The ultimate goal of this project is to assess the significance of endocrine disruptors that increase triiodothyronine (T3) hepatic uptake and glucuronidation on thyroid carcinogenesis. Many thyroid endocrine disruptors are suspected thyroid tumor promoters, which promote thyroid tumors by altering thyroid hormone homeostasis. It was previously proposed that endocrine disruptors alter the hypothalamus- pituitary-thyroid axis by increasing T4 glucuronidation and elimination, which reduces serum T4. As a compensatory feedback mechanism, thyroid stimulating hormone (TSH) is released from the pituitary, which stimulates the thyroid and results in thyroid cell proliferation and neoplasia. However, we have found that induction of T3 glucuronidation, rather than T4, is better correlated with increases in TSH of rats treated with thyroid endocrine disruptors. Therefore, we propose to test the importance of increased metabolism of T3 (ie., hepatic uptake and glucuronidation of T3) in mediating increases in TSH of endocrine disruptor-treated rats. In this application, we will test the hypothesis that thyroid hormone disruptors that specifically increase hepatic uptake and glucuronidation of T3 and increase serum TSH, are thyroid tumor promoters. We propose that the molecular mechanism by which these thyroid hormone disruptors increase hepatic uptake and glucuronidation of T3 is mediated through the ligand-activated pregnane-X-receptor (PXR), which increases the transcription and eventual protein levels of hepatic T3 sinusoidal transporters, as well as increases the glucuronosyltransferase(s) that glucuronidates T3. This results in an increase in the transport of T3 into hepatocytes and T3 glucuronidation, resulting in reduced blood levels of T3, reduced negative feedback effect at the hypothalamus and pituitary, increased serum TSH, stimulation of thyroid follicular cell proliferation, and ultimately thyroid tumor promotion. These studies will provide critical information on the relationship between thyroid hormone imbalance, TSH secretion, and thyroid tumor promotion of rats treated with thyroid endocrine disruptors. If the overall hypothesis is true, then it has important implications in toxicology and risk assessment, for many endocrine disruptors have been shown to disrupt thyroid hormone homeostasis. Also, if our hypothesis is true, that a specific glucuronosyltransferase is responsible for the glucuronidation of T3 that initiates the increase in serum TSH, then a biomarker for this type of endocrine disruption could be developed. If our molecular hypothesis is true, that the initial interaction that produces thyroid tumors is through an interaction of the endocrine disruptor with the PXR, a screen for potential thyroid-tumor promoters could be developed.
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