EVIDENCE THAT THE INHIBITORY EFFECTS OF IODIDE ON THYROID-CELL PROLIFERATION ARE DUE TO ARREST OF THE CELL-CYCLE AT G0G1 AND G2M PHASES

The thyroid gland is unique in its ability to respond to ambient level s of iodine to autoregulate thyroid function and, possibly, thyroid ce ll proliferation. Although the inhibitory effects of iodide on thyroid cell proliferation have been previously reported, the exact mechanism and site of action of iodide on cellular proliferation events are poo rly understood. Our initial experiments established the optimal cell p lating density and timing to achieve exponential cell growth of FRTL5 thyroid cells, and subsequent studies using flow cytometric DNA analys is established the normal cell cycle kinetics of FRTL5 thyroid cell pr oliferation. FRTL5 cells were then exposed to graded concentrations of sodium iodide to establish whether the inhibitory effects of iodide a re mediated through specific cell cycle events. We observed that incre asing concentrations of iodide inhibited FRTL5 thyroid cell proliferat ion. Analysis of the cell cycle revealed two specific effects of iodid e on cell cycle kinetics. The first was an arrest of cells in G0G1, ev idenced by an accumulation of cells in this phase and a concomitant re duction in the percentage of cells in the S-phase. The second was an a rrest of cells in the G2M phase of the cycle. G0G1 and G2M arrest occu rred within 24 h and then reached a plateau. Iodide exposure did not i ncrease the number of cells undergoing necrosis. The addition of methi mazole at two concentrations (0.2 and 2 mm) to cells exposed to 100 mm NaI prevented the accumulation of cells in G2M, but did not abolish t he accumulation of cells in G0G1 or the reduction in cell number. Thes e results indicate that the inhibitory effects of iodide on FRTL5 thyr oid cell proliferation are mediated by its action at two critical regu lating points of the cell cycle, G0G1 and G2M. It appears that organif ied iodine may mediate the cell cycle arrest in the G2M phase, whereas inorganic iodide may be responsible for the inhibitory effects at G0G 1.