New insights into iodide metabolism based on preclinical models: impact on radiotherapy efficacy and protection against radioactive iodine exposure

Abstract

Background: The main basic aspects of the regulation of thyroid metabolism by iodine has known, but given the complexity of the mechanisms involved, further analyzes in living animals are still required. Here, we provided new insights into iodine physiology but also into the optimization of radiotherapy with iodine, as well as effective countermeasures in the case of an exposure to radioactive iodine. Methods: We performed Single Photon Emission Computed Tomography (SPECT) coupled to an X-ray scanner to record radiotracers in living mice and rats. Our imaging system is like that routinely used in nuclear medicine but was specifically designed for studies with small animals. Different modalities of administration of iodine or its radioactive analogues combined with a low or high iodine diet have been studied in pregnant, lactating and control animals. To optimize countermeasures against acute or chronic iodine exposure, the protective effects of potassium iodide (KI) administration protocols were analyzed. Perchlorate was administered to study the iodine metabolism in the kidney and stomach. Results: Our results showed how the various organs capable of iodine uptake adapt to an iodine-deficient diet. Indeed, the uptake capacity of the thyroid gland, but also that of the salivary glands was significantly increased on a low iodine diet. In contrast, the iodine uptake capacity of the thyroid and lactating mammary glands was reduced on an iodide-rich diet. Our results also showed the physiological role of the kidneys in controlling excess circulating iodide. In addition, they revealed an active iodine cycle in the stomach. We also investigated the protective effects of daily KI administration during radioactive iodine exposure and found that the overall protection was better in rats (85%) than in mice (65%). We also included pregnant females and newborns in this series of experiments, and we revealed the existence of specific mechanisms for the inhibition of the fetal thyroid by circulating iodine. Indeed, an iodine-rich diet or repeated daily administration of KI led to a strong inhibition of the iodine uptake capacity of the fetal thyroid. Conclusions: Our study contributes to a better understanding of iodine metabolism and its regulation in the thyroid and in non-thyroidal organs in adult, fetal and newborn animals. Extrapolated to humans, our results not only provide better understanding of iodide withdrawal as a clinical preparatory measure for patients with differentiated thyroid cancer, but also help to optimize countermeasures in the case of an exposure to radioactive iodine.