Transient Genome-Wide Transcriptional Response to Low-Dose Ionizing Radiation In Vivo in Humans

Berglund, Susanne R.; Rocke, David M.; Dai, Jingjie; Schwietert, Chad W.; Santana, Alison; Stern, Robin L; Lehmann, Jöerg; Siantar, Christine L. Hartmann; Goldberg, Zelanna

doi:10.1016/j.ijrobp.2007.09.026

Cited by 40 publications

(40 citation statements)

References 31 publications

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“…Similar effects have been seen in vivo using human skin [41]. An interesting finding of our present study is that low-dose exposures induce a substantial number of genes that have been associated with carcinogenesis and metastasis, but whether their roles are protective or detrimental to cancer induction is unknown at this time; many of the genes involved are known for their protective functions.…”

Section: Mechanisms and Implicationssupporting

confidence: 83%

“…We compared our radiation-responsive genes (Table1 and Table S1) with findings of other low-dose transcript studies [13,15,[33][34][35][36][37][38][39]41]. Using our 81-gene set, elevated GGH transcript was in common with the mouse brain findings [19], TNFRSF6 with ML-1 cells [13], SCAMP1 with keratinocytes [34] and RPL5 with HUVE cells [36].…”

Section: Comparison Of Results With Other Low-dose Transcript Data Setsmentioning

confidence: 99%

“…Our study of brain tissue from irradiated mice [19] identified several hundred genes with modulated transcript levels after exposures of 10 cGy. Using skin biopsies from radiotherapy patients, Goldberg and colleagues identified low-dose genes, their variability and functional groups [39][40][41]. A proteomic survey identified several proteins that were phosphorylated or modulated at doses below 10 cGy in a variety of model systems [42].…”

Section: Introductionmentioning

confidence: 99%

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Low dose radiation response curves, networks and pathways in human lymphoblastoid cells exposed from 1 to 10cGy of acute gamma radiation

Wyrobek

Manohar

Krishnan

et al. 2011

Mutation Research/Genetic Toxicology and Environmental Mutagene

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We investigated the low dose dependency of the transcriptional response of human cells to characterize the shape and biological functions associated with the dose response curve and to identify common and conserved functions of low dose expressed genes across cells and tissues.Human lymphoblastoid (HL) cells from two unrelated individuals were exposed to graded doses of radiation spanning the range of 1-10 cGy were analyzed by transcriptome profiling, qPCR and bioinformatics, in comparison to sham irradiated samples. A set of ~80 genes showed consistent responses in both cell lines; these genes were associated with homeostasis mechanisms (e.g., membrane signaling, molecule transport), subcellular locations (e.g., Golgi, and endoplasmic reticulum), and involved diverse signal transduction pathways. The majority of radiation-modulated genes had plateau-like responses across 1-10 cGy, some with suggestive evidence that transcription was modulated at doses below 1 cGy. MYC, FOS and TP53 were the major network nodes of the low-dose response in HL cells. Comparison our low dose expression findings in HL cells with those of prior studies in mouse brain after whole body exposure, in human keratinocyte cultures, and in endothelial cells cultures, indicates that certain components of the low dose radiation response are broadly conserved across cell types and tissues, independent of proliferation status.

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Section: Mechanisms and Implicationssupporting

confidence: 83%

Section: Comparison Of Results With Other Low-dose Transcript Data Setsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Low dose radiation response curves, networks and pathways in human lymphoblastoid cells exposed from 1 to 10cGy of acute gamma radiation

Wyrobek

Manohar

Krishnan

et al. 2011

Mutation Research/Genetic Toxicology and Environmental Mutagene

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“…The (40), cydins (41,42), GADD45 (43), heat shock (41, 44), two that did not were the chemokine and fibronectin interleukins (45), RAD51 (19), serine/threonine kinases pathways. (46,47), tumor necrosis factor-3 (48), and topoisomerases There were 19 gene groups analyzed, of which seven showed (21,49). The radiation-responsive gene groups and pathways radiation-responsive differential gene expression.…”

Section: Resultsmentioning

confidence: 99%

Molecular Mechanisms of Nonlinearity in Response to Low Dose Ionizing Radiation

Goldberg¹,

Rocke²

2007

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Public reporting burden for this collection of information is estimated to average 1 hour per response, including the time for reviewing it he data needed, and completing and reviewing this collection of information. Send comments regarding this burden estimate or any othe ng this burden to Department of Defense, Washington Headquarters Services, Directorate for Information Operations and Reports (0704-4302. Respondents should be aware that notwithstanding any other provision of law, no person shall be subject to any penalty for faili, )ntly valid OMB control number. PLEASE DO NOT RETURN YOUR FORM TO THE ABOVE ADDRESS. Arlington, CA 22203-1768 REPORT DATE (DD-MM DISTRIBUTION I AVAILABILITY STATEMENTApprove for public release, distribution unlimited. SUPPLEMENTARY NOTES ABSTRACTIn this very new project we have begun a systematic evaluation ot the molecular mechanisms of radiation adaptation. We have developed a wound-healing model that will provide a functional assessment of the promitogenic effects of low dose radiation exposure. We have begun detailed cell cycle analysis of low dose radiation exposure on human keratinocytes and fibroblasts as well as survival assays following priming and challenge doses of ionizing radiation. Initial experiments suggest that doses in the range of 10 cGy provide a promitogenic signal. Further, a priming dose of 10-20 cGy seems to provide radiation protection against subsequent challenge doses up to 4 Gy. Beyond 4 Gy in challenge doses, the radioprotective effect of the priming dose seems to be overwhelmed. Genomic evaluation using the Illumina microarray platform is ongoing. This paper is the first to describe transcriptional responses to low-dose ionizing radiation in vivo in humans. The earlier dosimetry work allowed for accurate quantitation of precisely calibrated doses which were verified by TLD's and MOSFETs. Eight men were included in this study, a biopsy was taken prior to each patient's first radiation treatment and three biopsies were taken 3 hours post exposure at locations on the abdomen which received 1, 10 or 100 cGy doses. Each biopsy was processed and the RNA was interrogated on an Affymetrix HGU133 Plus 2.0 array. The data was analyzed using the method of Rocke et al as described above, which determined significant differential expression of pre-selected gene groups and pathways. The results identified seven of nineteen gene groups and five of seven gene pathways which were up or down regulated. The gene groups up regulated included: BCL6, cytokines, mitogen-activated protein kinases, and zinc finger proteins. The gene groups down regulated included: keratins, protein disulfide isomerase and S 100. The five pathways all displayed up regulation and included: transforming growth factor /cyclin/ubiquitin pathway, stress/apoptosis, inflammation, growth factor/insulin, and AKT/phosphoinositide-3-kinase. The gene groups and pathways found in this study have known functions in apoptosis, cell cycle arrest, DNA repair and inflammation. This indicates that the skin respo...

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“…have shown a definable response in the expression of genes involved in cell-cycle, inflammation and tissue-remodeling after LDIR (4). The molecular response of normal tissues to IR not only depends on the response of a cell type but by the interactions between different cellular systems and the dynamic equilibrium.…”

mentioning

confidence: 99%

Inflammatory Signature after Low Dose γ-Radiation in Mice Brain and Gut: Switch from Therapeutic Benefit to Inflammation

et al. 2013

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Low dose y-radiation (LDIR) has been used as curative/adjuvant/palliative treatment modality for a variety of medical conditions. However, LDIR has been casually linked to NFκB activation and inflammation. Here, we investigated the kinetics of cyto/chemokines and their influence on inflammation in normal tissues after LDIR. C57BL/6 mice exposed to LDIR (2–50cGy) and sacrificed after 1 h-8 days were examined for alterations in 95 cyto/chemokines in brain and gut (QPCR profiling) and selectively validated by assessing secreted levels (ELISA). Kinetics of LDIR-induced inflammation was assessed using DNA fragmentation and histomorphological changes in brain and gut. LDIR induced a dose-dependent upregulation of cyto/chemokines after 2–50cGy in both brain and gut. Two genes, Csf3 and Tnfa, were upregulated in a ‘dose- and tissue-independent’ manner. Transcriptional kinetics revealed induction of more genes both in brain and gut in early response time (1–48 h) after LDIR. Conversely, only few genes upregulated and more genes downregulated in these tissues after extended response (4–8 days) period. DNA fragmentation and histomorphological analysis revealed consistent dose-, time-and tissue-dependent inflammation after LDIR. Also, serum levels of TNF-α, VEGFA, IFN-γ, GM-CSF, MCP-1 reinstigates the inflammatory signature after LDIR. Together, these results suggest that LDIR significantly inflicts a dose- and tissue-dependent inflammation in normal tissues and this induced inflammation may equivocate over-time and, hence frequency of LDIR use may control the switch from therapeutic benefit to inflammatory response.

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Transient Genome-Wide Transcriptional Response to Low-Dose Ionizing Radiation In Vivo in Humans

Cited by 40 publications

References 31 publications

Low dose radiation response curves, networks and pathways in human lymphoblastoid cells exposed from 1 to 10cGy of acute gamma radiation

Low dose radiation response curves, networks and pathways in human lymphoblastoid cells exposed from 1 to 10cGy of acute gamma radiation

Molecular Mechanisms of Nonlinearity in Response to Low Dose Ionizing Radiation

Inflammatory Signature after Low Dose γ-Radiation in Mice Brain and Gut: Switch from Therapeutic Benefit to Inflammation

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