National Center for Computational Toxicology

Key Contact: Sigmund J. Degitz ;Mid-Continent Ecology Division; National Health and Environmental Effects Research Laboratory; Duluth, MN 55804; Phone 218-529-5168 email degtiz.sigmund@epa.gov

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. 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 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. In vivo testing for HPT effects will be improved through this research by providing a basis to link early molecular events to organismal outcomes. Recent developments in understanding the molecular events involved in TH homeostasis and action suggest that thyroid toxicity might be identifiable using appropriate molecular endpoints in an abbreviated test. This potential improvement, which will lower costs and reduce animal use, is currently more likely to succeed due to expanding genomic information. This project will focus on building linkages between early molecular events associated with exposure and organismal-level effects. Understanding these linkages and their relative importance will be assessed using the HPT model. Finally, extrapolating the effects of chemicals on thyroid function among species remains a major challenge. The ability to extrapolate is largely dependent on the presence of conserved biological functions. One of the major goals of this work is to populate the HPT model with data specifically at the molecular and biochemical levels which will provide a basis to interpret interspecies homology and comparative toxicity.