Grantee Research Project Results
2007 Progress Report: Low-Dose Effects of Thyroid Toxicants on Neurodevelopment
EPA Grant Number: R832137Title: 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 Period Covered by this Report: December 1, 2006 through November 30,2007
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: Environmental Justice , Endocrine Disruptors , Safer Chemicals
Objective:
The overall goal of this project is to test the hypothesis that thyroid hormone (TH) produces non-linear dose-dependent effects on endpoints within the developing brain, heart and liver, but that some endpoints are more sensitive than others to thyroid hormone. In addition, we propose that thyroid toxicants disrupting the HPT axis by different mechanisms will produce different dose-response curves on these endpoints. And finally, a principle mechanism shaping the dose-response curve to thyroid hormone – or by extension, thyroid disruptors – are changes in tissue metabolism of thyroid hormone in response to perturbations in the HPT axis.
Approach:
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.
Progress Summary:
We have made significant progress toward the stated goals, especially the formation of a cooperative agreement with the EPA and with investigators at the University of Georgia and now at the University of Illinois. Important new insights into the low-dose effects of thyroid toxicants have been derived from the current accomplishments. Important, in collaboration with the cooperating labs, we have shown that after exposure to low doses of the antithyroid drug propylthiouricil (PTU), the cellular structure of white matter is significantly altered by reductions in circulating levels of thyroid hormone as low as 28%. We have determined that oligodendrocyte numbers are reduced and astrocyte numbers are increased. However, these two cell types only account for about 50% of the cells that make up the corpus callosum and there is also a significant reduction in the total cell density as visualized with a fluorescent stain that binds strongly to DNA. This very simple measure may be a very valuable endpoint in screens and tests for endocrine disruptors because it is a structural change in the brain that could indicate developmental neurotoxicity.
In addition, we have found that changes in brain tissue levels of type 2 deiodinase (D2) are not associated with measures of “compensation”. There are two important implications to these data. The first is that there is a very tight correlation between tissue levels of D2 messenger ribonucleic acid (mRNA) and D2 activity. This means that we can capture regional changes in D2 mRNA levels and infer changes in D2 activity. Second, we provide very compelling evidence that the developing brain is not as capable as previously believed at compensating for changes in circulating levels of thyroid hormone. This has important implications for the interpretation of the relationship between serum thyroxine ( T4) and chemical or clinical factors. Moreover, although we do not know the full implication of these data, we can begin to address the role of thyroid hormone in brain development on a more realistic footing.
We have also shown for the first time that levels of perchlorate, a chemical used in rocket fuel that occurs in drinking water, are higher in the serum of lactating pups than in the dams. This has important implications for determining the risk to the human population from perchlorate exposure. Finally, we have also found that concentrations of polybrominated diphenylether (PBDE), a flame retardant, in various organs are not strictly related to the fatty content of the organ; thus, there may be specific transporters for PBDE uptake into tissues.
Expected Results:
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.
Future Activities:
The overall goal of this project is to determine the molecular mechanisms controlling the response to changes in circulating levels at low doses of various toxicants. We have generally characterized this for propylthiouricil (PTU), and we now must complete these measures for perchlorate and for PBDE exposure. We should reasonably complete these studies within the next few months.
Journal Articles on this Report : 12 Displayed | Download in RIS Format
Other project views: | All 36 publications | 23 publications in selected types | All 21 journal articles |
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Bansal R, Zoeller RT. Polychlorinated biphenyls (Aroclor 1254) do not uniformly produce agonist actions on thyroid hormone responses in the developing rat brain. Endocrinology 2008;149(8):4001-4008. |
R832137 (2007) R832137 (Final) |
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Brent GA, Braverman LE, Zoeller RT. Thyroid health and the environment. Thyroid 2007;17(9):807-809. |
R832137 (2007) R832137 (Final) |
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Degon M, Chipkin SR, Hollot CV, Zoeller RT, Chait Y. A computational model of the human thyroid. Mathematical Biosciences 2008;212(1):22-53. |
R832137 (2007) R832137 (Final) |
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Gauger KJ, Giera S, Sharlin DS, Bansal R, Iannacone E, Zoeller RT. Polychlorinated biphenyls 105 and 118 form thyroid hormone receptor agonists after cytochrome P4501A1 activation in rat pituitary GH3 cells. Environmental Health Perspectives 2007;115(11):1623-1630. |
R832137 (2007) R832137 (Final) |
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Ginsberg GL, Hattis DB, Zoeller RT, Rice DC. Evaluation of the U.S. EPA/OSWER preliminary remediation goal for perchlorate in groundwater:focus on exposure to nursing infants. Environmental Health Perspectives 2007;115(3):361-369. |
R832137 (2007) R832137 (Final) |
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Jagalur M, Pal C, Learned-Miller E, Zoeller RT, Kulp D. Analyzing in situ gene expression in the mouse brain with image registration, feature extraction and block clustering. BMC Bioinformatics 2007;8(Suppl 10):S5. |
R832137 (2007) R832137 (Final) |
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Sharlin DS, Tighe D, Gilbert ME, Zoeller RT. The balance between oligodendrocyte and astrocyte production in major white matter tracts is linearly related to serum total thyroxine. Endocrinology 2008;149(5):2527-2536. |
R832137 (2007) R832137 (Final) |
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Tan SW, Zoeller RT. Integrating basic research on thyroid hormone action into screening and testing programs for thyroid disruptors. Critical Reviews in Toxicology 2007;37(1-2):5-10. |
R832137 (2007) R832137 (Final) |
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Zoeller RT, Tyl RW, Tan SW. Current and potential rodent screens and tests for thyroid toxicants. Critical Reviews in Toxicology 2007;37(1-2):55-95. |
R832137 (2007) R832137 (Final) |
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Zoeller RT, Tan SW, Tyl RW. General background on the hypothalamic-pituitary-thyroid (HPT) axis. Critical Reviews in Toxicology 2007;37(1-2):11-53. |
R832137 (2007) R832137 (Final) |
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Zoeller RT, Tan SW. Implications of research on assays to characterize thyroid toxicants. Critical Reviews in Toxicology 2007;37(1-2):195-210. |
R832137 (2007) R832137 (Final) |
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Zoeller RT. Environmental chemicals impacting the thyroid: targets and consequences. Thyroid 2007;17(9):811-817. |
R832137 (2007) R832137 (Final) |
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Supplemental Keywords:
T4, T3, TSH, TTR, thyroxine binding globulin, TBG, Thyroid hormone, thyroid toxicant, propylthiouracil, polybrominated diphenyl, perchlorate, compensation, brain development, deiodinase, MCT8,, RFA, Health, Scientific Discipline, POLLUTANTS/TOXICS, Health Risk Assessment, Endocrine Disruptors - Environmental Exposure & Risk, Chemicals, Risk Assessments, endocrine disruptors, Biochemistry, Biology, Endocrine Disruptors - Human Health, neurotoxic, bioindicator, EDCs, thyroid toxicants, exposure studies, endocrine disrupting chemicals, sexual development, endocrine disrupting chemcials, human growth and development, toxicity, invertebrates, estrogen receptors, hormone production, ecological risk assessment modelProgress and Final Reports:
Original AbstractThe perspectives, information and conclusions conveyed in research project abstracts, progress reports, final reports, journal abstracts and journal publications convey the viewpoints of the principal investigator and may not represent the views and policies of ORD and EPA. Conclusions drawn by the principal investigators have not been reviewed by the Agency.