Induction of Chronic Inflammation and Altered Levels of DNA Hydroxymethylation in Somatic and Germinal Tissues of CBA/CaJ Mice Exposed to 48Ti Ions

Abstract

Although the lung is one of the target organs at risk for cancer induction from exposure to heavy ions found in space, information is insufficient on cellular/molecular responses linked to increased cancer risk. Knowledge of such events may aid in the development of new preventive measures. Furthermore, although it is known that germinal cells are sensitive to X- or γ-rays, there is little information on the effects of heavy ions on germinal cells. Our goal was to investigate in vivo effects of 1 GeV/n 48Ti ions (one of the important heavy ions found in the space environment) on somatic (lung) and germinal (testis) tissues collected at various times after a whole body irradiation of CBA/CaJ mice (0, 0.1, 0.25, or 0.5 Gy, delivered at 1 cGy/min). We hypothesized that 48Ti-ion-exposure induced damage in both tissues. Lung tissue was collected from each mouse from each treatment group at 1 week, 1 month, and 6 months postirradiation. For the testis, we collected samples at 6 months postirradiation. Hence, only late-occurring effects of 48Ti ions in the testis were studied. There were five mice per treatment group at each harvest time. We investigated inflammatory responses after exposure to 48Ti ions by measuring the levels of activated nuclear factor kappa B and selected pro-inflammatory cytokines in both tissues of the same mouse. These measurements were coupled with the quantitation of the levels of global 5-methylcytosine (5mC) and 5-hydroxymethylcytosine (5hmC). Our data clearly showed the induction of chronic inflammation in both tissues of exposed mice. A dose-dependent reduction in global 5hmC was found in the lung at all time-points and in testes collected at 6 months postirradiation. In contrast, significant increases in global 5mC were found only in lung and testes collected at 6 months postirradiation from mice exposed to 0.5 Gy of 1 GeV/n 48Ti ions. Overall, our data showed that 48Ti ions may create health risks in both lung and testicular tissues.

Galactic Cosmic Radiation Induces Persistent Epigenome Alterations Relevant to Human Lung Cancer

“…In some cases, these alterations are accompanied by altered levels of DNMTs, methylated DNA binding proteins, or the activation of miRNAs suggested to target DNMTs and other chromatin modifiers 30 , 32 , 35 , 36 , 38 . In contrast, exposure to protons and high-LET species ( 28 Si, 56 Fe, 48 Ti-ion) are often, though not always, associated with increases in global and/or repetitive element methylation 17 , 18 , 21 , 22 , 26 , 28 , 29 , 34 , 39 , 40 although this too exhibits significant dose, time (acute vs. latent) and tissue/cell type dependence 16 – 18 , 33 , 35 . Alterations at select genes have also been observed in response to high-LET ions 33 , 40 .…”

Late Effects of Low-Dose Radiation on the Bone Marrow, Lung, and Testis Collected From the Same Exposed BALB/cJ Mice

“…The methods for DNA isolation from the mouse BM cells and tissue lysates, using the DNeasy kit (Qiagen, ValenciaCalifornia), have been previously presented. 40,49 Prior to using for the measurements of levels of global 5mC and 5hmC, DNA concentrations and purities were measured using the BioPhotometer (Eppendorf Co). Subsequently, we used commercially available ELISA kits for the detection of global 5mC and 5hmC (Zymo Research, Inc, Irvine, California) to measure the percentage of global 5mC and 5hmC in the DNA samples isolated from the BM cells and the lung/testis lysates of these mice.…”

“…22 Likewise, our focus was also on the lung because it is one of the tissues known to be highly sensitive to radiation-induced acute and chronic inflammation and cell death. 47 -50 Further, an elevated incidence of lung cancer has been documented in atomic bomb survivors who were exposed to γ-rays and neutrons 51 as well as in the Mayak workers of a nuclear facility in the Russian Federation who were exposed to both γ-rays and α particles from inhaling plutonium ( 239 Pu). 52…”

The Lowest Radiation Dose Having Molecular Changes in the Living Body

“…Rithdech et al focused on the induction of chronic inflammation and altered levels of DNA hydroxymethylation in the somatic and germinal tissues of CBA/CaJ mice exposed to 48 Ti ions. 84 Mice were whole-body exposed to total body doses of 0.1, 0.25, or 0.5 Gy of 1 GeV/nucleon 48 Ti ions. They examined the level of activated nuclear factor-κ B (NF-κB), tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), IL-6, 5-methylcytosine (5mC), and 5-hydroxymethylcytosine (5hmC).…”