Chronic low dose-rate versus acute ionizing radiation induced gene expression in primary derived prostate fibroblasts
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ABSTRACT:
ORGANISM(S): Homo sapiens
SUBMITTER: J. Tyson McDonald
PROVIDER: E-GEOD-52918 | biostudies-arrayexpress |
REPOSITORIES: biostudies-arrayexpress
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Project description:In a recent egg injection study, we showed that in ovo exposure to perfluorohexane sulfonate (PFHxS) affects the pipping success of developing chicken (Gallus gallus domesticus) embryos. We also found evidence of thyroid hormone (TH) pathway interference at multiple levels of biological organization (i.e. somatic growth, mRNA expression and circulating free thyroxine levels). Based on these findings, we hypothesize that PFHxS exposure interferes with TH-dependent neurodevelopmental pathways. The present study investigates global transcriptional profiles of cerebral cortex tissue from chicken embryos following exposure to a solvent control, 890 or 38,000 ng PFHxS/g egg (n=4-5 per group); doses which lead to the adverse effects above. PFHxS significantly alters the expression (≥1.5-fold, p≤0.001) of 11 transcripts at the low dose (LD; 890 ng/g) and 101 transcripts at the high dose (HD; 38,000 ng/g). Functional enrichment analysis shows that PFHxS affects genes involved in tissue development and morphology, cellular assembly and organization, and cell-to-cell signalling. Pathway and interactome analyses suggest that genes may be affected through several potential regulatory molecules, including integrin receptors, myelocytomatosis viral oncogene and CCAAT/enhancer binding protein. This study identifies key functional and regulatory modes of PFHxS action involving TH-dependent and -independent neurodevelopmental pathways. Some of these TH-dependent mechanisms that occur during embryonic development include tight junction formation, signal transduction and integrin signaling, while TH-independent mechanisms include gap junction intercellular communication. Reference Design. Reference = pool of equal parts of all control and treated samples. Control groups and 2 treatment groups. Control samples were chicken embryonic cerebral cortex exposed DMSO only (solvent). Treatments were: chicken embryonic cerebral cortex exposed to 890 ng/g PFHxS (LD) and 38,000 ng/g PFHxS (HD).
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Project description:Accidents with ionizing radiation (IR) often involve acute high dose exposures that can lead to acute radiation syndrome and late effects. IR can induce genomic lesions, cell death or carcinogenesis. Here, we investigated acute IR-induced cellular genomic signatures at the genome wide level. After exposing the adenocarcinoma cell line A549 to an acute 6 Gy 240 kV X-Ray dose, four surviving clonogenic cells were recovered by minimal dilution and further expanded and analyzed by cytogenetics, chromosome painting and tiling-path array CGH, with the non-irradiated clone0 serving as control. It was found that acute X-ray exposure induced changes in modal chromosome number and specific translocations in the four irradiation surviving clones. Furthermore, clone4 displayed an increased radiosensitivity at D > 5 Gy. Array CGH disclosed unique and recurrent genomic changes, predominantly gains, and disclosed fragile sites FRA3B and FRA16D as preferential regions of genomic alterations in all irradiated clones, which likely relates to irradiation-induced genomic stress. Gene expression analysis revealed a specific profile of 364 genes in clone4, of which p53 pathway genes may contribute to its increased radiosensitivity. IR-induced genomic changes AND fragile site expression highlight the capacity of a single acute radiation exposure to resculpture the genome of tumor cells by inflicting genomic stress. Gene expression in A549 cell line was analysed after exposure to 6Gy X-rays at a dose rate of 1Gy/min.
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Project description:The endothelium is the barrier separating blood and tissue. Radiation-induced enhanced inflammation leading to permeability of this barrier may increase the risk of cardiovascular disease. The aim of this study was to investigate the onset of endothelial inflammatory pathways after radiation exposure. Human coronary artery endothelial cells (HCECest2) were exposed to radiation doses of 0, 0.25, 0.5, 2.0 and 10 Gy (60Co-γ). The cells were harvested 4 h, 24 h, 48 h and 1 wk post-irradiation. The proteomics analysis was performed in a label-free data-independent acquisition mode. The data were validated using bioinformatics and immunoblotting. The low- and moderate-dose-treated samples showed only small proteome changes. In contrast, an activation of DNA-damage repair, inflammation, and oxidative stress pathways was seen after high-dose treatments (2 and 10 Gy). The level of the DNA damage response protein DDB2 was enhanced early at the 10 Gy dose. The expression of proteins belonging to the inflammatory response or cGAS-STING pathway (STING, STAT1, ICAM1, ISG15) increased in a dose-dependent manner showing the strongest effects at 10 Gy after one week. This study suggests a connection between radiation-induced DNA damage and induction of inflammation and supports inhibition of cGAS-STING pathway in the prevention of radiation-induced cardiovascular disease.
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