enables the development of quantitative structure activity relationships (QSARs) by providing a basis for sorting chemicals by mode of action, a necessary step prior to quantifying features of chemical structure associated with a particular type of toxicity. If these relationships can ultimately be established, then predictive models can be developed to rank chemicals for future in vivo testing.