Dissecting the Role of Thyrotropin in the DNA Damage Response in Human Thyrocytes after I-131, gamma Radiation and H2O2

Background: The early molecular events in human thyrocytes after I-131 exposure have not yet been unravelled. Therefore, we investigated the role of TSH in the I-131-induced DNA damage response and gene expression in primary cultured human thyrocytes. Methods: Following exposure of thyrocytes, in the presence or absence of TSH, to I-131 (beta radiation), gamma radiation (3 Gy), and hydrogen peroxide (H2O2), we assessed DNA damage, proliferation, and cell-cycle status. We conducted RNA sequencing to profile gene expression after each type of exposure and evaluated the influence of TSH on each transcriptomic response. Results: Overall, the thyrocyte responses following exposure to beta or gamma radiation and to H2O2 were similar. However, TSH increased I-131-induced DNA damage, an effect partially diminished after iodide uptake inhibition. Specifically, TSH increased the number of DNA double-strand breaks in nonexposed thyrocytes and thus predisposed them to greater damage following I-131 exposure. This effect most likely occurred via G alpha(q) cascade and a rise in intracellular reactive oxygen species (ROS) levels. beta and gamma radiation prolonged thyroid cell-cycle arrest to a similar extent without sign of apoptosis. The gene expression profiles of thyrocytes exposed to beta/gamma radiation or H2O2 were overlapping. Modulations in genes involved in inflammatory response, apoptosis, and proliferation were observed. TSH increased the number and intensity of modulation of differentially expressed genes after I-131 exposure. Conclusions: TSH specifically increased (131I)-induced DNA damage probably via a rise in ROS levels and produced a more prominent transcriptomic response after exposure to I-131.