ENVIRONMENTAL HORMONES--EFFECTS ON THYROID FUNCTION

环境激素——对甲状腺功能的影响

• 批准号: 2872333
• 负责人: CURTIS D KLAASSEN
• 金额: $ 19.4万
• 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 2001-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2872333
• 关键词: cell proliferation; chemical carcinogenesis; endocrinology; environment related neoplasm /cancer; environmental toxicology; glucuronides; halobiphenyl /halotriphenyl compound; hormone metabolism; hormone regulation /control mechanism; hormone related neoplasm /cancer; hypothalamic pituitary axis; laboratory rat; methylcholanthrene; nitrosamines; pharmacokinetics; pituitary thyroid axis; proliferating cell nuclear antigen; thyroid function; thyroid neoplasm; thyrotropin; thyroxine; tumor promoters

DESCRIPTION (Adapted from the Investigator's Abstract): The ultimate goal of this project is to assess the significance of endocrine disruptors that increase thyroxine (T4) glucuronidation on thyroid carcinogenesis, because many endocrine disruptors are suspected to be thyroid tumor promoters. The mechanism by which endocrine disruptors promote thyroid tumors has been proposed to result from alterations in the hypothalamus-pituitary-thyroid axis. 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) will be released from the pituitary, which will stimulate the thyroid and result in thyroid cell proliferation and neoplasia. However, the preliminary studies suggest that a number of endocrine disruptors (3MC and PCB) 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. To test this hypothesis, there are five specific aims: (1) This aim is to test the hypothesis that endocrine disruptors, which increase serum TSH, produce thyroid follicular cell proliferation via proliferating cell nuclear antigen (PCNA) immunocytochemistry. In aim (2), the hypothesis that the tumor promoting effects of endocrine disruptors are not correlated with the decrease in serum T4, but with the increase in serum TSH will be tested in a 25-week bioassay. Rats will be given the thyroid initiating agent, N-bis(2-hydroxypropyl)nitrosamine (DHPN), followed by exposure to endocrine disruptors. 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. Aim (3) is to test the hypothesis that endocrine disruptors decrease plasma T4 pharmacokinetically by increasing its glucuronidation. The pharmacokinetics of T4, as well as T3, will be determined to understand the mechanism(s) by which endocrine disruptors decrease serum T4 in the final aim (4), the mechanism by which 3MC and PCBs "blunt" the TSH response to reduced serum T4 will be examined, testing physiologic, pathologic or thyroid receptor binding mechanisms. If the overall hypothesis is true, then it has important implications in toxicology, for many endocrine disruptors have been shown to reduce serum T4. However, their effect on TSH is, at best, variable. The expectation 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 the investigators demonstrate that TSH mediates endocrine disruptor thyroid tumor promoting activity, then as long as the promotional mechanism is prevented (increase in serum TSH), cancer would be prevented.

描述（改编自研究者摘要）：最终目标 该项目的目的是评估内分泌干扰物的重要性， 增加甲状腺素（T4）葡萄糖醛酸化对甲状腺癌的作用，因为 许多内分泌干扰物被怀疑是甲状腺肿瘤的促进剂。 的 内分泌干扰物促进甲状腺肿瘤的机制一直是 推测是由于下丘脑-垂体-甲状腺 轴线 内分泌干扰物改变下丘脑-垂体-甲状腺轴， 增加T4葡萄糖醛酸化和消除，从而降低血清T4作为 补偿反馈机制，促甲状腺激素（TSH）将 会刺激甲状腺，导致 甲状腺细胞增殖和瘤形成。 然而，初步研究 这表明，一些内分泌干扰物（3 MC和PCB）干扰 正常的下丘脑-垂体-甲状腺轴，因为这些内分泌 干扰物不增加血清TSH。 因此， 这种应用是内分泌干扰物， 葡萄糖醛酸化只有在血清中 促甲状腺激素 为了验证这一假设，有五个具体目标：（1）这一目标 是为了验证一个假设，即内分泌干扰物， 促甲状腺激素，通过增殖细胞产生甲状腺滤泡细胞增殖 核抗原（PCNA）免疫细胞化学。 在目的（2）中，假设 内分泌干扰物的促肿瘤作用与 血清T4降低，但血清TSH升高将被检测 在25周的生物测定中。 大鼠将被给予甲状腺启动剂， N-双（2-羟丙基）亚硝胺（DHPN），然后暴露于内分泌 破坏者 这项研究将提供关键信息， 甲状腺激素失衡、TSH分泌与甲状腺功能的关系 用内分泌干扰物处理的大鼠的肿瘤促进。 目标（3）是 测试内分泌干扰物降低血浆T4的假设 通过增加其葡萄糖醛酸化作用来进行药代动力学研究。 药代动力学 T4和T3的，将被确定为理解机制， 内分泌干扰物降低血清T4的最终目的（4）， 3 MC和PCB“钝化”TSH对血清T4降低的反应的机制 将进行检查，检测生理、病理或甲状腺受体 约束机制 如果总体假设是正确的，那么 毒理学的重要意义，因为许多内分泌干扰物 降低血清T4。 然而，它们对TSH的影响充其量是， 变量 预计血清TSH的增加，而不是 血清T4降低是甲状腺致瘤性的更好指标 是由于暴露于内分泌干扰物而导致的。 如果研究者 证明TSH介导内分泌干扰物甲状腺肿瘤促进 活动，那么只要阻止促销机制（增加 在血清TSH中），癌症将被预防。