Endocrine Disruptors: Effects on the ThyroidEPA Grant Number: R826297
Title: Endocrine Disruptors: Effects on the Thyroid
Investigators: Klaassen, Curtis D.
Institution: University of Kansas Medical Center
EPA Project Officer: Reese, David H.
Project Period: December 15, 1997 through December 14, 2000
Project Amount: $594,660
RFA: Endocrine Disruptors (1997) RFA Text | Recipients Lists
Research Category: Endocrine Disruptors , Economics and Decision Sciences , Health , Safer Chemicals
Description:The ultimate goal of this project is to access the significance of endocrine disruptors that increase thyroxine (T4) glucuronidation on thyroid carcinogenesis because many endocrine disruptors are suspected to be thyroid promoters. The mechanism by which endocrine disruptors promote thyroid tumors has been proposed to result from alterations in the thyroid- pituitary-hypothalamus axis. Endocrine disruptors alter the thyroid-pituitary-hypothalamus axis by increasing T4 glucuronidation and elimination, will be released from the pituitary, which will stimulate the thyroid, and result in thyroid follicular cell proliferation and ultimately neoplasia. However, the preliminary studies suggest that a number of endocrine disruptors interfere with the normal hypothalamus-pituitary-thyroid axis because these endocrine disruptors do not increase serum TSH. Therefore, the central hypothesis of this application is that endocrine disruptors that increase T4 glucuronidation are thyroid tumor promoters only when they increase serum TSH.
Approach:To test this hypothesis, there are four specific aims: The first (1) aim is to test the hypothesis that endocrine disruptors decrease plasma T4 pharmacokinetically by increasing its glucuronidation. The pharmacokinetics (clearance, biliary and urinary excretion and in vitro metabolism) of T4, as well as, T3, will be determined to understand the mechanism(s) by which endocrine disruptors decrease serum T4 levels. In the second (2) aim, the mechanism by which some polycyclic aromatic hydrocarbon (PAH)-type endocrine disruptors (such as 3-MC and PCBs) "blunt" the TSH response to reduced serum T4 will be examined, either physiologically, pathologically or by thyroid receptor binding assays. In the third (3) aim, the hypothesis is that endocrine disruptors, which increase serum TSH levels, produce thyroid follicular cell proliferation will be examined via proliferating cell nuclear antigen (PCNA) immunocytochemistry. In the final (4) aim, the hypothesis that the tumor promoting effects of endocrine disruptors are not correlated with the decrease in serum T4, but with the increase in TSH will be tested in a 26-week bioassay. Rats will be given the thyroid initiating agent, N-bis(2-dihydroxy-propyl)nitrosamine (DHPN), followed by exposure to endocrine disruptors.
Expected Results:This study will provide critical information on the relationship between thyroid hormone imbalance, TSH secretion, and thyroid tumor promotion of rats treated with endocrine disruptors. If our hypothesis is true, then it has important implications in toxicology, for many endocrine disruptors. If our hypothesis is true, then it has important implications in toxicology, for many endocrine disruptors have been shown to reduce serum T4 levels. However, their effect on TSH is, at best, variable. Our expectations from the proposed studies is that increases in serum TSH, rather than reductions in serum T4, is a better indicator for thyroid tumorigenicity resulting from exposure to endocrine disruptors. If we demonstrate that the TSH mediates endocrine disruptor thyroid tumor promoting activity, then these endocrine disruptors could be regulated on knowledge rather than ignorance.
Publications and Presentations:Publications have been submitted on this project: View all 5 publications for this project
Journal Articles:Journal Articles have been submitted on this project: View all 2 journal articles for this project
Supplemental Keywords:thyroid, polycyclic aromatic hydrocarbons, polychlorinated byphenyls, endocrine disruptors., RFA, Health, Scientific Discipline, Toxics, Environmental Chemistry, Health Risk Assessment, Chemistry, Endocrine Disruptors - Environmental Exposure & Risk, HAPS, endocrine disruptors, Biochemistry, Children's Health, Biology, Endocrine Disruptors - Human Health, adverse outcomes, toxicokinetic, DHPN, PCBs, Polychlorinated biphenyls (Aroclors), pharmacokinetics, animal models, developmental processes, mice, polychlorinated biphenyls, tumors, carcinogens, models, thyroid function, pituitary, biological effects
Progress and Final Reports:1999 Progress Report