Grantee Research Project Results
Final 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 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.
Summary/Accomplishments (Outputs/Outcomes):
Currently, thyroid toxicants are evaluated for their potency and potential adverse consequences by characterizing their ability to cause a reduction in circulating levels of thyroid hormone (TH). However, the degree to which TH levels must decline before adverse consequences are produced is not known. To address this, serum TSH levels are often measured in addition to measures of thyroid histopathology. Neither of these endpoints reflect direct measures of TH action in tissues, and it is becoming clear that thyroid toxicants may affect TH action in various tissues in a manner that is not correlated to changes in circulating levels of TH. We tested this hypothesis by evaluating a broad dose-response of three chemicals that act on the thyroid system in very different ways. Perchlorate interferes with iodine uptake into the thyroid gland thereby interfering with thyroid hormone synthesis. In contrast, propylthiouracil (PTU) blocks the thyroperoxidase enzyme responsible for the attachment of iodine onto the tyrosyl residues of thyroglobulin. Finally, polybrominated diphenyls (PBDEs) are believed to activate liver enzymes that clear thyroid hormone from serum, thereby reducing serum TH levels. However, some hydroxylated PBDEs are also reported to bind to the thyroid hormone receptor, and this is likely to be an isoform-selective binding (binding to TRb1 appears to be 40-fold stronger than the TRa1 subtype).
Conclusions:
The data we have generated have provided new insights into thyroid toxicology in general and should be incorporated by the agency in discussions concerning the analysis of data related to thyroid toxicants and public health. First, we have documented that perchlorate exposure to dams in drinking water is transferred to the pre-weaning pups such that serum levels are nearly two-fold that of maternal serum. Moreover, we observed significant changes in serum binding proteins for thyroid hormones. In contrast, PTU produced a graded reduction in serum thyroid hormone levels in both the dams and pups and this was associated with progressive changes in the expression of thyroid hormone-regulated genes in the brain and peripheral organs. Moreover, we found that specific neurodevelopmental events are affected by PTU-induced changes in circulating levels of thyroid hormone. These findings do not support the concept that the developing brain exhibits effective compensatory responses to low thyroid hormone produced by a thyroperoxidase inhibitor. Finally, we found that PBDE exposure produces effects on serum TH levels similar to that of PTU; that is, a graded reduction in serum T4. However, the effect of PBDE exposure on measures of TH signaling in the liver and heart were dramatically different from that following PTU exposure. These findings demonstrate that serum TH levels do not allow one to predict the effect of a thyroid toxicant on TH signaling in various tissues. Moreover, it is likely that the mechanisms by which serum TH levels can be dissociated from TH action in tissues will differ among classes of thyroid toxicants.
Journal Articles on this Report : 21 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. |
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Brent GA, Braverman LE, Zoeller RT. Thyroid health and the environment. Thyroid 2007;17(9):807-809. |
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Crofton KM, Zoeller RT. Mode of action: neurotoxicity induced by thyroid hormone disruption during development—hearing loss resulting from exposure to PHAHs. Critical Reviews in Toxicology 2005;35(8-9):757-769. |
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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. |
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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. |
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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. |
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Gore AC, Heindel JJ, Zoeller RT. Endocrine disruption for endocrinologists (and others). Endocrinology 2006;147(6 Suppl):S1-S3. |
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. |
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Rice DC, Reeve EA, Herlihy A, Zoeller RT, Thompson WD, Markowski VP. Developmental delays and locomotor activity in the C57BL6/J mouse following neonatal exposure to the fully-brominated PBDE, decabromodiphenyl ether. Neurotoxicology and Teratology 2007;29(4):511-520. |
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Sharlin DS, Bansal R, Zoeller RT. Polychlorinated biphenyls exert selective effects on cellular composition of white matter in a manner inconsistent with thyroid hormone insufficiency. Endocrinology 2006;147(2):846-858. |
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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. |
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Sharlin DS, Gilbert ME, Taylor MA, Ferguson DC, Zoeller RT. The nature of the compensatory response to low thyroid hormone in the developing brain. Journal of Neuroendocrinology 2010;22(3):153-165. |
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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. |
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Woodruff TJ, Zeise L, Axelrad DA, Guyton KZ, Janssen S, Miller M, Miller GG, Schwartz JM, Alexeeff G, Anderson H, Birnbaum L, Bois F, Cogliano VJ, Crofton K, Euling SY, Foster PMD, Germolec DR, Gray E, Hattis DB, Kyle AD, Luebke RW, Luster MI, Portier C, Rice DC, Solomon G, Vandenberg J, Zoeller RT. Meeting report:moving upstream-evaluating adverse upstream end points for improved risk assessment and decision-making. Environmental Health Perspectives 2008;116(11):1568-1575. |
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Zoeller RT, Crofton KM. Mode of action: developmental thyroid hormone insufficiency--neurological abnormalities resulting from exposure to propylthiouracil. Critical Reviews in Toxicology 2005;35(8-9):771-781. |
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Zoeller RT. Collision of basic and applied approaches to risk assessment of thyroid toxicants. Annals of the New York Academy of Sciences 2006;1076:168-190. |
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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. |
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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. |
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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. |
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Zoeller RT. Environmental chemicals impacting the thyroid: targets and consequences. Thyroid 2007;17(9):811-817. |
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Zoeller RT. Environmental neuroendocrine and thyroid disruption: relevance for reproductive medicine? Fertility and Sterility 2008;89(2 Suppl):e99-e100. |
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Supplemental Keywords:
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 modelRelevant Websites:
http://www.bio.umass.edu/biology/zoeller/ ExitProgress 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.