Radiation-induced changes in DNA methylation and their relationship to chromosome aberrations in nuclear power plant workers

Lee, Younghyun; Kim, Yang Jee; Choi, Young Joo; Lee, Joong Won; Lee, Sunyeong; Cho, Yoon Hee; Chung, Hai Won

doi:10.3109/09553002.2015.969847

Cited by 34 publications

(19 citation statements)

References 45 publications

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“…The frequencies of MN and aneuploidy and levels of genomic DNA methylation were significantly different between radiographers and controls, indicating that occupational exposure to radiation, including at low doses, can induce chromosomal damage (both clastogenic and aneugenic effects) as well as methylation changes in genomic DNA. These outcomes are concordant with other publications [Cho et al, ; Lee et al, ; Pogribny et al, , ]. Therefore, we further investigated the effects of low‐level occupational radiation exposure among radiographers.…”

Section: Discussionsupporting

confidence: 91%

LINE‐1 hypomethylation is associated with radiation‐induced genomic instability in industrial radiographers

Cho

Jang

Woo

et al. 2018

Environ and Mol Mutagen

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Global DNA hypomethylation is proposed as a potential biomarker for cancer risk associated with genomic instability, which is an important factor in radiation‐induced cancer. However, the associations among radiation exposure, changes in DNA methylation, and carcinogenesis are unclear. The aims of this study were (1) to examine whether low‐level occupational radiation exposure induces genomic DNA hypomethylation; and (2) to determine the relationships between radiation exposure, genomic DNA hypomethylation and radiation‐induced genomic instability (RIGI) in industrial radiographers. Genomic DNA methylation levels were measured in blood DNA from 40 radiographers and 28 controls using the LINE‐1 pyrosequencing assay and the luminometric methylation assay. Further, the micronucleus‐centromere assay was performed to measure aneuploidy of chromosomes 1 and 4 as a marker of delayed RIGI. Genomic DNA methylation levels were significantly lower in radiographers than those in controls. LINE‐1 hypomethylation was not significantly correlated with recent 1‐year, recent 3‐year, or total cumulative radiation doses in radiographers; however, LINE‐1 hypomethylation significantly correlated with the cumulative radiation dose without recent 3‐year exposure data (D3dose, r = −0.39, P < 0.05). In addition, LINE‐1 hypomethylation was a significant contributor to aneuploidy frequency by D3dose (F (2, 34) = 13.85, P < 0.001), in which a total of 45% of the variance in aneuploidy frequency was explained. Our results provide suggestive evidence regarding the delayed effects of low‐dose occupational radiation exposure in radiographers and its association with LINE‐1 hypomethylation; however, additional studies using more subjects are needed to fully understand the relationship between genomic DNA hypomethylation and RIGI. Environ. Mol. Mutagen. 60: 174–184, 2019. © 2018 Wiley Periodicals, Inc.

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Section: Discussionsupporting

confidence: 91%

LINE‐1 hypomethylation is associated with radiation‐induced genomic instability in industrial radiographers

Cho

Jang

Woo

et al. 2018

Environ and Mol Mutagen

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“…Interestingly, in one experiment (0.5 Gy of low LET) increased LINE-1 methylation was observed [7]. In another study [51], LINE-1 methylation was increased in peripheral blood cells of occupational radiation-exposed power plant workers. Methylation of satellite 2 DNA which is mainly localized in the large paracentromeric heterochromatin blocks of chromosomes 1 and 16 did not differ between workers and controls.…”

Section: Discussionmentioning

confidence: 99%

Analysis of global DNA methylation changes in primary human fibroblasts in the early phase following X-ray irradiation

Maierhofer¹,

Flunkert²,

Dittrich

et al. 2017

PLoS ONE

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Epigenetic alterations may contribute to the generation of cancer cells in a multi-step process of tumorigenesis following irradiation of normal body cells. Primary human fibroblasts with intact cell cycle checkpoints were used as a model to test whether X-ray irradiation with 2 and 4 Gray induces direct epigenetic effects (within the first cell cycle) in the exposed cells. ELISA-based fluorometric assays were consistent with slightly reduced global DNA methylation and hydroxymethylation, however the observed between-group differences were usually not significant. Similarly, bisulfite pyrosequencing of interspersed LINE-1 repeats and centromeric α-satellite DNA did not detect significant methylation differences between irradiated and non-irradiated cultures. Methylation of interspersed ALU repeats appeared to be slightly increased (one percentage point; p = 0.01) at 6 h after irradiation with 4 Gy. Single-cell analysis showed comparable variations in repeat methylation among individual cells in both irradiated and control cultures. Radiation-induced changes in global repeat methylation, if any, were much smaller than methylation variation between different fibroblast strains. Interestingly, α-satellite DNA methylation positively correlated with gestational age. Finally, 450K methylation arrays mainly targeting genes and CpG islands were used for global DNA methylation analysis. There were no detectable methylation differences in genic (promoter, 5' UTR, first exon, gene body, 3' UTR) and intergenic regions between irradiated and control fibroblast cultures. Although we cannot exclude minor effects, i.e. on individual CpG sites, collectively our data suggest that global DNA methylation remains rather stable in irradiated normal body cells in the early phase of DNA damage response.

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“…LUMA targets all CCGG sequences in the genome by using methylation specific enzymes to differentiate between methylated and non-methylated DNA by pyrosequencing, and 5-mC assay covers the whole genome by incorporation of antibody-labeled 5-mC (Lee et al, 2008, Karimi et al, 2006a). These assays differ by targeted genomic regions and have different methodological advantages and limitations, but both assays have been used to determine associations of global DNA methylation and environmental exposures and/or disease outcomes (Deneberg et al, 2010; Karimi et al, 2006b; Lee et al, 2008, 2014; Romermann et al, 2007). In confirmation of our hypothesis, DNA hypomethylation in the lungs as evidenced by both the LUMA and 5-mC assays was demonstrated following MWCNT exposure (Figure 7A and B).…”

Section: Discussionmentioning

confidence: 99%

Alterations in DNA methylation corresponding with lung inflammation and as a biomarker for disease development after MWCNT exposure

et al. 2015

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Use of multi-walled carbon nanotubes (MWCNT) is growing which increases occupational exposures to these materials. Their toxic potential makes it important to have an in-depth understanding of the inflammation and disease that develops due to exposure. Epigenetics is one area of interest that has been quickly developing to assess disease processes due to its ability to change gene expression and thus the lung environment after exposure. In this study, promoter methylation of inflammatory genes (IFN-γ and TNF-α) was measured after MWCNT exposure using the pyrosequencing assay and found to correlate with initial cytokine production. In addition, methylation of a gene involved in tissue fibrosis (Thy-1) was also altered in a way that matched collagen deposition. In addition to using epigenetics to better understand disease processes, it has also been used as a biomarker of exposure and disease. In this study, global methylation was determined in the lung to ascertain whether MWCNT alter global methylation at the site of exposure and if those alterations coincide with disease development. Then, global methylation levels were determined in the blood to ascertain whether global methylation could be used as a biomarker of exposure in a more easily accessible tissue. Using the LuUminometric Methylation Assay (LUMA) and 5-Methylcytosine (5-mC) Quantification assay, we found that MWCNT lead to DNA hypomethylation in the lung and blood, which coincided with disease development. This study provides initial data showing that alterations in gene-specific methylation correspond with an inflammatory response to MWCNT exposure. In addition, global DNA methylation in the lung and blood coincides with MWCNT-induced disease development, suggesting its potential as a biomarker of both exposure and disease development.

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Radiation-induced changes in DNA methylation and their relationship to chromosome aberrations in nuclear power plant workers

Abstract: Occupational exposure to low-dose radiation could affect DNA methylation levels, and the radiation-induced DNA methylation alterations may be associated with chromosome aberrations.

Cited by 34 publications

References 45 publications

LINE‐1 hypomethylation is associated with radiation‐induced genomic instability in industrial radiographers

LINE‐1 hypomethylation is associated with radiation‐induced genomic instability in industrial radiographers

Analysis of global DNA methylation changes in primary human fibroblasts in the early phase following X-ray irradiation

Alterations in DNA methylation corresponding with lung inflammation and as a biomarker for disease development after MWCNT exposure

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