Promotion of thyroid tumors in rats by pregnenolone-16alpha-carbonitrile (PCN) and polychlorinated biphenyl (PCB).
Promotion of thyroid tumors in rats by pregnenolone-16alpha-carbonitrile (PCN) and polychlorinated biphenyl (PCB).
复制标题
孕烯醇酮-16α-甲腈 (PCN) 和多氯联苯 (PCB) 促进大鼠甲状腺肿瘤。
DOI：
10.1093/toxsci/kfh197
复制
发表时间：
2004
期刊：
影响因子：
--
通讯作者：
Klaassen,CurtisD
中科院分区：
文献类型：
--
作者：
Vansell,NicholeR;Muppidi,JaganR;Habeebu,SultanM;Klaassen,CurtisD
孕烯醇酮-16 α-腈（PCN）和多氯联苯1254（PCB）均降低大鼠的血清甲状腺激素水平，但只有PCN持续升高血清促甲状腺激素（TSH）。PCN介导的TSH增加导致甲状腺滤泡细胞增殖和增生增加，这可能代表导致瘤形成的形态连续体上的早期事件。本研究的目的是评估PCN（一种增加血清TSH的化合物）和PCB（不增加TSH）是否会在两阶段致癌模型中促进甲状腺肿瘤。雄性SD大鼠给予甲状腺肿瘤引发剂二异丙醇亚硝胺（2.5 g/kg，sc），7天后喂食对照饲料、含1000 ppm PCN的饲料或含100 ppm PCB的饲料19周。体重不受多氯化萘治疗，但减少了21%，19周的PCB治疗相比，控制。PCN治疗显着降低血清T4通过第3周，然后返回到控制浓度，而T4水平PCB治疗后下降到第3周的检测限以下，并保持大幅减少，通过第19周。在PCN处理的大鼠中，TSH浓度在第2周增加了3倍，然后在第19周下降至接近对照值。PCB治疗一周后，TSH浓度达到对照组的近两倍，并持续到第6周。甲状腺滤泡细胞增生性病变的发生率，包括囊性和滤泡性增生，囊性和滤泡性腺瘤，滤泡性癌，在PCN治疗后显着增加，但PCB治疗后没有。PCB治疗引起甲状腺癌的增加（22只大鼠中有4只），尽管TSH血清浓度增加，但与PCN产生的增殖型病变无关。总之，PCN似乎促进甲状腺肿瘤的方式与已知的过度TSH刺激的影响一致。然而，多氯联苯治疗引起的甲状腺癌表明，传统上被认为是微粒体酶诱导剂的化学品在啮齿动物中产生甲状腺癌存在不同的机制。
Pregnenolone-16α-carbonitrile (PCN) and Aroclor 1254 (PCB) both reduce serum thyroid hormone levels in rats, but only PCN consistently produces an increase in serum thyrotropin (TSH). PCN-mediated increases in TSH result in increased thyroid follicular cell proliferation and hyperplasia, which may represent early events on a morphological continuum leading to neoplasia. The purpose of this study was to assess whether PCN, a compound that increases serum TSH, and PCB, which does not increase TSH, promote thyroid tumors in a two-stage carcinogenesis model. Male SD rats were administered the thyroid tumor initiator diisopropanolnitrosamine (2.5 g/kg, sc), and after seven days were fed control diet, diet containing 1000 ppm PCN, or diet containing 100 ppm PCB for 19 weeks. Body weights were unaffected by PCN treatment, but were reduced 21% after 19 weeks of PCB treatment compared to control. PCN treatment significantly reduced serum T4through week 3 before returning to control concentrations, whereas T4levels following PCB treatment fell below detection limits by week 3 and remained drastically reduced through week 19. TSH concentrations in PCN-treated rats increased three-fold at week 2, then declined to near control values at week 19. After one week of PCB treatment, TSH concentrations reached nearly twice that of controls, and were sustained until week 6. The incidence of thyroid follicular cell proliferative lesions, including cystic and follicular hyperplasia, cystic and follicular adenoma, and follicular carcinoma, was significantly increased following PCN treatment, but not following PCB treatment. PCB treatment caused an increase in thyroid carcinomas (4 of 22 rats) not associated with the proliferative-type lesions produced by PCN, despite an increase in TSH serum concentrations. In conclusion, PCN appears to promote thyroid tumors in a manner consistent with known effects of excessive TSH stimulation. However, thyroid carcinomas stemming from PCB treatment indicate that separate mechanisms exist for the production of thyroid cancer in rodents by chemicals classically considered microsomal enzyme inducers.