Amiodarone bioconcentration and suppression of metamorphosis in Xenopus
Amiodarone bioconcentration and suppression of metamorphosis in Xenopus
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胺碘酮在非洲爪蟾中的生物富集和变态抑制
DOI：
10.1016/j.aquatox.2020.105623
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发表时间：
2020
影响因子：
4.5
通讯作者：
Kashiwagi Akihiko
中科院分区：
文献类型：
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作者：
Sanoh Seigo;Hanada Hideki;Kashiwagi Keiko;Mori Tsukasa;Goto-Inoue Naoko;Suzuki Ken-ichi T.;Mori Junpei;Nakamura Naoki;Yamamoto Takashi;Kitamura Shigeyuki;Kotake Yaichiro;Sugihara Kazumi;Ohta Shigeru;Kashiwagi Akihiko
在许多国家的水生环境中都检测到了多种微量药物活性化合物，这些化合物被认为有可能对非目标生物体产生不利影响。胺碘酮（AMD）就是综合医院常用的一种高风险化合物。众所周知，AMD 会改变正常的甲状腺激素 (TH) 功能，但有关这种破坏发生的具体机制的信息很少。无尾蝌蚪变态是 TH 控制的发育过程，已被证明可作为筛选工具，用于筛选怀疑破坏 TH 功能的环境污染物。在本研究中，我们的目的是阐明 AMD 对非洲爪蟾变态的影响，并评估该药物在肝脏中的生物浓度。我们发现AMD抑制了前变态阶段蝌蚪的自发变态，包括尾部退化和后肢伸长，这是由内源性循环TH控制的，表明AMD是TH拮抗剂。在转基因X中。携带含有 TH 反应元件 (TRE) 和与绿色荧光蛋白 (EGFP) 基因连接的 TH 受体 (TR) βA1 基因 5' 上游启动子区域的质粒 DNA 的马尾蝌蚪，暴露于三碘甲腺原氨酸 (T3) 会诱导后肢强烈的 EGFP 表达，而在 T3 中添加 AMD 会抑制 EGFP 表达，表明该药物干扰 T3 与 TR 的结合，从而抑制 TR 介导的基因表达。我们还发现 AMD 在 pro-metamorphicX 的肝脏中高度生物浓缩。热带蝌蚪，我们使用质谱成像（MSI）监测该药物的肝脏蓄积。我们的研究结果表明，AMD 通过破坏 TH 稳态而给水生野生动物带来潜在风险，并进一步有可能在食物链高层的生物体中积累。
Trace concentrations of a number of pharmaceutically active compounds have been detected in the aquatic environment in many countries, where they are thought to have the potential to exert adverse effects on non-target organisms. Amiodarone (AMD) is one such high-risk compound commonly used in general hospitals. AMD is known to alter normal thyroid hormone (TH) function, although little information is available regarding the specific mechanism by which this disruption occurs. Anuran tadpole metamorphosis is a TH-controlled developmental process and has proven to be useful as a screening tool for environmental pollutants suspected of disrupting TH functions. In the present study, our objective was to clarify the effects of AMD onXenopusmetamorphosis as well as to assess the bioconcentration of this pharmaceutical in the liver. We found that AMD suppressed spontaneous metamorphosis, including tail regression and hindlimb elongation in pro-metamorphic stage tadpoles, which is controlled by endogenous circulating TH, indicating that AMD is a TH antagonist. In transgenicX. laevistadpoles carrying plasmid DNA containing TH-responsive element (TRE) and a 5′-upstream promoter region of the TH receptor (TR) βA1 gene linked to a green fluorescent protein (EGFP) gene, triiodothyronine (T3) exposure induced a strong EGFP expression in the hind limbs, whereas the addition of AMD to T3suppressed EGFP expression, suggesting that this drug interferes with the binding of T3to TR, leading to the inhibition of TR-mediated gene expression. We also found AMD to be highly bioconcentrated in the liver of pro-metamorphicX. tropicalistadpoles, and we monitored hepatic accumulation of this drug using mass spectrometry imaging (MSI). Our findings suggest that AMD imposes potential risk to aquatic wildlife by disrupting TH homeostasis, with further possibility of accumulating in organisms higher up in the food chain.