Sewall C H, Flagler N, Vanden Heuvel J P, Clark G C, Tritscher A M, Maronpot R M, Lucier G W
National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina 27709, USA.
Toxicol Appl Pharmacol. 1995 Jun;132(2):237-44. doi: 10.1006/taap.1995.1104.
2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is a multisite carcinogen. Although the hepatocarcinogenic actions of TCDD have received the most attention, it has been demonstrated in several rodent carcinogenicity bioassays that TCDD causes a dose-related increase in thyroid follicular cell adenomas and carcinomas. The purpose of the present experiment was to investigate the dose-response relationship for thyroid function alterations in female Sprague-Dawley rats following chronic treatment with TCDD. TCDD was administered via oral gavage biweekly for 30 weeks at average daily equivalent doses of 0.1-125 ng/kg/day, thereby more than encompassing the dose range historically used in previous TCDD rodent bioassays. The endpoints examined include serum levels of thyroxine (T4), triiodothyronine (T3), and thyroid-stimulating hormone (TSH). In addition, the induction of the dioxin-responsive genes UDP-glucuronosyltransferase-1 (UGT1) and cytochrome P450 1A1 (CYP1A1) in liver were measured using reverse-transcriptase-polymerase chain reaction (RT-PCR). In agreement with previous hypotheses, TCDD appears to alter thyroid function via a secondary mechanism, namely increased excretion of T4-glucuronide resulting from TCDD induction of UGT1. The observed follicular cell hyperplasia and hypertrophy are consistent with the observed elevated TSH levels and may represent the early stages in the progression of thyroid carcinogenesis. Therefore, TCDD induces alterations in thyroid hormone function, probably as a result of chronic perturbations of liver-pituitary-thyroid axis.
2,3,7,8-四氯二苯并对二恶英（TCDD）是一种多部位致癌物。尽管TCDD的肝致癌作用受到了最多关注，但在多项啮齿动物致癌性生物测定中已证明，TCDD会导致甲状腺滤泡细胞腺瘤和癌的剂量相关性增加。本实验的目的是研究雌性Sprague-Dawley大鼠经TCDD慢性处理后甲状腺功能改变的剂量反应关系。通过每周两次口服灌胃给予TCDD，持续30周，平均每日等效剂量为0.1 - 125 ng/kg/天，从而涵盖了以往TCDD啮齿动物生物测定中使用的剂量范围。检测的终点指标包括血清甲状腺素（T4）、三碘甲状腺原氨酸（T3）和促甲状腺激素（TSH）水平。此外，使用逆转录聚合酶链反应（RT-PCR）测量肝脏中二恶英反应基因尿苷二磷酸葡萄糖醛酸基转移酶-1（UGT1）和细胞色素P450 1A1（CYP1A1）的诱导情况。与先前的假设一致，TCDD似乎通过一种次要机制改变甲状腺功能，即TCDD诱导UGT1导致T4-葡萄糖醛酸排泄增加。观察到的滤泡细胞增生和肥大与观察到的TSH水平升高一致，可能代表甲状腺致癌进展的早期阶段。因此，TCDD诱导甲状腺激素功能改变，可能是肝-垂体-甲状腺轴慢性紊乱的结果。
