Environmental Hormones: Effects on Thyroid Function

本项目的最终目的是评估增加三碘甲状腺原氨酸（T3）肝脏摄取和葡萄糖醛酸化的内分泌干扰物在甲状腺癌发生中的意义。许多甲状腺内分泌干扰物被怀疑是甲状腺肿瘤促进剂，它们通过改变甲状腺激素的稳态来促进甲状腺肿瘤。先前有人提出，内分泌干扰物通过增加T4糖醛酸化和消除来改变下丘脑-垂体-甲状腺轴，从而降低血清T4。促甲状腺激素（thyroid stimulating hormone， TSH）是一种代偿反馈机制，由垂体释放，刺激甲状腺，导致甲状腺细胞增生和肿瘤形成。然而，我们发现，与甲状腺内分泌干扰物治疗大鼠的TSH升高相关的是T3糖醛酸化，而不是T4。因此，我们建议测试T3代谢增加的重要性(即。肝摄取和葡萄糖醛酸化T3)介导了内分泌干扰物治疗大鼠TSH的增加。在这个应用中，我们将测试一个假设，即甲状腺激素干扰物，特别是增加肝脏对T3的摄取和葡萄糖醛酸化，增加血清TSH，是甲状腺肿瘤促进剂。我们提出，这些甲状腺激素干扰物增加肝脏对T3的摄取和葡萄糖醛酸化的分子机制是通过配体激活的孕激素- x受体（PXR）介导的，PXR增加了肝脏T3窦转运体的转录和最终的蛋白质水平，并增加了葡萄糖醛酸化T3的葡萄糖醛酸转移酶(s)。这导致T3转运到肝细胞和T3糖醛酸化增加，导致血液T3水平降低，下丘脑和垂体负反馈效应减弱，血清TSH升高，刺激甲状腺滤泡细胞增殖，最终促进甲状腺肿瘤。这些研究将为甲状腺内分泌干扰物治疗大鼠甲状腺激素失衡、TSH分泌和甲状腺肿瘤促进之间的关系提供重要信息。如果整个假设是正确的，那么它对毒理学和风险评估具有重要意义，因为许多内分泌干扰物已被证明会破坏甲状腺激素的稳态。此外，如果我们的假设是正确的，即一种特定的葡萄糖醛酸糖基转移酶负责T3的葡萄糖醛酸化，从而启动血清TSH的增加，那么这种内分泌干扰的生物标志物可能会被开发出来。如果我们的分子假设是正确的，即产生甲状腺肿瘤的最初相互作用是通过内分泌干扰物与PXR的相互作用，那么就可以开发出潜在甲状腺肿瘤促进剂的筛选。

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.