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

Abstract

Background The early molecular events in human thyrocytes after 131I exposure have not yet been unravelled. Therefore, we investigated the role of TSH in the 131I-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 131I (β radiation), γ 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 β or γ radiation and to H2O2 were similar. However, TSH increased 131I-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 131I exposure. This effect most likely occurred via Gα q cascade and a rise in intracellular reactive oxygen species (ROS) levels. β and γ radiation prolonged thyroid cell-cycle arrest to a similar extent without sign of apoptosis. The gene expression profiles of thyrocytes exposed to β/γ 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 131I 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 131I.

Long-term transcriptomic and proteomic effects in Sprague Dawley rat thyroid and plasma after internal low dose 131I exposure

“…However, none of these were found in the present study. In vitro studies on thyroid cells have shown that DNA damage after 131 I exposure increases in the presence of high levels of TSH [57]. Thyroid function has also been evaluated, by measurements of the IL-6 TNF-αand NO proteins in serum samples using a rat model using four week old rats irradiated with 5.5 MBq 131 I [58].…”

Thyrotropin (TSH) and thyroid autoimmunity are predictive factors for the incidental discovery of papillary thyroid microcarcinoma during thyroidectomy

“…In in vivo transgenic mice models, TSH signaling was required for BRAFV600E-induced thyroid tumorigenesis, but also conferred more aggressive features in BRAFV600E-induced thyroid tumours [15,30]. In vitro, it was shown that TSH induced DNA damage in human thyrocytes, probably through an increase in intracellular levels of reactive oxygen species (ROS) [31].…”

Polyamine Oxidase Expression Is Downregulated by 17β-Estradiol via Estrogen Receptor 2 in Human MCF-7 Breast Cancer Cells

“…For example, polyamines effectively prevent bone loss in ovariectomized mice [ 20 ]. In addition, polyamine reduction leads to increased H 2 O 2 and ROS levels, which, as previously mentioned, contribute to inflammatory diseases [ 63 ]. Therefore, we propose that preventing polyamine decline, for example by repressing or inhibiting PAOX, could be a potential treatment for alleviating postmenopausal symptoms.…”