Profound DNA methylomic differences between single- and multi-fraction alpha irradiations of lung fibroblasts

Clinical Epigenetics

Research

John M. Danforth¹  Aaron A. Goodarzi¹  Marilyne Stuart²  Marjorie Brand³  Marilyn N. Vera-Chang⁴  Richard B. Richardson⁵ 

[1] Departments of Biochemistry and Molecular Biology and Oncology, Cumming School of Medicine, Robson DNA Science Centre, Charbonneau Cancer Institute, University of Calgary, T2N 1N4, Calgary, AB, Canada;Environment and Waste Technologies Branch, Chalk River Laboratories, Canadian Nuclear Laboratories, K0J 1J0, Chalk River, ON, Canada;Ottawa Hospital Research Institute, K1H 8L6, Ottawa, ON, Canada;Department of Cellular and Molecular Medicine, University of Ottawa, K1H 8L6, Ottawa, ON, Canada;Radiobiology and Health Branch, Chalk River Laboratories, Canadian Nuclear Laboratories, K0J 1J0, Chalk River, ON, Canada;Radiobiology and Health Branch, Chalk River Laboratories, Canadian Nuclear Laboratories, K0J 1J0, Chalk River, ON, Canada;McGill Medical Physics Unit, Cedars Cancer Centre-Glen Site, H4A 3J1, Montreal, QC, Canada;

关键词: Alpha particles;    Radon;    Lung;    Methylome;    Aging;    Cancer;    Mitochondria;    Radiation;   

DOI  :  10.1186/s13148-023-01564-z

 received in 2023-05-30, accepted in 2023-09-05,  发布年份 2023

来源: Springer

【 摘 要 】

BackgroundAlpha (α)-radiation is a ubiquitous environmental agent with epigenotoxic effects. Human exposure to α-radiation at potentially harmful levels can occur repetitively over the long term via inhalation of naturally occurring radon gas that accumulates in enclosed spaces, or as a result of a single exposure from a nuclear accident. Alterations in epigenetic DNA methylation (DNAm) have been implicated in normal aging and cancer pathogenesis. Nevertheless, the effects of aberrations in the methylome of human lung cells following exposure to single or multiple α-irradiation events on these processes remain unexplored.ResultsWe performed genome-wide DNAm profiling of human embryonic lung fibroblasts from control and irradiated cells using americium-241 α-sources. Cells were α-irradiated in quadruplicates to seven doses using two exposure regimens, a single-fraction (SF) where the total dose was given at once, and a multi-fraction (MF) method, where the total dose was equally distributed over 14 consecutive days. Our results revealed that SF irradiations were prone to a decrease in DNAm levels, while MF irradiations mostly increased DNAm. The analysis also showed that the gene body (i.e., exons and introns) was the region most altered by both the SF hypomethylation and the MF hypermethylation. Additionally, the MF irradiations induced the highest number of differentially methylated regions in genes associated with DNAm biomarkers of aging, carcinogenesis, and cardiovascular disease. The DNAm profile of the oncogenes and tumor suppressor genes suggests that the fibroblasts manifested a defensive response to the MF α-irradiation. Key DNAm events of ionizing radiation exposure, including changes in methylation levels in mitochondria dysfunction-related genes, were mainly identified in the MF groups. However, these alterations were under-represented, indicating that the mitochondria undergo adaptive mechanisms, aside from DNAm, in response to radiation-induced oxidative stress.ConclusionsWe identified a contrasting methylomic profile in the lung fibroblasts α-irradiated to SF compared with MF exposures. These findings demonstrate that the methylome response of the lung cells to α-radiation is highly dependent on both the total dose and the exposure regimen. They also provide novel insights into potential biomarkers of α-radiation, which may contribute to the development of innovative approaches to detect, prevent, and treat α-particle-related diseases.Graphical abstract

【 授权许可】

CC BY   
© His Majesty the King in Right of Canada 2023

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