Iodide (I-) is an essential micronutrient for the synthesis of thyroid hormones (TH). The NA+/I− symporter (NIS) actively transports iodide through the basolateral membrane to the thyroid cells where it is oxidized to be part of the precursors of TH. But iodide is also an important factor that regulates thyroid function and growth. The imbalance of this trace element can trigger the impairment of thyroid function. Indeed, both iodide excess and iodide deficiency can lead to the development of various thyroid pathologies and even thyroid cancer [[1], [2], [3]].

Thyroid-stimulating hormone (TSH) and IGF-1/insulin exert complementary functions on the regulation of thyroid cell proliferation [4]. It has been demonstrated that IGF-1/insulin inhibits TSH stimulation of NIS gene expression and iodide uptake through the activation of PI3K/AKT pathway [5,6]. Iodide excess also activates PI3K/AKT pathway through increased reactive oxygen species (ROS) production leading to inhibition of NIS expression [[7], [8], [9]]. Different sources of ROS have been described to be stimulated by iodide excess. Iodide-induced mitochondrial superoxide (O2•−) production has been demonstrated in the rat thyroid cell lines [8,10]. Recently, we showed that iodide treatment increased the NADPH oxidase NOX4 expression and induced ROS production. Moreover, NOX4 silencing inhibited NIS iodide-induced mRNA repression, suggesting a crucial role of this NADPH oxidase in thyroid autoregulation mediated by iodide [11].

Several studies have shown that iodide excess induces the downregulation of NIS and a temporarily inhibition of hormone secretion, a phenomenon known as the Wolff-Chaikoff effect [12,13]. Despite high iodide levels, an adaptation or escape from Wolff-Chaikoff effect occurs by the inhibition of iodide uptake which allows the organification process to return to normal activity [14,15]. This is an autoregulatory mechanism that allows the gland to control its own function and growth depending on the intrathyroidal availability of iodine. In this sense it has been suggested that, as consequence of the induction of oxidation by iodide excess, other oxidized species or iodinated intermediates participate on thyroid autoregulation [[16], [17], [18]]. The biosynthesis of iodolipids has been observed in the thyroid gland from several species, probably when iodine binds to membrane lipids as part of free radical-induced damage. Among them, 6-iodo delta lactone (IL-δ) [[19], [20], [21]] and the 2-α-iodohexadecanal (2-IHD) [22,23] demonstrated to mimic some of the inhibitory effects of excess iodide on several thyroid parameters [[24], [25], [26], [27], [28]].

Since the efficacy of radioactive iodine therapy in the treatment of advanced thyroid cancers have decreased, the main targeting for theranostic in thyroid cancer is NIS. It has been shown the ability of various antioxidant agents to restore the expression and in some cases, the functionality of NIS [[29], [30], [31], [32]]. In thyroid autoregulation studies, Arriagada et al., showed that the inhibitory effect of iodide excess on NIS-mediated I- transport, could be reverted by antioxidants [33]. In this sense, Leoni et al. described that Selenium (Se) increases NIS expression and activity [7].

Selenium is an essential trace element, required in the biosynthesis of selenoproteins, involved in controlling inflammation and immunity through redox-regulating activity of selenoproteins [34]. Selenium deficiency increases cell sensitivity to damage caused by ROS [35]. In thyroid, Se has a crucial role since its deficiency impairs thyroid function and TH production and secretion [36]. In fact, oxidative stress seems to be involved in the pathogenesis of thyroid autoimmune diseases and thyroid cancer [37]. The selenoproteins GSH peroxidases (GPx) and thioredoxin reductase-1 (TXNRD1) defend the thyroid gland against continuous hydrogen peroxide (H2O2) production during hormonogenesis [38,39].

Given that iodide excess also activates PI3K/AKT pathway through increased ROS production leading to inhibition of NIS expression, we speculate that Se could interfere with AKT phosphorylation impacting on NIS expression positively. Therefore the current studies test the hypothesis that Se status is decisive on the sensitivity to iodide excess effects on thyroid cells. In this study, we have analyzed the influence of NOX4 and Sodium Selenite on AKT phosphorylation and others parameters involved in thyroid autoregulation in TSH-stimulated thyroid cells exposed to iodide excess. For this purpose, the differentiated rat thyroid cell line (FRTL-5) which is Se-deficient [40,41] was employed.