Article révisé par les pairs
Résumé : Context:Radiation is an established cause of thyroid cancer and growing evidence supports a role for hydrogen peroxide (H2O2) in spontaneous thyroid carcinogenesis. Little is known about the molecular programs activated by these agents in thyrocytes.Objective:Compare the responses thyrocytes and T-cells to H2O2 and radiation.Methods:We profiled the DNA damage and cell death induced by γ-radiation (0.1-5 Gy) and H2O2 (0.0025-0.3mM) in primary human thyrocytes and T-cells. We next prepared thyroid and T-cell primary cultures from 8 donors operated for non-cancerous thyroid pathologies and profiled their genome-wide transcriptional response 4hrs after 1) exposure to 1 Gy radiation, 2) treatment with H2O2 and 3) no treatment. Two H2O2 concentrations were investigated, calibrated in each cell type to elicit levels of single- and double-strand breaks equivalent to 1 Gy γ-radiation.Results:While thyrocytes and T-cell types had comparable radiation responses, 3- to 10-fold more H2O2 was needed to induce detectable DNA damage in thyrocytes. At H2O2 and radiation doses inducing double strand breaks (DSBs), cell death occurred after 24 hours in T-cells, but not in thyrocytes. The transcriptional responses of thyrocytes and T-cells to radiation were similar, involving DNA repair and cell death genes. In addition to this transcriptional program, H2O2 also upregulated antioxidant genes in thyrocytes, including glutathione peroxidases (GPXs) and heme oxygenase at the DSB-inducing concentration. In contrast, a transcriptional storm involving thousands of genes was raised in T-cells. Finally, we showed that inhibiting GPX activity increased the DNA damaging effect of H2O2 in thyrocytes.Conclusion:We propose that high H2O2 production in thyrocytes is matched with specific transcriptionally regulated antioxydant protection.

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