Dissecting the role of thyrotropin in the DNA damage response in human thyrocytes after 131I, γ radiation and H2O2.

This work aimed to better understand the early molecular events occasioned in human thyrocytes following exposure to genotoxic agents than can lead to thyroid mutagenesis and cancer. Similar in vitro data in human physiological models remain scarce.The reported incidence of papillary thyroid carcinoma (PTC), has been increasing worldwide but the pathogenesis of sporadic PTC remains unravelled. H2O2 has long been postulated by the host laboratory and by other groups as a potential thyroid mutagen since it is capable to cause DNA damage and it affects γ radiation-induced DNA damage in thyrocytes. Thyrotropin (TSH) has recently been advocated as a potential risk factor for PTC: it has been associated with advanced stage disease and with progression of microcarcinoma during active surveillance. TSH signalling was found to be essential for BRAF-induced thyroid carcinogenesis in mouse models. Radiation (γ and β) is the only clearly established environmental risk factor for PTC; the cancer relative risk is rising linearly beyond a threshold of 100mGy thyroid absorbed dose. We studied in human thyrocytes in primary cultures the early molecular events following 131I exposure (β radiation) in comparison to γ radiation and H2O2 exposure, and their modulation by TSH. We assessed cell survival, DNA damage, DNA repair, gene expression, cell proliferation and apoptosis. Although we globally observed that the thyrocyte responses following exposure to β, γ radiation or H2O2 showed similarities, TSH, unlike other proliferative agents tested, specifically increased DNA damage both in non-exposed and in 131I-exposed thyrocytes. TSH did not influence γ radiation- or H2O2-induced damage. The effect of TSH on DNA damage in non-exposed thyrocytes decreased after incubation with an antioxidant agent and in 131I-exposed thyrocytes was partially alleviated after inhibition of iodide uptake. Therefore, in our experimental conditions, TSH seemed to predispose thyroid cells to greater DNA damage after exposure to 131I via Gαq-mediated ...