Abstract
Human deep space and planetary travel is limited by uncertainties regarding the health risks associated with exposure to galactic cosmic radiation (GCR), and in particular the high linear energy transfer (LET), heavy ion component. Here we assessed the impact of two high-LET ions 56Fe and 28Si, and low-LET X rays on genome-wide methylation patterns in human bronchial epithelial cells. We found that all three radiation types induced rapid and stable changes in DNA methylation but at distinct subsets of CpG sites affecting different chromatin compartments. The 56Fe ions induced mostly hypermethylation, and primarily affected sites in open chromatin regions including enhancers, promoters and the edges (“shores”) of CpG islands. The 28Si ion-exposure had mixed effects, inducing both hyper and hypomethylation and affecting sites in more repressed heterochromatic environments, whereas X rays induced mostly hypomethylation, primarily at sites in gene bodies and intergenic regions. Significantly, the methylation status of 56Fe ion sensitive sites, but not those affected by X ray or 28Si ions, discriminated tumor from normal tissue for human lung adenocarcinomas and squamous cell carcinomas. Thus, high-LET radiation exposure leaves a lasting imprint on the epigenome, and affects sites relevant to human lung cancer. These methylation signatures may prove useful in monitoring the cumulative biological impact and associated cancer risks encountered by astronauts in deep space.
Highlights
IntroductionExposure to low-linear energy transfer (LET) X-irradiation has been associated with global or repetitive element hypomethylation[16,17,19,30,31,32,35], gene- and CpG site- specific hypermethylation[19,36,37] and hypomethylation[38] have been observed, and the specific effects exhibit tissue, gender, and strain-specificity[19,20,31,37,39]
We identified 935 CpG sites where the methylation status was moderately associated with dose of 56Fe ions (849 hypermethylated; 86 hypomethylated, p < 0.001); 300 sites where the methylation status was associated with 28Si ion dose (158 hypermethylated, 142 hypomethylated, p < 0.001) and 1,150 where the methylation status was associated with X ray dose (252 hypermethylated; 898 hypomethylated, p < 0.001) (Supplemental Table 1). 56Fe ion exposure tended to affect CpG sites that are less methylated at baseline and to induce their hypermethylation (Fig. 1d), whereas 28Si ion exposure primarily affected CpG sites that start with intermediate DNA methylation levels and had a roughly equivalent tendency to promote their hyper or hypomethylation (Fig. 1e)
The degree to which these cancer risk estimates can be directly extrapolated to astronauts and space radiation exposure is fraught with uncertainties, due in part to incomplete understanding of the biological impact of high-linear energy transfer (LET) radiation exposure and how it differs from terrestrial radiation sources as well as other confounding factors such as smoking status[46,51]
Summary
Exposure to low-LET X-irradiation has been associated with global or repetitive element hypomethylation[16,17,19,30,31,32,35], gene- and CpG site- specific hypermethylation[19,36,37] and hypomethylation[38] have been observed, and the specific effects exhibit tissue, gender, and strain-specificity[19,20,31,37,39] 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]. Together these results speak to an epigenetic ‘memory’ of space radiation exposure
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