Mode of Action of Thyroid Tumor Formation in the Male Long–Evans Rat Administered High Doses of Alachlor
Mode of Action of Thyroid Tumor Formation in the Male Long–Evans Rat Administered High Doses of Alachlor
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DOI：
10.1006/faat.1996.0138
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发表时间：
1996-09
影响因子：
3.8
通讯作者：
Alan G. E. Wilson;D. Thake;W. Heydens;D. W. Brewster;K. Hotz
中科院分区：
文献类型：
--
作者：
Alan G. E. Wilson;D. Thake;W. Heydens;D. W. Brewster;K. Hotz
以前的研究表明，在饮食中长期给予126毫克/公斤/天的甲草胺会导致雄性Long-Evans大鼠良性甲状腺滤泡细胞肿瘤的增加。通过评估与激素介导的甲状腺肿瘤作用模式相关的参数变化，研究了甲氯草胺诱导雄性大鼠甲状腺肿瘤的机制。雄性Long-Evans大鼠通过日粮给予126 mg甲草胺/kg体重/天，持续120天。一组动物在60天后停用经甲氯草胺处理的饲料，并在另外60天内继续饲喂未经处理的饲料。在治疗第7、14、28、60和120天测定肝脏和甲状腺重量、血清三碘甲状腺原氨酸（T3）、甲状腺素（T4）和促甲状腺激素（TSH）水平，以及肝脏尿苷二磷酸葡萄糖醛酸转移酶（UDPGT）活性。甲草胺组动物的肝脏和甲状腺重量、肝脏UDPGT活性和循环TSH水平均显著升高。这些增加早在甲草胺给药后7天就出现了。与对照组相比，七氯草胺处理动物的T4循环水平在第7天显著降低，但在第60天恢复到对照组水平。除第28天外，所有时间点T3水平均升高。从饮食中去除甲草胺后，TSH和T3水平、肝脏UDPGT活性和肝脏重量的变化都是可逆的。从饮食中去除甲草胺后，甲状腺重量并没有完全恢复到控制水平，尽管有些恢复是明显的。本研究的结果清楚地表明，在之前用甲草胺进行的慢性生物测定中观察到的甲草胺诱导的甲状腺瘤变与循环TSH水平的增加有关。通过肝酶偶联（即T4- udpgt）增加T4代谢似乎是导致TSH水平升高的原因。这些影响在停止接触甲草胺后是可逆的。总之，有证据表明激素介导的甲状腺滤泡细胞瘤的发展过程。
Chronic administration of alachlor in the diet at a level of 126 mg/kg/day has previously been shown to cause an increase in benign thyroid follicular cell tumors in male Long-Evans rats. Studies were conducted to elucidate the mechanism of the alachlor-induced thyroid tumors in the male rat by evaluating changes in parameters that are collectively associated with a hormonally mediated mode of action for thyroid neoplasia. Male Long-Evans rats were administered 126 mg alachlor/kg body wt/day via the diet for up to 120 days. One group of animals was removed from alachlor-treated diet after 60 days and received untreated diet for an additional 60 days. Liver and thyroid weights and serum levels of triiodothyronine (T3), thyroxine (T4), and thyroid-stimulating hormone (TSH), as well as hepatic uridine diphosphate glucuronosyl transferase (UDPGT) activity, were determined at 7, 14, 28, 60, and 120 days of treatment. Liver and thyroid weights, hepatic UDPGT activity, and circulating levels of TSH were significantly increased in animals administered alachlor. These increases were seen as early as 7 days after alachlor administration. Circulating levels of T4 in alachlor-treated animals were significantly decreased compared with controls at 7 days, but had returned to control levels by 60 days. T3 levels were elevated at all time points except at 28 days. The changes in TSH and T3 levels, hepatic UDPGT activity, and liver weights were all reversible on elimination of alachlor from the diet. Thyroid weights did not completely return to control levels after removal of alachlor from the diet, although some recovery was evident. The results of this study clearly suggest that alachlor-induced thyroid neoplasia, observed in previous chronic bioassays with alachlor, was associated with increases in circulating TSH levels. Increased metabolism of T4 via hepatic enzymatic conjugation (i.e., T4-UDPGT) appeared to be responsible for the increased TSH levels. These effects were shown to be reversible on cessation of exposure to alachlor. In summary, evidence is presented for a hormonally mediated process for the development of thyroid follicular cell tumors.