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Gene expression-based dosimetry by dose and time in mice following acute radiation exposure.

ABSTRACT: Rapid and reliable methods for performing biological dosimetry are of paramount importance in the event of a large-scale nuclear event. Traditional dosimetry approaches lack the requisite rapid assessment capability, ease of use, portability and low cost, which are factors needed for triaging a large number of victims. Here we describe the results of experiments in which mice were acutely exposed to (60)Co gamma rays at doses of 0 (control) to 10 Gy. Blood was obtained from irradiated mice 0.5, 1, 2, 3, 5, and 7 days after exposure. mRNA expression levels of 106 selected genes were obtained by reverse-transcription real time PCR. Stepwise regression of dose received against individual gene transcript expression levels provided optimal dosimetry at each time point. The results indicate that only 4-7 different gene transcripts are needed to explain ? 0.69 of the variance (R(2)), and that receiver-operator characteristics, a measure of sensitivity and specificity, of ? 0.93 for these statistical models were achieved at each time point. These models provide an excellent description of the relationship between the actual and predicted doses up to 6 Gy. At doses of 8 and 10 Gy there appears to be saturation of the radiation-response signals with a corresponding diminution of accuracy. These results suggest that similar analyses in humans may be advantageous for use in a field-portable device designed to assess exposures in mass casualty situations.

SUBMITTER: Tucker JD

PROVIDER: S-EPMC3865163 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

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Gene expression-based dosimetry by dose and time in mice following acute radiation exposure.

Tucker James D JD Divine George W GW Grever William E WE Thomas Robert A RA Joiner Michael C MC Smolinski Joseph M JM Auner Gregory W GW

PloS one 20131216 12

Rapid and reliable methods for performing biological dosimetry are of paramount importance in the event of a large-scale nuclear event. Traditional dosimetry approaches lack the requisite rapid assessment capability, ease of use, portability and low cost, which are factors needed for triaging a large number of victims. Here we describe the results of experiments in which mice were acutely exposed to (60)Co gamma rays at doses of 0 (control) to 10 Gy. Blood was obtained from irradiated mice 0.5, ...[more]

PMID: 24358280

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Project description:Chlorpyrifos (CPF) is a widely used organophosphorus insecticide (OP) and putative developmental neurotoxicant in humans. The acute toxicity of CPF is elicited by acetylcholinesterase (AChE) inhibition. We characterized dose-related (0.1, 0.5, 1 and 2mg/kg) gene expression profiles and changes in cell signaling pathways 24h following acute CPF exposure in 7-day-old rats. Microarray experiments indicated that approximately 9% of the 44,000 genes were differentially expressed following either one of the four CPF dosages studied (546, 505, 522, and 3,066 genes with 0.1, 0.5, 1.0 and 2.0mg/kg CPF). Genes were grouped according to dose-related expression patterns using K-means clustering while gene networks and canonical pathways were evaluated using Ingenuity Pathway Analysis®. Twenty clusters were identified and differential expression of selected genes was verified by RT-PCR. The four largest clusters (each containing from 276 to 905 genes) constituted over 50% of all differentially expressed genes and exhibited up-regulation following exposure to the highest dosage (2mg/kg CPF). The total number of gene networks affected by CPF also rose sharply with the highest dosage of CPF (18, 16, 18 and 50 with 0.1, 0.5, 1 and 2mg/kg CPF). Forebrain cholinesterase (ChE) activity was significantly reduced (26%) only in the highest dosage group. Based on magnitude of dose-related changes in differentially expressed genes, relative numbers of gene clusters and signaling networks affected, and forebrain ChE inhibition only at 2mg/kg CPF, we focused subsequent analyses on this treatment group. Six canonical pathways were identified that were significantly affected by 2mg/kg CPF (MAPK, oxidative stress, NF?B, mitochondrial dysfunction, arylhydrocarbon receptor and adrenergic receptor signaling). Evaluation of different cellular functions of the differentially expressed genes suggested changes related to olfactory receptors, cell adhesion/migration, synapse/synaptic transmission and transcription/translation. Nine genes were differentially affected in all four CPF dosing groups. We conclude that the most robust, consistent changes in differential gene expression in neonatal forebrain across a range of acute CPF dosages occurred at an exposure level associated with the classical marker of OP toxicity, AChE inhibition. Disruption of multiple cellular pathways, in particular cell adhesion, may contribute to the developmental neurotoxicity potential of this pesticide.

Project description:BACKGROUND:Exposure to ionizing radiation induces complex stress responses in cells, which can lead to adverse health effects such as cancer. Although a variety of studies investigated gene expression and affected pathways in human fibroblasts after exposure to ionizing radiation, the understanding of underlying mechanisms and biological effects is still incomplete due to different experimental settings and small sample sizes. Therefore, this study aims to identify the time point with the highest number of differentially expressed genes and corresponding pathways in primary human fibroblasts after irradiation at two preselected time points. METHODS:Fibroblasts from skin biopsies of 15 cell donors were exposed to a high (2Gy) and a low (0.05Gy) dose of X-rays. RNA was extracted and sequenced 2?h and 4?h after exposure. Differentially expressed genes with an adjusted p-value <?0.05 were flagged and used for pathway analyses including prediction of upstream and downstream effects. Principal component analyses were used to examine the effect of two different sequencing runs on quality metrics and variation in expression and alignment and for explorative analysis of the radiation dose and time point of analysis. RESULTS:More genes were differentially expressed 4?h after exposure to low and high doses of radiation than after 2?h. In experiments with high dose irradiation and RNA sequencing after 4?h, inactivation of the FAT10 cancer signaling pathway and activation of gluconeogenesis I, glycolysis I, and prostanoid biosynthesis was observed taking p-value (<?0.05) and (in) activating z-score (?2.00 or???-?2.00) into account. Two hours after high dose irradiation, inactivation of small cell lung cancer signaling was observed. For low dose irradiation experiments, we did not detect any significant (p?<?0.05 and z-score???2.00 or???-?2.00) activated or inactivated pathways for both time points. CONCLUSIONS:Compared to 2?h after irradiation, a higher number of differentially expressed genes were found 4?h after exposure to low and high dose ionizing radiation. Differences in gene expression were related to signal transduction pathways of the DNA damage response after 2?h and to metabolic pathways, that might implicate cellular senescence, after 4?h. The time point 4?h will be used to conduct further irradiation experiments in a larger sample.

Dataset Information

Gene expression-based dosimetry by dose and time in mice following acute radiation exposure.

Publications

Gene expression-based dosimetry by dose and time in mice following acute radiation exposure.

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