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 (56Fe) in the mouse lung. Exposure to 56Fe (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 56Fe, 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.

Late-occurring chromosome aberrations and global DNA methylation in hematopoietic stem/progenitor cells of CBA/CaJ mice exposed to silicon (28Si) ions

“…These exchanges included translocations (Robertsonian and incomplete translocation). Most of the translocations belong to the one-way type because fragments were missing, similar to those found in human lymphocytes irradiated in vitro to 0.3 or 3 Gy of 56 Fe ions [34], or in BM cells of BALB/cJ mice exposed whole body to 100 MeV protons, one of the most abundant type of radiation produced during a solar particle event [20]. Robertsonian translocations (RTs) between non-homologous chromosomes were detected in all groups of mice, including the non-irradiated sham-control.…”

“…Even though it is known that exposure to low LET radiation (such as X or ␥ rays) induces changes in the patterns of DNA methylation [49][50][51][52][53][54][55][56][57], little is known about the effects of high LET radiation (such as HZE particles found in the space environment) on global or gene-specific DNA methylation patterns [54,55]. Changes in 5mC patterns of specific genes (e.g.…”

“…Yet, the profiles of 5hmC were not investigated in these studiers [49][50][51][52][53][54]56]. This is due to the fact that 5hmC, unlike 5mC, has just been the topic of interest only in recent years.…”

In Vitro Mass-Screening of Lactic Acid Bacteria as Potential Biosorbents of Cesium and Strontium Ions

“…Romanenko et al (2012) reported that exposure to low doses and to low dose-rates of radiation from post-Chornobyl cleanup work was associated with a significant increase of risk in leukemia. Nzabarushimana et al (2014) report exposure to low doses of 56 Fe causes an increased in chemokine Ccl3, and interleukin Il-4 expression; and interloikine and global DNA hypermethylation in the mouse lung. Taira et al (2014) reported forewing size reduction, growth retardation, high mortality rates, and high abnormality rates in pale grass blue butterflies, Zizeeria maha, captured from the Fukushima area.…”

2017 Michael Fry Award Lecture When DNA is Actually Not a Target: Radiation Epigenetics as a Tool to Understand and Control Cellular Response to Ionizing Radiation

“…For instance, exposure to low mean absorbed doses of heavy iron ions ( 56 Fe) resulted in dose-dependent DNA hypermethylation in the mouse lung (32). While there were no changes in gene-specific DNA methylation, including changes in the genes frequently hypermethylated in lung cancer, dose-dependent DNA hypermethylation of REs was observed.…”