3-Iodothyronamine Decreases Expression of Genes Involved in Iodide Metabolism in Mouse Thyroids and Inhibits Iodide Uptake in PCCL3 Thyrocytes

Background: 3-Iodothyronamine (3-T₁AM) is an endogenous decarboxylated thyroid hormone (TH) metabolite. Pharmacological doses of 3-T₁AM decrease heart rate, body temperature, and metabolic rate in rodents-effects that are contrary to classic TH excess. Furthermore, a single dose of 3-T₁AM was shown to suppress the hypothalamic-pituitary-thyroid (HPT) axis in rats. It was hypothesized that 3-T₁AM might play a role in the fine-tuning of TH action and might have a direct regulatory effect on the thyroid gland.

Methods: This study tested whether repeated 3-T₁AM 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-T₁AM or vehicle daily for seven days. Additionally, the effects of 3-T₁AM on the differentiated rat thyrocyte cell line PCCL3 were analyzed.

Results: Repeated administration of 3-T₁AM 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-T₁AM 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-T₁AM decreased the thyrotropin-dependent expression of Nis and functional iodide uptake in PCCL3 cells in vitro. Additionally, uptake and metabolism of 3-T₁AM by PCCL3 cells was observed, as well as 3-T₁AM-dependent changes in intracellular Ca²⁺ concentration that might be involved in mediating the reported effects.

Conclusions: In conclusion, 3-T₁AM 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.