Effects of Gadolinium-Based Contrast Agents on Thyroid Hormone Receptor Action and Thyroid Hormone-Induced Cerebellar Purkinje Cell Morphogenesis.
Effects of Gadolinium-Based Contrast Agents on Thyroid Hormone Receptor Action and Thyroid Hormone-Induced Cerebellar Purkinje Cell Morphogenesis.
复制标题
DOI：
10.3389/fendo.2016.00115
复制
发表时间：
2016
影响因子：
5.2
通讯作者：
Koibuchi N
中科院分区：
文献类型：
--
作者：
Ariyani W;Iwasaki T;Miyazaki W;Khongorzul E;Nakajima T;Kameo S;Koyama H;Tsushima Y;Koibuchi N
钆（Gd）基造影剂（GBCA）用于诊断成像，以提高磁共振成像或血管造影的质量。静脉注射后，GBCA可在脑中蓄积。甲状腺激素（TH）对中枢神经系统的发育和功能维持至关重要。脑内TH的作用主要通过核内TH受体（TRs）发挥。我们研究了GBCA对TR介导的CV-1细胞转录的影响，采用瞬时转染为基础的报告基因分析和TH介导的小脑浦肯野细胞形态发生的原代培养。我们还测量了在培养的CV-1细胞中代表性GBCA处理后Gd的细胞积累和活力。线性（Gd-二亚乙基三胺五乙酸-双甲基酸，Gd-DTPA-BMA）和大环（Gd-四氮杂环十二烷四乙酸，Gd-DOTA）GBCA在CV-1细胞中积累而不诱导细胞死亡。相比之下，氯化钆（GdCl 3）处理诱导约100倍的Gd积累，并显着减少细胞的数量。低剂量的Gd-DTPA-BMA（10−8至10− 6 M）增强TR介导的转录，但在较高剂量（10−5至10− 4 M）下转录受到抑制，β-半乳糖苷酶活性降低表明细胞毒性。TR介导的转录没有被Gd-DOTA或GdCl 3改变，但后者在高剂量下诱导β-半乳糖苷酶活性显著降低，表明细胞毒性。在小脑培养物中，10− 9 M T4诱导的浦肯野细胞树突树枝化被低剂量Gd-DTPA-BMA（10− 7 M）增强，但被高剂量（10− 5 M）抑制。低剂量Gd-DTPA-BMA在10− 9 M T3中没有观察到这种增强作用，可能是因为T3使树突树枝化更大;然而，T3的树枝化被较高剂量的Gd-DTPA-BMA（10− 5 M）抑制，如T4治疗中所见。Gd-DOTA对枝晶树枝化的影响比其他化合物弱得多。这些结果表明，暴露于特定的GBCA可能会，至少部分地，在大脑中引起的毒性作用，破坏了行动的TH对TRs。GBCA的毒性作用可能取决于GBCA的化学结构和剂量。因此，选择合适的GBCA进行成像以防止不良副作用非常重要。
Gadolinium (Gd)-based contrast agents (GBCAs) are used in diagnostic imaging to enhance the quality of magnetic resonance imaging or angiography. After intravenous injection, GBCAs can accumulate in the brain. Thyroid hormones (THs) are critical for the development and functional maintenance of the central nervous system. TH actions in brain are mainly exerted through nuclear TH receptors (TRs). We examined the effects of GBCAs on TR-mediated transcription in CV-1 cells using transient transfection-based reporter assay and TH-mediated cerebellar Purkinje cell morphogenesis in primary culture. We also measured the cellular accumulation and viability of Gd after representative GBCA treatments in cultured CV-1 cells. Both linear (Gd-diethylene triamine pentaacetic acid-bis methyl acid, Gd-DTPA-BMA) and macrocyclic (Gd-tetraazacyclododecane tetraacetic acid, Gd-DOTA) GBCAs were accumulated without inducing cell death in CV-1 cells. By contrast, Gd chloride (GdCl3) treatment induced approximately 100 times higher Gd accumulation and significantly reduced the number of cells. Low doses of Gd-DTPA-BMA (10−8 to 10−6M) augmented TR-mediated transcription, but the transcription was suppressed at higher dose (10−5 to 10−4M), with decreased β-galactosidase activity indicating cellular toxicity. TR-mediated transcription was not altered by Gd-DOTA or GdCl3, but the latter induced a significant reduction in β-galactosidase activity at high doses, indicating cellular toxicity. In cerebellar cultures, the dendrite arborization of Purkinje cells induced by 10−9M T4 was augmented by low-dose Gd-DTPA-BMA (10−7M) but was suppressed by higher dose (10−5M). Such augmentation by low-dose Gd-DTPA-BMA was not observed with 10−9M T3, probably because of the greater dendrite arborization by T3; however, the arborization by T3 was suppressed by a higher dose of Gd-DTPA-BMA (10−5M) as seen in T4 treatment. The effect of Gd-DOTA on dendrite arborization was much weaker than that of the other compounds. These results indicate that exposure to specific GBCAs may, at least in part, cause toxic effects in the brain by disrupting the action of THs on TRs. The toxic effects of GBCAs may depend on the chemical structure of GBCA and the dose. Thus, it is very important to choose appropriate GBCAs for imaging to prevent adverse side effects.