Environmental Hormones: Effects on Thyroid Function

环境激素：对甲状腺功能的影响

• 批准号: 6524762
• 负责人: CURTIS D KLAASSEN
• 金额: $ 37.5万
• 依托单位: UNIVERSITY OF KANSAS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-02-01 至 2006-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6524762
• 关键词: carcinogenesis; cell proliferation; drug /agent; enzyme activity; glucuronosyltransferase; hormone regulation /control mechanism; hypothalamic pituitary axis; laboratory rat; liver metabolism; pituitary thyroid axis; thyroid function; thyroid neoplasm; thyrotropin; triiodothyronine; tumor promoters

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.

本项目的最终目标是评估内分泌干扰物对甲状腺癌发生的意义，这些干扰物可增加三碘甲状腺原氨酸（T3）的肝脏摄取和葡萄糖醛酸化。 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而促进甲状腺肿瘤。 以前提出，内分泌干扰物通过增加T4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。 作为一种代偿性反馈机制，促甲状腺激素（TSH）从垂体释放，刺激甲状腺并导致甲状腺细胞增殖和瘤形成。 然而，我们发现T3葡萄糖醛酸化的诱导，而不是T4，与甲状腺内分泌干扰物治疗的大鼠的TSH增加更好地相关。 因此，我们建议测试T3代谢增加的重要性（即，肝脏摄取和T3的葡萄糖醛酸化）介导内分泌干扰物处理大鼠的TSH增加。 在本申请中，我们将检验甲状腺激素干扰物特异性增加肝脏摄取和T3葡萄糖醛酸化并增加血清TSH是甲状腺肿瘤促进剂的假设。 我们提出，这些甲状腺激素干扰物增加肝脏摄取和T3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，PXR增加肝脏T3正弦转运蛋白的转录和最终蛋白水平，以及增加葡萄糖醛酸化T3的葡萄糖醛酸转移酶。 这导致T3转运至肝细胞和T3葡萄糖醛酸化增加，导致T3血液水平降低，下丘脑和垂体负反馈效应降低，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。 这些研究将提供关于甲状腺激素失衡、TSH分泌和甲状腺内分泌干扰物治疗大鼠甲状腺肿瘤促进之间关系的关键信息。 如果总体假设是正确的，那么它在毒理学和风险评估方面具有重要意义，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基转移酶负责T3的葡萄糖醛酸化，启动血清TSH的增加，那么这种类型的内分泌干扰的生物标志物可以开发。 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，那么可以开发潜在的甲状腺肿瘤促进剂的筛选。