Environmental Hormones: Effects on Thyroid Function

该项目的最终目标是评估内分泌干扰物增加三碘甲状腺原氨酸(T3)肝脏摄取和葡萄糖醛酸化作用在甲状腺癌发生中的意义。许多甲状腺内分泌干扰物被认为是甲状腺肿瘤的促进剂，通过改变甲状腺激素的动态平衡促进甲状腺肿瘤的发生。以前有人提出，内分泌干扰物通过增加T4的葡萄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(TSH)作为一种代偿性反馈机制，从垂体释放出来，刺激甲状腺，导致甲状腺细胞增殖和肿瘤发生。然而，我们发现，在接受甲状腺内分泌干扰物治疗的大鼠中，诱导T3糖醛酸化反应，而不是T4，与TSH升高有更好的相关性。因此，我们建议测试T_3代谢增加(即肝脏摄取T_3和糖醛酸化T_3)在调节内分泌干扰物治疗的大鼠促甲状腺激素升高中的重要性。在这项应用中，我们将检验甲状腺激素干扰物是甲状腺肿瘤促进剂的假设，这些干扰物特异性地增加肝脏对T3的摄取和葡萄糖醛酸化作用，并增加血清TSH。我们认为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烷X受体(PXR)介导的，它增加了肝脏T3正弦转运体的转录和最终蛋白水平，并增加了使T3糖醛酸化的葡萄糖醛酸基转移酶(S)。这导致T3进入肝细胞的转运增加和T3糖醛酸化，导致血液中T3水平降低，下丘脑和垂体的负反馈作用减弱，血清TSH增加，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激素失衡、TSH分泌和甲状腺内分泌干扰物治疗大鼠促甲状腺肿瘤之间的关系提供重要信息。如果整个假设是正确的，那么它在毒理学和风险评估中具有重要的意义，因为许多内分泌干扰物已经被证明扰乱甲状腺激素的动态平衡。此外，如果我们的假设是正确的，即特定的葡萄糖醛酸基转移酶负责T3的葡萄糖醛酸化作用，从而启动血清TSH的增加，那么这种类型的内分泌干扰的生物标记物就可以被开发出来。如果我们的分子假说是正确的，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，那么就可以开发出一种潜在的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.