Molecular characterization of thyroid toxicity: anchoring gene expression profiles to biochemical and pathologic end points.
Molecular characterization of thyroid toxicity: anchoring gene expression profiles to biochemical and pathologic end points.
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DOI：
10.1289/ehp.7690
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发表时间：
2005-10
影响因子：
10.4
通讯作者：
Delker DA
中科院分区：
文献类型：
--
作者：
Glatt CM;Ouyang M;Welsh W;Green JW;Connor JO;Frame SR;Everds NE;Poindexter G;Snajdr S;Delker DA
有机碘化物已被证明可诱导大鼠甲状腺肥大并增加胶体的变化，尽管这种毒性的机制尚不清楚。为了评估游离碘对甲状腺毒性的影响，我们每天给大鼠喂食碘化钠 (NaI)，为期两周。为了比较具有替代机制（分别增加甲状腺激素代谢和减少甲状腺激素合成）的化合物的作用，我们还检查了苯巴比妥（PB）和丙硫氧嘧啶（PTU）作为模型甲状腺毒物。 PB处理的大鼠的甲状腺中存在滤泡细胞肥大和浅色胶体，而PTU处理的大鼠的甲状腺中存在更严重的肥大/胶体变化以及弥漫性增生。在PB和PTU治疗的大鼠中，促甲状腺激素（TSH）水平显着升高，而甲状腺素和三碘甲状腺氨酸激素水平显着降低。 PB 诱导肝脏尿苷二磷酸葡萄糖醛酸转移酶 (UDPGT) 活性几乎增加 2 倍，而 PTU 将肝脏 5'-脱碘酶 I (5'-DI) 活性降低至对照的 < 10%，这支持了之前有关每种化学物质作用机制的报道。 NaI 还显着改变肝脏重量和 UDPGT 活性，但不影响甲状腺激素水平或甲状腺病理。使用 Affymetrix U34A GeneChips、正则化 t 检验、基因图注释器和通路分析器进行的甲状腺基因表达分析表明，所有测试的化学物质中视紫红质样 G 蛋白偶联受体转录物均发生显着变化。 NaI 证明了多个氧化应激相关基因的剂量依赖性变化，这也是通过主成分和线性回归分析确定的。在暴露于 PB 和 PTU 的大鼠中观察到差异转录谱，包括参与 Wnt 信号传导和核糖体蛋白表达的基因，可能与啮齿动物滤泡细胞肿瘤结果相关。
Organic iodides have been shown to induce thyroid hypertrophy and increase alterations in colloid in rats, although the mechanism involved in this toxicity is unclear. To evaluate the effect that free iodide has on thyroid toxicity, we exposed rats for 2 weeks by daily gavage to sodium iodide (NaI). To compare the effects of compounds with alternative mechanisms (increased thyroid hormone metabolism and decreased thyroid hormone synthesis, respectively), we also examined phenobarbital (PB) and propylthiouracil (PTU) as model thyroid toxicants. Follicular cell hypertrophy and pale-staining colloid were present in thyroid glands from PB-treated rats, and more severe hypertrophy/colloid changes along with diffuse hyperplasia were present in thyroid glands from PTU-treated rats. In PB-and PTU-treated rats, thyroid-stimulating hormone (TSH) levels were significantly elevated, and both thyroxine and triiodothyronine hormone levels were significantly decreased. PB induced hepatic uridine diphosphate-glucuronyltransferase (UDPGT) activity almost 2-fold, whereas PTU reduced hepatic 5′-deiodinase I (5′-DI) activity to < 10% of control in support of previous reports regarding the mechanism of action of each chemical. NaI also significantly altered liver weights and UDPGT activity but did not affect thyroid hormone levels or thyroid pathology. Thyroid gene expression analyses using Affymetrix U34A GeneChips, a regularized t-test, and Gene Map Annotator and Pathway Profiler demonstrated significant changes in rhodopsin-like G-protein–coupled receptor transcripts from all chemicals tested. NaI demonstrated dose-dependent changes in multiple oxidative stress–related genes, as also determined by principal component and linear regression analyses. Differential transcript profiles, possibly relevant to rodent follicular cell tumor outcomes, were observed in rats exposed to PB and PTU, including genes involved in Wnt signaling and ribosomal protein expression.
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通讯作者：
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