Ionising Radiation Induces Promoter DNA Hypomethylation and Perturbs Transcriptional Activity of Genes Involved in Morphogenesis during Gastrulation in Zebrafish

Abstract

Embryonic development is particularly vulnerable to stress and DNA damage, as mutations can accumulate through cell proliferation in a wide number of cells and organs. However, the biological effects of chronic exposure to ionising radiation (IR) at low and moderate dose rates (< 6 mGy/h) remain largely controversial, raising concerns for environmental protection. The present study focuses on the molecular effects of IR (0.005 to 50 mGy/h) on zebrafish embryos at the gastrula stage (6 hpf), at both the transcriptomics and epigenetics levels. Our results show that exposure to IR modifies the expression of genes involved in mitochondrial activity from 0.5 to 50 mGy/h. In addition, important developmental pathways, namely, the Notch, retinoic acid, BMP and Wnt signalling pathways, were altered at 5 and 50 mGy/h. Transcriptional changes of genes involved in the morphogenesis of the ectoderm and mesoderm were detected at all dose rates, but were prominent from 0.5 to 50 mGy/h. At the epigenetic level, exposure to IR induced a hypomethylation of DNA in the promoter of genes that colocalised with both H3K27me3 and H3Kme4 histone marks and correlated with changes in transcriptional activity. Finally, pathway enrichment analysis demonstrated that the DNA methylation changes occurred in the promoter of important developmental genes, including morphogenesis of the ectoderm and mesoderm. Together, these results show that the transcriptional program regulating morphogenesis in gastrulating embryos was modified at dose rates greater than or equal to 0.5 mGy/h, which might predict potential neurogenesis and somitogenesis defects observed at similar dose rates later in development.

Population transcriptogenomics highlights impaired metabolism and small population sizes in tree frogs living in the Chernobyl Exclusion Zone

“…The changes in gene expression observed in the CEZ are thus not solely a consequence of genetic differentiation inside the CEZ but rather the result of ITDR differences, despite other environmental characteristics specific to the CEZ cannot be completely excluded. Furthermore, the biological effects detected by the transcriptomic analysis, collectively point toward deregulations of mitochondrial activity and muscle functions in frogs living in the CEZ, which fits with the known effects of chronic exposures to IR [ 62 – 65 ].…”

Revealing the Increased Stress Response Behavior through Transcriptomic Analysis of Adult Zebrafish Brain after Chronic Low to Moderate Dose Rates of Ionizing Radiation

“…Genes with |fold change| ≥ 1.5 and p -value corrected for multiple testing, fdr < 0.05 (false discovery rate [ 63 ]) were considered as differentially expressed in all analysis. Afterwards, functional enrichments was performed using Gene ontology (GO) with R package clusterProfiler using zebrafish genes and human orthologues retrieved by Ensembl biomart (as published before, [ 64 , 65 , 66 ]) as gene annotation is more abundant in this species. The significance was considered when fdr from Fisher’s exact test was <0.05.…”

Plasma metabolomic signatures from patients following high-dose total body irradiation

“…Indeed, it has been shown that radiation can lead to hypomethylation of DNA, as demonstrated by hepatic methionine depletion in rodent models. 15,[46][47][48] Thereby, radiation-induced aberrant methylation activity may be partly responsible for elevated PE, LPE, and reduced PC levels. Furthermore, the decreased levels of plasma PC could be related to their rapid turnover in stressed or damaged cells, which resulted in increased uptake of PC from the blood.…”