ENVIRONMENTAL HORMONES--EFFECTS ON THYROID FUNCTION

环境激素——对甲状腺功能的影响

• 批准号: 6150721
• 负责人: CURTIS D KLAASSEN
• 金额: $ 19.87万
• 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/6150721
• 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《调查者摘要》)：最终目标 这个项目的目的是评估内分泌干扰物的重要性 增加甲状腺激素(T4)葡萄糖醛酸化在甲状腺癌发生中的作用，因为 许多内分泌干扰物被怀疑是甲状腺肿瘤的促进剂。这个 内分泌干扰物促进甲状腺肿瘤的机制一直以来 可能是由于下丘脑-垂体-甲状腺的变化所致 轴心。内分泌干扰物通过以下方式改变下丘脑-垂体-甲状腺轴 增加T4葡萄糖醛酸化和清除，从而降低血清T4作为一种 代偿反馈机制，促甲状腺激素(TSH)将 从脑下垂体释放出来，会刺激甲状腺并导致 甲状腺细胞增殖和肿瘤形成。然而，初步研究表明 提示一些内分泌干扰物(3mc和多氯联苯)会干扰 正常的下丘脑-垂体-甲状腺轴是因为这些内分泌 干扰物不会增加血清TSH。因此，核心假说是 这个应用是增加T4的内分泌干扰物 只有当葡萄糖醛酸化反应增加血清时，它们才是甲状腺肿瘤的促进剂 太好了。为了验证这一假设，有五个具体的目标：(1)这个目标 是为了验证内分泌干扰物会增加血清的假说 促甲状腺激素，通过增殖细胞促进甲状腺滤泡细胞增殖 核抗原(PCNA)免疫细胞化学。在Aim(2)中，假设 内分泌干扰物的促癌作用与 血清T4降低，但随着血清TSH升高，将进行检测 在为期25周的生物化验中。大鼠将被给予甲状腺启动剂， N-二(2-羟丙基)亚硝胺(DHPN)，然后暴露于内分泌 颠覆者。这项研究将提供有关 甲状腺激素失衡、促甲状腺激素分泌与甲状腺的关系 内分泌干扰物对大鼠肿瘤的促进作用。目标(3)是 检验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实现药代动力学。药代动力学 T4的，以及T3的，将通过以下方式来确定了解机制(S) 在最终目标(4)中，哪些内分泌干扰物降低血清T4 3MC和多氯联苯“钝化”TSH对血清T4降低反应的机制 将进行检查，测试生理、病理或甲状腺受体 约束机制。如果总体假设是正确的，那么它是正确的。 在毒理学中的重要意义，因为许多内分泌干扰物 已被证明能降低血清T4。然而，它们对促甲状腺激素的影响充其量只是 变量。人们的预期是，血清TSH的增加，而不是 血清T4水平降低是甲状腺肿瘤发生的较好指标 由于暴露在内分泌干扰物中。如果调查人员 TSH介导内分泌干扰物促甲状腺肿瘤的实验研究 活动，那么只要防止(增加)促进机制 在血清TSH中)，癌症就会被预防。