Low-Dose Effects of Thyroid Toxicants on NeurodevelopmentEPA Grant Number: R832137
Title: Low-Dose Effects of Thyroid Toxicants on Neurodevelopment
Investigators: Zoeller, R. Thomas
Institution: University of Massachusetts - Amherst
EPA Project Officer: Hahn, Intaek
Project Period: December 1, 2004 through November 30, 2008
Project Amount: $738,971
RFA: Development and Characterization of Biological Systems for Studying Low Dose Effects of Endocrine Disrupting Chemicals (2004) RFA Text | Recipients Lists
Research Category: Economics and Decision Sciences , Endocrine Disruptors , Health , Safer Chemicals , Health Effects
The experiments proposed in this application are designed to identify the critical determinants affecting the shape of the dose-response relationship between thyroid hormone and developmental endpoints of thyroid hormone action.
We will test the hypothesis that small changes in circulating levels of thyroid hormone produce non-linear dose-dependent effects on specific endpoints of thyroid hormone action in the developing brain, heart and liver. Moreover, we will test whether toxicants that act at different points of regulation within the HPT axis can change the relationship between circulating levels of thyroid hormone and developmental endpoints of thyroid hormone action and will identify mechanisms underlying these effects. This hypothesis is generated by our previous work showing that PCBs can lower circulating levels of thyroid hormones to the same extent as known goitrogens, but that the effects on endpoints of thyroid hormone action are not predicted by effects on hormone levels.
To accomplish these goals we will: 1) characterize the dose-response of a variety of developmental endpoints in rats to thyroid hormone levels ranging in degrees of insufficiency; 2) test whether known thyroid toxicants – perchlorate, propylthiouracil, or polybrominated diphenyl ethers – produce dose-dependent effects on these endpoints that can be predicted by their effects on serum thyroid hormones; and 3) investigate mechanisms accounting for the shape of the dose-responses across these endpoints. We have chosen developmental endpoints that will provide a comprehensive picture of thyroid hormone action during development, including endpoints of gene expression and developmental anatomy. To obtain a comprehensive picture of thyroid "economy", we will measure serum total and "free" T4 and T3, TSH, the binding proteins transthyretin (TTR) and thyroxine binding globulin (TBG, which is expressed in rats especially during development). We will develop new radioimmunoassays for measurement of these two binding proteins, as well as for serum thyroglobulin, which is a measure of thyroid function. Four potential mechanisms accounting for non-linear dose-responses include differential effects on hormonal profiles (T4/T3), relationship to serum thyroid hormone binding proteins (TTR/TBG), deiodinase activity in tissues, and thyroid hormone receptors.
The proposed studies will identify critical temporal windows of sensitivity to these effects, which are likely to be endpoint specific, gender differences, and long-term consequences of thyroid toxicants on brain development. These studies will aid in risk assessment by providing appropriate screens and tests for identifying thyroid toxicants. The detailed dose-response curves generated from these studies will form the basis for evidence-based design of such screens and tests.