Nadph oxidase duox1 promotes long-term persistence of oxidative stress after an exposure to irradiation

Introduction: Ionizing radiation (IR) causes not only acute tissue damage but also late effects in several cell generations after the initial exposure. The mechanism by which the radiation exposure is memorized and lead to delayed DNA breakage remains to be determined. Objectives: We investigated the mechanism by which IR induced ROS generation several days after irradiation. We focused on NADPH oxidases, which are specialized ROS-generating enzymes known as NOX/DUOX. Methodology: Human thyroid cell line, primary human thyroid cells and 35 frozen tissues (20 radio-induced thyroid tumors, 9 sporadic tumors and 6 normal tissues) were included in this study. Results: IR (10 Gy) induces a delayed NADPH oxidase DUOX1-dependent H2O2 production in a dose-dependent manner, which was sustained for several days. Pretreatment of cells with catalase, a scavenger of H2O2, or DUOX1 downregulation by siRNA abrogate IR-induced DNA-damage. Analysis of human thyroid tissues showed that DUOX1 is elevated in human radio-induced thyroid tumors. Conclusion: Our data reveal a key role of DUOX1-dependent H2O2 production in long-term persistent radio-induced DNA damage. Our data also show that DUOX1-dependent H2O2 production, which induces DNA double strand breaks, can cause genomic instability and promote generation of neoplastic cells through its mutagenic effect.