2006 Progress Report: Development of a BBPK Model for the Thyroid Axis in the Pregnant Rat and Fetus for the Dose Response Analysis of Developmental NeurotoxicityEPA Grant Number: R832134
Title: Development of a BBPK Model for the Thyroid Axis in the Pregnant Rat and Fetus for the Dose Response Analysis of Developmental Neurotoxicity
Investigators: Fisher, Jeffrey W. , Ferguson, Duncan , Wagner, John
Institution: University of Georgia
EPA Project Officer: Hahn, Intaek
Project Period: December 1, 2004 through November 30, 2008 (Extended to November 30, 2009)
Project Period Covered by this Report: December 1, 2005 through November 30, 2006
Project Amount: $749,127
RFA: Development and Characterization of Biological Systems for Studying Low Dose Effects of Endocrine Disrupting Chemicals (2004) RFA Text | Recipients Lists
Research Category: Endocrine Disruptors , Health Effects , Economics and Decision Sciences , Health , Safer Chemicals
The goal of this project is to develop biologically based pharmacokinetic (BBPK) maternal/neonatal models of the hypothalamic-pituitary-thyroid (HPT) axis in the rat for use in assessing developmental neurotoxicity mediated via the HPT axis. These BBPK HPT models will describe the highly non-linear relationship(s) among administered dose of thyroid active chemical, mode of action (MOA)-specific perturbation in the HPT axis, and developmental neurotoxicity.
Studies were conducted with timed pregnant rats administered propylthiouracil (PTU) in drinking water (0, 0.3, 1, 3, and 10 ppm) and perchlorate (150 ppm). One objective of these studies, relative to the computational modeling goal of this project, was to obtain information on HPT axis adaptive responses in the maturing rat pup HPT axis beyond what can be inferred from monitoring serum. The dose-response characteristics of chemical-induced changes in the HPT axis in the dam and pup are still under investigation. However, the following paragraph provides a general summary of our findings.
Using PTU as a prototypical chemical, serum T4 levels in pups dropped dramatically and T3 levels to a lesser degree, whereas serum thyroid stimulating hormone (TSH) levels were greatly elevated, as expected. D2 activity in the brain (cortex) increased and hepatic D1 activity decreased. An inverse relationship was noted between serum T4 levels and cortical D2 activity measurements, and a linear relationship was noted between cortical D2 activity and serum TSH levels. Thyroglobulin (TG) and sodium iodide symporter (NIS) mRNA levels were elevated in perchlorate- and PTU-treated animals, respectively. Long-term potentiation (LTP) deficits were observed in pups of dams administered PTU.
A stable iodide model with the HPT axis feedback system has been developed for the adult rat. The adult rat is now the template that will be used to understand how to develop an HPT axis model for the maturing rat pup. A model for perturbation of the HPT axis from iodide insufficiency is nearly complete in the adult rat and will be applied to the developing rat pup. A submodel for perchlorate will be used with the pup iodide-HPT axis model to provide a demonstration of how these models can be used to better understand dose-response characteristics of thyroid active chemicals and developmental neurotoxicity. Several adaptive HPT responses will be integrated into the maturing pup model to gain resolution in predicting developmental neurotoxicity deficits.
Computational efforts to develop HPT axis model(s) for different reproductive states will be undertaken. A third rat study will be conducted at the University of Georgia at Athens (UGA) to gain better information on dose-response characteristics of the HPT axis in the brain of the pup.