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A Systems Approach to Characterizing and Predicting Thyroid Toxicity Using an Amphibian Model

Project Purpose:
The primary objective of this work is to develop a sufficient understanding of the amphibian HPT so that screening and testing protocols can be abbreviated, predictive models can be developed, and efforts in inter-species and inter-chemical extrapolation can be improved. As part of this broader research project we have tested several pharmaceuticals. Methimazole and PTU which have therapeutic uses in both human and animal medicine were used as model thyroid axis inhibitors because of their well established mode of action as T4 synthesis inhibitions. Additional we have examined the effect of beta 17 beta-trenbolone on amphibian larval development. Trenbolone was tested in order to understand if excessive androgen levels affect amphibian metamorphosis

Project Description(s):
The main objective of this work is to develop a hypothalamic-pituitary-thyroid (HPT) model which is capable of integrating data from different levels of biological organization into a coherent system. This model will provide a rational framework to organize and interpret toxicological data from the molecular to the organismal levels and will serve as a basis for development of predictive tools related to thyroid toxicity. Initial model development will be based on the current understanding of the HPT and the compensatory processes involved in thyroid hormone (TH) homeostasis. Experiments will be conducted to better understand the relationships of the critical sub-components of the system. Particular emphasis will be 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 TH synthesis.

These molecular changes will be linked with functional measurements of key hormones and enzymes that are part of the HPT pathway, all of which will be interpreted in the context of organismal-level effects.

Project Outcomes:
The primary benefit 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. The EPA was recently mandated to evaluate the potential effects of chemicals on endocrine function and has identified Xenopus as a model organism to use as the basis for a thyroid disruption screening assay. Development of this assay is progressing, but its widespread use on Agency chemical inventories will be limited due to limited resources. As a consequence, a strategy to objectively rank and prioritize the order of chemical testing needs to be developed. One of the most likely uses for a HPT systems model is to aid in the understanding and discrimination of different toxic modes of action. As such, these models further enable the development of 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. In vivo testing for HPT effects will be improved through this research by providing a basis to link early molecular events to organismal outcomes.

Sigmund Degitz at degitz.sigmund@epa.gov

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