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Extramural Research

2008 Progress Report: Development of a BBPK Model for the Thyroid Axis in the Pregnant Rat and Fetus for the Dose Response Analysis of Developmental Neurotoxicity

EPA 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: Laessig, Susan A.
Project Period: December 1, 2004 through November 30, 2008 (Extended to November 30, 2009)
Project Period Covered by this Report: December 1, 2007 through November 30,2008
Project Amount: $749,127
RFA: Development and Characterization of Biological Systems for Studying Low Dose Effects of Endocrine Disrupting Chemicals (2004)
Research Category: Endocrine Disruptors , Health Effects , Economics and Decision Sciences

Description:

Objective:

The goal under this cooperative agreement is to develop biologically based pharmacokinetic (BBPK) maternal/neonatal models of the hypothamalic-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) between administered dose of thyroid active chemical, mode of action (MOA) specific perturbation in the HPT axis, and developmental neurotoxicity.

Progress Summary:

Laboratory studies were needed to develop a thyroid axis model in adult and developing rats, and to then use the BBDR HPT axis model to describe dose dependent chemical induced perturbations in the HPT axis. At UGA, the first 2 years of the cooperative agreement resulted in the collection of data in the developing rat pup of mothers administered various doses of a prototypical thyroid active drug, PTU. A variety of traditional and a few non-traditional biological measures of the thyroid axis status were obtained in treated and control rat pups. Perhaps the most striking finding was that the thyroid hormone metabolizing enzyme deiodinase II, in the fetal rat brain, was upregulated in a dose- and time- dependent manner. This response may be more sensitive to perturbations in the hypothalamic-pituitary-thyroid (HPT) axis than serum measures of the negative feedback loop (serum TSH and T4 concentrations). In Year 3 and this current year (Year 4) of the cooperative agreement, iodide deficiency studies were conducted by at the US EPA RTP,NC (Drs. Mary Gilbert and Kevin Crofton) with Dr. Tom Zoeller (UMass cooperative agreement R832137) and Dr. Jeff Fisher providing significant input on study design and analysis of samples after the study was completed. These studies included adult rats for the first pilot study, and then pregnant rats for the second full scale neurodevelopmental study. Rat pups from the second study were evaluated for a variety of endpoints related to neurodevelopmental toxicity (mediated by disruption of the HPT axis). A third pregnant rat iodide deficiency study was started in May 2009. In this study the fetus will be evaluated for several endpoints related to neurodevelopmental toxicity mediated by hypothyroidism (Fall of 2009).

Also during this period at UGA, an adult rat study was undertaken to gather mechanistic information on how the thyroid gland responds to perchlorate, since our modeling efforts suggested that perchlorate alters the HPT axis by a mechanism beyond that of simply blocking thyroidal uptake of iodide (See 2009 publication below). To summarize, 80 young rats were placed on rat chow with extremely low iodide or with normal iodide levels for two months. During this two month period urine was collected for later analysis of iodide. At two months, half of the rats from the iodide deficient chow and iodide sufficient chow were placed on perchlorate in drinking water(10/mg/kg/day). Control and perchlorate treated rats on the two iodide chows were killed after either one day (40 rats) or 14 days (40 rats) of treatment. Thyroids were excised and serum collected. Urine was collected from the rats during the 14 days of perchlorate treatment. Sera were analyzed for thyroid hormones and TSH (completed at UGA, Tifton, GA), urine for iodide and perchlorate (at CDC now in Atlanta, GA), thyroids to New York State Department of Health for Mass Spectrometry analyses of T4, T4, rT3, two forms of T2 and T1 (data completed), gene array analysis of thyroid gland (work completed by Affymetrix, Inc) and pathway analysis (under analysis now by Dr. James McDougal at Wright State University), and metabolomic analysis of urine (Dr. Matthew Henderson, US EPA Athens,GA). This effort will provide a comprehensive comparison of how the rat thyroid gland responds to iodide deficiency compared to perchlorate and what influence iodide deficiency has on the potency of perchlorate to disturb the HPT axis. Dr. Deborah Keys (statistician) has completed statistical analysis of selected available data.

BBDR HPT axis models in the adult rat were completed as a first step in the development of reproductive state specific models of the HPT axis. Models were developed for the euthyroid and iodide deficient rat and then extended to describe the perturbations in the HPT axis caused by the thyroid active chemical perchlorate. The BBDR-HPT axis sub-models for the adult rat were constructed using simple model structures that allowed us to focus on an empirical ‘system based evaluation’ of key biochemical features of the HPT axis, such as the negative feedback loop. For example, the production of thyroid hormones is controlled, in part, by the model predicted serum TSH concentration, while the maximal rate of active sequestration of iodide into the thyroid is also controlled by the serum TSH concentration. Key features of the BBDR-HPT axis model included the negative feedback loop, thyroid hormone production (using available dietary iodide), and the metabolism of thyroid hormones. The iodide metabolite of thyroid hormone metabolism was available for reuse in thyroid hormone production or excreted in urine. The euthyroid steady-state BBDR-HPT axis model relied on dietary iodide as the only exogenous input. Finally, the calibrated euthyroid, iodide sufficient adult rat BBDR-HPT axis model was tested for its ability to predict perturbations in the system under iodide deficient conditions and for perchlorate insult.

Future Activities:

Computational efforts to develop HPT axis model(s) for different reproductive states will be undertaken. Progress is underway to include the HPT axis of the fetus (GD17.5-birth) and dam, with the negative feedback loop controlling TSH production based on fetal and dam brain T3 concentrations.


Journal Articles on this Report : 5 Displayed | Download in RIS Format

Other project views: All 15 publications 5 publications in selected types All 5 journal articles

Type Citation Project Document Sources
Journal Article Fisher JW, Campbell J, Muralidhara S, Bruckner JV, Ferguson D, Mumtaz M, Harmon B, Hedge JM, Crofton KM, Kim H, Almekinder TL. Effect of PCB 126 on hepatic metabolism of thyroxine and perturbations in the hypothalamic-pituitary-thyroid axis in the rat. Toxicological Sciences 2006;90(1):87-95 R832134 (2008)
not available
Journal Article McLanahan ED, Campbell JL, Ferguson DC, Harmon B, Hedge JM, Crofton KM, Mattie DR, Braverman L, Keys DA, Mumtaz M, Fisher JW. Low-dose effects of ammonium perchlorate on the hypothalamic-pituitary-thyroid axis of adult male rats pretreated with PCB126. Toxicological Sciences 2007;97(2):308-317 R832134 (2008)
not available
Journal Article McLanahan ED, Andersen ME, Fisher JW. A biologically based dose-response model for dietary iodide and the hypothalamic-pituitary-thyroid axis in the adult rat:evaluation of iodide deficiency. Toxicological Sciences 2008;102(2):241-253. R832134 (2007)
R832134 (2008)
  • Abstract from PubMed
  • Journal Article McLanahan ED, Andersen ME, Campbell Jr. JL, Fisher JW. Competitive inhibition of thyroidal uptake of dietary iodide by perchlorate does not describe perturbations in rat serum total T4 and TSH. Environmental Health Perspectives 2009;117(5):731-738. R832134 (2008)
  • Full-text: Environmental Health Perspectives
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  • Abstract: Environmental Health Perspectives
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  • Other: Environmental Health Perspectives PDF
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  • Journal Article Taylor MA, Swant J, Wagner JJ, Fisher JW, Ferguson DC. Lower thyroid compensatory reserve of rat pups after maternal hypothyroidism: correlation of thyroid, hepatic, and cerebrocortical biomarkers with hippocampal neurophysiology. Endocrinology 2008;149(7):3521-3530. R832134 (2007)
    R832134 (2008)
  • Abstract from PubMed
  • Supplemental Keywords:

    BBDR HPT axis model, PBPK model, thyroid, endocrine disruptors, risk assessment, children, fetus, toxics;, RFA, Health, Scientific Discipline, PHYSICAL ASPECTS, Environmental Chemistry, Health Risk Assessment, Endocrine Disruptors - Environmental Exposure & Risk, endocrine disruptors, Risk Assessments, Biochemistry, Physical Processes, Biology, Endocrine Disruptors - Human Health, bioindicator, neurotoxic, dose response, EDCs, endocrine disrupting chemicals, exposure, exposure studies, sexual development, thyroid toxicants, developmental biology, human growth and development, toxicity, endocrine disrupting chemcials, hormone production, ecological risk assessment model, assessment technology, human health risk

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