Cigarette Smoke Extract Disrupts Transcriptional Activities Mediated by Thyroid Hormones and Its Receptors
Cigarette Smoke Extract Disrupts Transcriptional Activities Mediated by Thyroid Hormones and Its Receptors
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DOI：
10.1248/bpb.b17-00735
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发表时间：
2018-03-01
影响因子：
2
通讯作者：
Moriyama, Kenji
中科院分区：
文献类型：
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作者：
Hayashi, Misa;Futawaka, Kumi;Moriyama, Kenji
香烟烟雾含有 4800 多种化合物，其中至少有 200 种有毒物质或内分泌干扰物。目前，香烟烟雾对甲状腺激素（TH）水平的影响仍有待阐明。在这里，我们证明香烟烟雾提取物 (CSE) 具有甲状腺激素特性，并在 TH 存在的情况下作为甲状腺激素受体 (TR) 的部分激动剂发挥协同作用。在瞬时基因表达实验中，CSE 以剂量依赖性方式刺激 TH 的转录活性。尽管在没有 TH 的情况下 CSE 不会激活 TR，但在生理 TH 浓度下观察到了刺激作用。溶解在补充有 1 nM TH 的磷酸盐缓冲盐水 (PBS) 中的 CSE (5%) 大约分别相当于 3.2 +/- 0.1 和 2.3 +/- 0.2 nM 的 TR α 1 和 TR β 1。为了说明 CSE 激动活性的可能机制，研究了辅助因子对 TR 介导的转录功能的影响。通过哺乳动物双杂交测定，CSE 将核辅激活剂糖皮质激素受体相互作用蛋白 1 (GRIP1) 和类固醇受体辅激活剂 1 (SRC1) 招募到 TR。不饱和羰基化合物、丙烯醛、巴豆醛和甲基乙烯基酮（CSE 的代表性成分）保留了这种激动特性，并可能有助于刺激作用。结果表明，CSE 招募转录激活因子，并可能进一步增强 TH 与 TR 的结合，从而导致基因表达。 CSE 部分激动 TH 作用，并可能扰乱各种核激素受体类型及其辅助因子的功能，从而破坏生理过程。
Cigarette smoke contains over 4800 compounds, including at least 200 toxicants or endocrine disruptors. Currently, effects of cigarette smoke on thyroid hormone (TH) levels remains to be clarified. Here, we demonstrate that cigarette smoke extract (CSE) possesses thyroid hormone properties and acts synergistically as a partial agonist for thyroid hormone receptors (TRs) in the presence of TH. In transient gene expression experiments, CSE stimulated transcriptional activity with TH in a dose-dependent manner. Stimulatory effects were observed with physiological TH concentrations, although CSE did not activate TRs without TH. CSE (5%) dissolved in phosphate-buffered saline (PBS) supplemented with 1 nM TH was approximately comparable to 3.2 +/- 0.1 and 2.3 +/- 0.2 nM of TR alpha 1 and TR beta 1, respectively. To illustrate probable mechanisms of the CSE agonistic activity, effects on TR mediated transcriptional functions with cofactors were investigated. With a mammalian two-hybrid assay, CSE recruited the nuclear coactivators glucocorticoid receptor interacting protein 1 (GRIP1) and steroid receptor coactivator 1 (SRC1) to the TR. Unsaturated carbonyl compounds, acrolein, crotonaldehyde, and methyl vinyl ketone, representative constituents of CSE, retained such agonistic properties and possibly contributed to stimulatory effects. The results suggest that CSE recruits a transcriptional activator and may reinforce TH binding to the TR additively, resulting in gene expression. CSE partially agonizes TH action and may disturb the function of various nuclear hormone receptor types and their cofactors to disrupt the physiological processes.