Trialkyltin Rexinoid-X Receptor Agonists Selectively Potentiate Thyroid Hormone Induced Programs of Xenopus laevis Metamorphosis
Trialkyltin Rexinoid-X Receptor Agonists Selectively Potentiate Thyroid Hormone Induced Programs of Xenopus laevis Metamorphosis
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DOI：
10.1210/en.2016-1062
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发表时间：
2016-07-01
期刊：
影响因子：
4.8
通讯作者：
Furlow, J. David
中科院分区：
文献类型：
--
作者：
Mengeling, Brenda J.;Murk, Albertinka J.;Furlow, J. David
三烷基锡、三丁基锡 (TBT) 和三苯基锡 (TPT) 可用作类维生素 X 受体 (RXR) 激动剂。我们最近证明 RXR 激动剂可以改变哺乳动物垂体 TH 反应报告细胞系 GH3 中的甲状腺激素 (TH) 信号传导。 TRE-卢克。环境中 TBT 和 TPT 的普遍存在促使我们测试它们是否也会影响 TH 信号传导。两种三烷基锡均单独诱导整合的荧光素酶报告基因，并在低剂量下增强 TH 激活。三甲基锡不是 RXR 激动剂，但没有。我们转向一个简单、稳健且特异的 TH 作用体内模型系统：非洲爪蛙的变态。使用早变态测定，我们发现 1nM TBT 和 TPT（但不是三甲基锡）极大地增强了 TH 处理对尾部（在变态时丢失）和头部（经历包括鳃丢失在内的广泛重塑）吸收表型的影响。与这些反应一致，TH 诱导的尾部 caspase-3 激活通过与 TBT 共同处理而增强。单独的 TBT 不能诱导转基因报告基因、内源性胶原酶 3 (mmp13) 和成纤维细胞激活蛋白-α (fap) 基因的诱导，但 TBT 显着增强 TH 诱导。然而，TH 对其他 TH 受体靶基因（如 TR beta 和脱碘酶 3）的诱导不受 TBT 共处理的影响。这些数据表明，可充当 RXR 激动剂的三烷基锡可选择性地增强体内 TH 信号传导引导的基因表达和由此产生的形态程序。
The trialkyltins tributyltin (TBT) and triphenyltin (TPT) can function as rexinoid-X receptor (RXR) agonists. We recently showed that RXR agonists can alter thyroid hormone (TH) signaling in a mammalian pituitary TH-responsive reporter cell line, GH3. TRE-Luc. The prevalence of TBT and TPT in the environment prompted us to test whether they could also affect TH signaling. Both trialkyltins induced the integrated luciferase reporter alone and potentiated TH activation at low doses. Trimethyltin, which is not an RXR agonist, did not. We turned to a simple, robust, and specific in vivo model system of TH action: metamorphosis of Xenopus laevis, the African clawed frog. Using a precocious metamorphosis assay, we found that 1nM TBT and TPT, but not trimethyltin, greatly potentiated the effect of TH treatment on resorption phenotypes of the tail, which is lost at metamorphosis, and in the head, which undergoes extensive remodeling including gill loss. Consistent with these responses, TH-induced caspase-3 activation in the tail was enhanced by co-treatment with TBT. Induction of a transgenic reporter gene and endogenous collagenase 3 (mmp13) and fibroblast-activating protein-alpha (fap) genes were not induced by TBT alone, but TH induction was significantly potentiated by TBT. However, induction of other TH receptor target genes such as TR beta and deiodinase 3 by TH were not affected by TBT cotreatment. These data indicate that trialkyltins that can function as RXR agonists can selectively potentiate gene expression and resultant morphological programs directed by TH signaling in vivo.