Iodide excess induces apoptosis in thyroid cells through a p53-independentmechanism involving oxidative stress

Thyroid toxicity of iodide excess has been demonstrated in animals fed with an iodide-rich diet; in vitro iodide is cytotoxic, inhibits cell growth, a nd induces morphological changes in thyroid cells of some species. In this study, we investigated the effect of iodide excess in an immortalized thyro id cell line (TAD-2) in primary cultures of human thyroid cells and in cell s of nonthyroid origin. Iodide displayed a dose-dependent cytotoxicity in b oth TAD-2 and primary thyroid cells, although at different concentrations, whereas it had no effect on cells of nonthyroid origin. Thyroid cells treat ed with iodide excess underwent apoptosis, as evidenced by morphological ch anges, plasma membrane phosphatidylserine exposure, and DNA fragmentation. Apoptosis was unaffected by protein synthesis inhibition, whereas inhibitio n of peroxidase enzymatic activity by Dropylthiouracil completely blocked i odide cytotoxicity. During KI treatment, reactive oxygen species were produ ced, and lipid peroxide levels increased markedly. Inhibition of endogenous p53 activity did not affect the sensitivity of TAD-2 cells to iodide, and Western blot analysis demonstrated that p53, Bcl-2, Bcl-XL, and Bar protein expression did not change when cells were treated with iodide. These data indicate that excess molecular iodide, generated by oxidation of ionic iodi ne by endogenous peroxidases, induces apoptosis in thyroid cells through a mechanism involving generation of free radicals. This type of apoptosis is p53 independent, does not require protein synthesis, and is not induced by modulation of Bcl-2, Bcl-XL, or Bar protein expression.