Schanze Nancy, Jacobi Simon Friedrich, Rijntjes Eddy, Mergler Stefan, Del Olmo Marta, Hoefig Carolin Stephanie, Khajavi Noushafarin, Lehmphul Ina, Biebermann Heike, Mittag Jens, Köhrle Josef
1 Institut für Experimentelle Endokrinologie, Charité-Universitätsmedizin Berlin , Berlin, Germany .
2 Department of Cell and Molecular Biology, Karolinska Institutet , Stockholm, Sweden .
Thyroid. 2017 Jan;27(1):11-22. doi: 10.1089/thy.2016.0182. Epub 2016 Dec 21.
3-Iodothyronamine (3-TAM) is an endogenous decarboxylated thyroid hormone (TH) metabolite. Pharmacological doses of 3-TAM decrease heart rate, body temperature, and metabolic rate in rodents-effects that are contrary to classic TH excess. Furthermore, a single dose of 3-TAM was shown to suppress the hypothalamic-pituitary-thyroid (HPT) axis in rats. It was hypothesized that 3-TAM might play a role in the fine-tuning of TH action and might have a direct regulatory effect on the thyroid gland.
This study tested whether repeated 3-TAM treatment interfered with thyroid function and the HPT axis in mice. Therefore, male C57BL/6 mice were intraperitoneally injected with 5 mg/kg of 3-TAM or vehicle daily for seven days. Additionally, the effects of 3-TAM on the differentiated rat thyrocyte cell line PCCL3 were analyzed.
Repeated administration of 3-TAM decreased thyroidal mRNA content of the sodium iodide symporter (Nis), thyroglobulin, and pendrin in mice. No interference with the HPT axis was observed, as determined by unaltered pituitary mRNA levels of triiodothyronine-responsive genes, including thyrotropin subunit β. Furthermore, 3-TAM treatment did not change transcript levels of hepatic triiodothyronine-responsive genes, such as deiodinase 1. In line with this, serum TH concentrations were not changed after the treatment period of seven days. In concordance with the in vivo findings, 3-TAM decreased the thyrotropin-dependent expression of Nis and functional iodide uptake in PCCL3 cells in vitro. Additionally, uptake and metabolism of 3-TAM by PCCL3 cells was observed, as well as 3-TAM-dependent changes in intracellular Ca concentration that might be involved in mediating the reported effects.
In conclusion, 3-TAM application decreased expression of selected TH synthesis genes by acting directly on the thyroid gland, and it might therefore affect TH synthesis without involvement of the HPT axis.
3-碘甲腺原氨酸（3-TAM）是一种内源性脱羧甲状腺激素（TH）代谢产物。药理剂量的3-TAM可降低啮齿动物的心率、体温和代谢率，这些作用与经典的甲状腺激素过量情况相反。此外，单次给予3-TAM可抑制大鼠的下丘脑-垂体-甲状腺（HPT）轴。据推测，3-TAM可能在甲状腺激素作用的微调中发挥作用，并且可能对甲状腺具有直接调节作用。
本研究测试了重复给予3-TAM是否会干扰小鼠的甲状腺功能和HPT轴。因此，雄性C57BL/6小鼠每天腹腔注射5 mg/kg的3-TAM或溶剂，持续7天。此外，分析了3-TAM对分化的大鼠甲状腺细胞系PCCL3的影响。
重复给予3-TAM可降低小鼠甲状腺中碘化钠转运体（Nis）、甲状腺球蛋白和pendrin的mRNA含量。未观察到对HPT轴的干扰，这是通过三碘甲状腺原氨酸反应基因（包括促甲状腺激素亚基β）的垂体mRNA水平未改变来确定的。此外，3-TAM处理并未改变肝脏中三碘甲状腺原氨酸反应基因（如脱碘酶1）的转录水平。与此一致，在7天的治疗期后，血清甲状腺激素浓度未发生变化。与体内研究结果一致，3-TAM在体外降低了PCCL3细胞中促甲状腺激素依赖性Nis的表达和功能性碘摄取。此外，观察到PCCL3细胞对3-TAM的摄取和代谢，以及3-TAM依赖性细胞内钙浓度变化，这些变化可能参与介导所报道的效应。
总之，应用3-TAM可通过直接作用于甲状腺来降低选定的甲状腺激素合成基因的表达，因此它可能在不涉及HPT轴的情况下影响甲状腺激素合成。
