Hood A, Liu Y P, Gattone V H, Klaassen C D
Department of Pharmacology, Toxicology, and Therapeutics, University of Kansas Medical Center, Kansas City 66160-7140, USA.
Toxicol Sci. 1999 Jun;49(2):263-71. doi: 10.1093/toxsci/49.2.263.
Antithyroid drugs and phenobarbital (PB) have been shown to promote thyroid tumors in rats. It has been proposed that increased thyroid-stimulating hormone (TSH) mediates the thyroid tumor-promoting effect of antithyroid drugs and PB, and is increased because of decreased thyroxine (T4) concentration. However, PB is much less effective than antithyroid drugs at increasing TSH. It has been proposed that small increases in serum TSH produced by PB treatment is sufficient to promote thyroid tumors. However, the level to which TSH must be increased to stimulate the thyroid gland has not been reported. Therefore, we have examined the effect of increasing serum TSH concentration on thyroid growth by measuring thyroid gland weight and thyroid follicular cell proliferation. Serum TSH concentrations were increased by feeding rats various concentrations of propylthiouracil (PTU) or methimazole (MMI) for 21 days. Serum total T4, free T4, total T3 (triiodothyronine), free T3, and TSH concentrations were measured by radioimmunoassay. Thyroid follicular cell proliferation was measured by autoradiography and expressed as a labeling index (LI). PTU and MMI treatments reduced total and free T4 more than 95% by day 21, whereas total and free T3 were reduced 60%. TSH, thyroid follicular cell proliferation and thyroid weight were increased 560%, 1400%, and 200%, respectively, by day 21. TSH was significantly correlated with thyroid weight and LI. Moderate increases in serum TSH of between 10 and 20 ng/ml increased the number of proliferating thyroid follicular cells, but had no effect on thyroid weight. These results support that small increases in serum TSH can be sufficient to stimulate thyroid follicular cell proliferation. Furthermore, thyroid follicular cell proliferation may be more useful than thyroid weight alone for assessing alterations in thyroid growth in rats treated with chemicals that produce only small to moderate increases in serum TSH.
抗甲状腺药物和苯巴比妥（PB）已被证明可促进大鼠甲状腺肿瘤的发生。有人提出，促甲状腺激素（TSH）升高介导了抗甲状腺药物和PB的甲状腺肿瘤促进作用，且由于甲状腺素（T4）浓度降低而升高。然而，PB在升高TSH方面的效果远不如抗甲状腺药物。有人提出，PB治疗引起的血清TSH小幅升高足以促进甲状腺肿瘤。然而，尚未报道TSH必须升高到何种水平才能刺激甲状腺。因此，我们通过测量甲状腺重量和甲状腺滤泡细胞增殖来研究血清TSH浓度升高对甲状腺生长的影响。通过给大鼠喂食不同浓度的丙硫氧嘧啶（PTU）或甲巯咪唑（MMI）21天来升高血清TSH浓度。通过放射免疫测定法测量血清总T4、游离T4、总T3（三碘甲状腺原氨酸）、游离T3和TSH浓度。通过放射自显影测量甲状腺滤泡细胞增殖，并表示为标记指数（LI）。到第21天时，PTU和MMI治疗使总T4和游离T4降低超过95%，而总T3和游离T3降低60%。到第21天时，TSH、甲状腺滤泡细胞增殖和甲状腺重量分别增加了560%、1400%和200%。TSH与甲状腺重量和LI显著相关。血清TSH适度升高至10至20 ng/ml可增加增殖的甲状腺滤泡细胞数量，但对甲状腺重量无影响。这些结果支持血清TSH小幅升高足以刺激甲状腺滤泡细胞增殖。此外，对于评估用仅使血清TSH产生小幅至中度升高的化学物质处理的大鼠的甲状腺生长变化，甲状腺滤泡细胞增殖可能比单独的甲状腺重量更有用。
