title: Exposure to low-dose (56)Fe-ion radiation induces long-term epigenetic alterations in mouse bone marrow hematopoietic progenitor and stem cells.
abstract: There is an increasing need to better understand the long-term health effects of high-linear energy transfer (LET) radiation due to exposure during space missions, as well as its increasing use in clinical treatments. Previous studies have indicated that exposure to (56)Fe heavy ions increases the incidence of acute myeloid leukemia (AML) in mice but the underlying molecular mechanisms remain elusive. Epigenetic alterations play a role in radiation-induced genomic instability and the initiation and progression of AML. In this study, we assessed the effects of low-dose (56)Fe-ion irradiation on epigenetic alterations in bone marrow mononuclear cells (BM-MNCs) and hematopoietic progenitor and stem cells (HPSCs). Exposure to (56)Fe ions (600 MeV, 0.1, 0.2 and 0.4 Gy) resulted in significant epigenetic alterations involving methylation of DNA, the DNA methylation machinery and expression of repetitive elements. Four weeks after irradiation, these changes were primarily confined to HPSCs and were exhibited as dose-dependent hypermethylation of LINE1 and SINE B1 repetitive elements [4.2-fold increase in LINE1 (P < 0.001) and 7.6-fold increase in SINE B1 (P < 0.01) after exposure to 0.4 Gy; n = 5]. Epigenetic alterations were persistent and detectable for at least 22 weeks after exposure, when significant loss of global DNA hypomethylation (1.9-fold, P < 0.05), decreased expression of Dnmt1 (1.9-fold, P < 0.01), and increased expression of LINE1 and SINE B1 repetitive elements (2.8-fold, P < 0.001 for LINE1 and 1.9-fold, P < 0.05 for SINE B1; n = 5) were observed after exposure to 0.4 Gy. In contrast, exposure to (56)Fe ions did not result in accumulation of increased production of reactive oxygen species (ROS) and DNA damage, exhibited as DNA strand breaks. Furthermore, no significant alterations in cellular senescence and apoptosis were detected in HPSCs after exposure to (56)Fe-ion radiation. These findings suggest that epigenetic reprogramming is possibly involved in the development of radiation-induced genomic instability and thus, may have a causative role in the development of AML.
authors: Department of Environmental and Occupational Health, University of Arkansas for Medical Sciences, Little Rock, Arkansas.
authors: Isabelle R
authors: IR
authors: Miousse
authors: Division of Radiation Health, Department of Pharmaceutical Sciences, University of Arkansas for Medical Sciences, Little Rock, Arkansas.
authors: Lijian
authors: L
authors: Shao
authors: Division of Radiation Health, Department of Pharmaceutical Sciences, University of Arkansas for Medical Sciences, Little Rock, Arkansas.
authors: Jianhui
authors: J
authors: Chang
authors: Division of Radiation Health, Department of Pharmaceutical Sciences, University of Arkansas for Medical Sciences, Little Rock, Arkansas.
authors: Wei
authors: W
authors: Feng
authors: Division of Radiation Health, Department of Pharmaceutical Sciences, University of Arkansas for Medical Sciences, Little Rock, Arkansas.
authors: Yingying
authors: Y
authors: Wang
authors: Division of Radiation Health, Department of Pharmaceutical Sciences, University of Arkansas for Medical Sciences, Little Rock, Arkansas.|Department of Neurological Surgery, University of California San Francisco, San Francisco, California.
authors: Antiño R
authors: AR
authors: Allen
authors: Department of Behavioral Neuroscience, ONPRC, Oregon Health and Science University, Portland, Oregon.
authors: Jennifer
authors: J
authors: Turner
authors: Department of Behavioral Neuroscience, ONPRC, Oregon Health and Science University, Portland, Oregon.
authors: Blair
authors: B
authors: Stewart
authors: Department of Behavioral Neuroscience, ONPRC, Oregon Health and Science University, Portland, Oregon.|Department of Neurology, ONPRC, Oregon Health and Science University, Portland, Oregon.|Department of Division of Neuroscience, ONPRC, Oregon Health and Science University, Portland, Oregon.
authors: Jacob
authors: J
authors: Raber
authors: Division of Radiation Health, Department of Pharmaceutical Sciences, University of Arkansas for Medical Sciences, Little Rock, Arkansas.
authors: Daohong
authors: D
authors: Zhou
authors: Department of Environmental and Occupational Health, University of Arkansas for Medical Sciences, Little Rock, Arkansas.
authors: Igor
authors: I
authors: Koturbash
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics / Q000528:radiation effects; D016922:Cellular Senescence / Q000235:genetics / Q000528:radiation effects; D004249:DNA Damage / Q000235:genetics; D019175:DNA Methylation / Q000528:radiation effects; D004307:Dose-Response Relationship, Radiation; D044127:Epigenesis, Genetic / Q000528:radiation effects*; D018628:Gene Dosage / Q000528:radiation effects; D006412:Hematopoietic Stem Cells / Q000378:metabolism* / Q000528:radiation effects*; D007501:Iron / Q000009:adverse effects*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D017382:Reactive Oxygen Species / Q000378:metabolism; D012091:Repetitive Sequences, Nucleic Acid / Q000528:radiation effects; D013997:Time Factors
chemical_list: D017382:Reactive Oxygen Species; D007501:Iron