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.
Highlights
Chronic exposure to pollutions is associated in wild animals with immunosuppression, increased sensitivity to stress and cancerogenesis, all contributing to loss of fitness and raising concerns for species conservation [1,2,3,4,5,6,7]
The largest overlap was observed for the two highest dose rates, 5 and 50 mGy/h (589 differentially expressed genes (DEG), 21.6%, n = 2716 genes), which suggests that the transcriptomic responses induced in these two conditions were partially overlapping
In this study, we investigated how the early step of zebrafish embryonic development can be altered after exposure to Ionising radiation (IR) by studying genome-wide gene expression and DNA methylation
Summary
Chronic exposure to pollutions is associated in wild animals with immunosuppression, increased sensitivity to stress and cancerogenesis, all contributing to loss of fitness and raising concerns for species conservation [1,2,3,4,5,6,7]. The early phases of embryonic development are sensitive to stress and DNA mutations [10], as somatic mutations can accumulate through cell proliferation in a wide number of cells and organs, increasing the risks of morphological defects and cancers [11], especially at high doses of IR (more than 0.1 Gy). The level of DNA methylation changes dramatically during this early phase of embryogenesis, as the parental DNA methylation marks are erased rapidly in order to reach totipotency [15]. This process of DNA methylation reprogramming is observed in rodents and zebrafish, which suggests that it could be a common process in vertebrates, but differences exists between these species. The gene regulatory networks that drive vertebrate germ layer morphogenesis are well documented, especially in zebrafish and in Xenopus as these species are amenable to experimentations after fertilisation [18,19], which allows a detailed analysis of altered processes
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