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 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
Many environmental chemicals are known to disturb the hypothalamic-pituitary-thyroid (HPT or thyroid) thyroid pituitary-hypothalamus (T-P/H) axis of laboratory animals and humans. Despite the long-standing association between maternal iodide deficiency and cognitive defects in offspring, the specific consequences of fetal hypothyroidism on subsequent CNS function is relatively uncharacterized at the molecular and cellular level of understanding. An important need exists to develop approaches to establish and interpret non-linear dose-response relationships for perturbations in the thyroid axis. A biological based pharmacokinetic (BBPK) model for the thyroid hormone axis will be developed to help understand (quantitatively) non-linear feedback systems. Perturbations in the thyroid axis will be carried out by placing pregnant rats on an insufficient iodide diet and by providing the pregnant rats with low doses of perchlorate in their drinking water.
(a) Develop a biologically based pharmacokinetic (BBPK) model for the thyroid hormone axis in the pregnant rat to predict perchlorate induced maternal hypothyroidism during GD 2 to 16. The fetus relies on placental transfer of thyroid hormones during this phase of development. Model predictions for low doses of perchlorate will be correlated with learning and memory (synaptic plasticity) in pups. (b) To determine the impact of thyroid hormone disturbances induced via maternal perchlorate exposure on a cellular model of learning & memory (i.e. synaptic plasticity) in the CA1 region of the rat hippocampal slice preparation. This research extends the recent modeling effort to describe inhibition of uptake of radiolabeled iodide in the pregnant rat/fetus by including the thyroid axis feedback systems.
The biological based model for the thyroid will be created using literature derived information, unpublished studies, and collecting data sets to allow the successful development and validation of the thyroid model in the pregnant rat. Memory and learning studies in pups whose mother’s were exposed to perchlorate and low dietary iodide will conducted using slices of their brains and obtaining electrophysiological information.
This project is expected to assist the US EPA in the development of dose-response assessment methodology for chemical induced hypothyroidism in rodents.