title: Long-term epigenetic effects of exposure to low doses of 56Fe in the mouse lung.
abstract: Despite significant progress, the long-term health effects of exposure to high charge (Z) and energy (E) nuclei (HZEs) and the underlying mechanisms remain poorly understood. Mouse studies show that space missions can result in pulmonary pathological states. The goal of this study was to evaluate the pro-fibrotic and pro-carcinogenic effects of exposure to low doses of heavy iron ions ((56)Fe) in the mouse lung. Exposure to (56)Fe (600 MeV; 0.1, 0.2 and 0.4 Gy) resulted in minor pro-fibrotic changes, detected at the beginning of the fibrotic phase (22 weeks post exposure), which were exhibited as increased expression of chemokine Ccl3, and interleukin Il4. Epigenetic alterations were exhibited as global DNA hypermethylation, observed after exposure to 0.4 Gy. Cadm1, Cdh13, Cdkn1c, Mthfr and Sfrp1 were significantly hypermethylated after exposure to 0.1 Gy, while exposure to higher doses resulted in hypermethylation of Cdkn1c only. However, expression of these genes was not affected by any dose. Congruently with the observed patterns of global DNA methylation, DNA repetitive elements were hypermethylated after exposure to 0.4 Gy, with minor changes observed after exposure to lower doses. Importantly, hypermethylation of repetitive elements coincided with their transcriptional repression. The findings of this study will aid in understanding molecular determinants of pathological states associated with exposure to (56)Fe, as well as serve as robust biomarkers for the delayed effects of irradiation. Further studies are clearly needed to investigate the persistence and outcomes of molecular alterations long term after exposure.
authors.affiliation: Department of Environmental and Occupational Health, College of Public Health, University of Arkansas for Medical Sciences, 4301 West Markham Street, #820-11, Little Rock, 72205-7199, AR, USA.
authors.forename: Etienne
authors.initials: E
authors.lastname: Nzabarushimana
authors.affiliation: Department of Environmental and Occupational Health, College of Public Health, University of Arkansas for Medical Sciences, 4301 West Markham Street, #820-11, Little Rock, 72205-7199, AR, USA.
authors.forename: Isabelle R
authors.initials: IR
authors.lastname: Miousse
authors.affiliation: Division of Radiation Health, Department of Pharmaceutical Sciences, University of Arkansas for Medical Sciences, 4301 West Markham Street, #820-11, Little Rock, 72205-7199, AR, USA.
authors.forename: Lijian
authors.initials: L
authors.lastname: Shao
authors.affiliation: Division of Radiation Health, Department of Pharmaceutical Sciences, University of Arkansas for Medical Sciences, 4301 West Markham Street, #820-11, Little Rock, 72205-7199, AR, USA.
authors.forename: Jianhui
authors.initials: J
authors.lastname: Chang
authors.affiliation: Division of Radiation Health, Department of Pharmaceutical Sciences, University of Arkansas for Medical Sciences, 4301 West Markham Street, #820-11, Little Rock, 72205-7199, AR, USA.
authors.forename: Antiño R
authors.initials: AR
authors.lastname: Allen
authors.affiliation: Department of Behavioral Neuroscience, ONPRC, Oregon Health and Science University, 3181 S.W. Sam Jackson Park Rd, Portland, 97239-3098, OR, USA.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Turner
authors.affiliation: Department of Behavioral Neuroscience, ONPRC, Oregon Health and Science University, 3181 S.W. Sam Jackson Park Rd, Portland, 97239-3098, OR, USA.
authors.forename: Blair
authors.initials: B
authors.lastname: Stewart
authors.affiliation: Department of Behavioral Neuroscience, ONPRC, Oregon Health and Science University, 3181 S.W. Sam Jackson Park Rd, Portland, 97239-3098, OR, USA Department of Neurology, ONPRC, Oregon Health and Science University, 3181 S.W. Sam Jackson Park Rd, Portland, 97239-3098, OR, USA Division of Cancer Biology and Radiobiology, and Division of Neuroscience, ONPRC, Oregon Health and Science University, 3181 S.W. Sam Jackson Park Rd, Portland, 97239-3098, OR, USA.
authors.forename: Jacob
authors.initials: J
authors.lastname: Raber
authors.affiliation: Department of Environmental and Occupational Health, College of Public Health, University of Arkansas for Medical Sciences, 4301 West Markham Street, #820-11, Little Rock, 72205-7199, AR, USA ikoturbash@uams.edu.
authors.forename: Igor
authors.initials: I
authors.lastname: Koturbash
mesh_terms: D000818:Animals; D019175:DNA Methylation / Q000528:radiation effects; D044127:Epigenesis, Genetic / Q000528:radiation effects*; D020450:Heavy Ions / Q000009:adverse effects*; D006801:Humans; D007501:Iron / Q000008:administration & dosage / Q000633:toxicity*; D008168:Lung / Q000528:radiation effects*; D055370:Lung Injury / Q000209:etiology / Q000235:genetics; D008175:Lung Neoplasms / Q000209:etiology / Q000235:genetics; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009381:Neoplasms, Radiation-Induced / Q000209:etiology / Q000235:genetics; D011658:Pulmonary Fibrosis / Q000209:etiology / Q000235:genetics; D011833:Radiation Injuries, Experimental / Q000209:etiology / Q000235:genetics; D013026:Space Flight
chemical_list: D007501:Iron
keywords: DNA methylation; epigenetics; heavy iron ions; lung cancer; pulmonary fibrosis; repetitive elements