exposure to ionizing radiation has dramatically 
 increased in modern 
 society , raising serious health concerns . ionizing radiation is widely used in medicine for research , diagnosis , 
 and therapy ; it is also used in manufacturing and construction . in addition , accidental exposure to ionizing radiation occurs during 
 air travel and space missions . the deleterious consequences of ionizing 
 radiation exposure can result in cancer and non - cancer - related diseases , including cardiovascular diseases and cognitive decline . it has therefore 
 become a priority to develop new tools that can effectively and rapidly 
 screen populations for radiation exposures . methods for rapid 
 and efficient biological dosimetry could find 
 applications not only for estimating the risk of disease induced by 
 medical , occupational , or accidental exposure to radiation but also for countermeasures . radiological incidents 
 like the recent fukushima explosion on december 2013 underscore the 
 need for a quick and reliable way to identify exposed individuals 
 in the days immediately following a radiological accident so that 
 medical management can begin as soon as possible thereafter . while 
 cytogenetics remains the gold standard for assessing radiation exposure , 
 such a technique might not be sensitive enough to detect subtle molecular 
 changes evoked by radiation exposure before the occurrence of cellular 
 and organ damage , nor does it give insight into signaling pathways 
 triggered by ionizing radiation . radiation biology has traditionally 
 focused on dna damage and repair , 
 mutation induction , and chromosomal rearrangements . until recently , 
 comparatively little attention was paid to other molecular consequences 
 of irradiation that may underlie the risk of pathology . in addition 
 to interacting with genomic dna , however , ionizing radiation may alter 
 the structure and function of key cellular components such as proteins 
 and lipids , activating a pro - inflammatory response and ultimately 
 affecting cell signaling . recent radiation research 
 is , therefore , beginning to adopt a systems biology approach to investigate 
 the pleiotropic effects of exposure to ionizing radiation on multiple 
 cellular components . metabolic phenotyping is a modern analytical approach that 
 uses 
 state - of - the - art instrumentation such as mass spectrometry to characterize 
 the molecular composition ( i.e. , the phenotype ) of biofluids . to date , 
 metabolic phenotyping investigations in radiation research have mainly 
 focused on biomarker discovery in urine . the capability to phenotype blood , 
 however , provides novel opportunities to investigate the molecular 
 response to radiation , thus yielding mechanistic insights as well 
 as discovering novel biomarkers . evidence indeed suggests that blood 
 factors induced by irradiation may reflect and contribute to an ongoing 
 inflammatory response to the initial radiation - induced injury . here , we applied a multiplatform mass 
 spectrometry - based metabolic 
 phenotyping strategy to investigate in mouse serum the molecular response 
 to acute -radiation exposure and describe a lipidomic biosignature 
 that has the potential to be used as an indicator of radiation exposure 
 and as a potential target for therapeutic interventions . all chemicals were purchased from sigma - aldrich 
 ( seelze , germany ) and were of analytical - grade purity or higher . lipid 
 standards were purchased from avanti polar lipids ( alabaster , al , 
 usa ) , cayman chemical ( ann arbor , mi , usa ) , biomol ( plymouth meeting , 
 pa , usa ) , and larodan fine chemicals ( malm , sweden ) . for solid - phase 
 extraction , 96-well , waters oasis hlb plates ( 60 mg ) were obtained 
 from waters corporation ( milford , ma , usa ) . n = 5 ) were irradiated 
 at georgetown university with 8 gy of  rays ( cs source , 1.67 gy / min ) , corresponding to an exposure to radiation 
 that is expected to kill half of the exposed population within 30 
 days ( ld50/30 ) . sham control male c57bl/6 mice ( 810 
 weeks old ; n = 5 ) were treated the same way as irradiated 
 mice . in particular , they were transported to the irradiator at the 
 same time , introduced into the irradiation pie , and spun in the irradiator , 
 minus the radiation exposure . serum was collected using serum separators ( bd biosciences , ca , 
 usa ) . all experimental conditions and 
 animal handling were carried out in accordance with animal protocols 
 approved by the georgetown university animal care and use committee 
 ( guacuc ) . total metabolites were extracted 
 from serum samples by 1:40 dilution in 66% acetonitrile containing 
 2 m debrisoquine sulfate and 30 m 4-nitrobenzoic acid 
 as internal controls . following centrifugation at 13  000 g , the supernatant was stored at 80 c for further 
 analysis . metabolites were separated using an acquity uplc system 
 ( waters corporation , milford , ma , usa ) fitted with a beh hilic 2.1 
  100 mm , 1.7 m column maintained at 30 c . mobile phase a consisted of 95:5 acetonitrile / water 
 ( v / v ) containing 10 mm ammonium acetate ( ph 8.0 ) ; mobile phase b consisted 
 of 50:50 acetonitrile / water ( v / v ) containing 10 mm ammonium acetate 
 ( ph 8.0 ) . a 10 min linear gradient from 100 to 80% a with a 3 min 
 re - equilibration time was applied . ms analyses were performed on a 
 synapt g2-s mass spectrometer ( waters corporation , wilmslow , uk ) acquiring 
 from 50 to 1500 m / z in positive 
 electrospray ionization mode . data were 
 collected in two channels all of the time : low collision energy ( 6.0 
 v ) , for the molecular ions , and high collision energy ( 1540 
 v ) , for product ions . the ion mobility spectrometry ( ims ) gas was 
 nitrogen , and the ims t - wave velocity and height were 900 m / s and 
 40 v , respectively . lipids were extracted from 25 l of 
 serum following protein precipitation using 100 l of 2:1 chloroform / methanol 
 ( v / v ) . samples were vortex - mixed and centrifuged for 10 min at 10  000 g and 4 c . the bottom phase was collected , dried , 
 and resuspended in 100 l of 50:50 acetonitrile / isopropanol 
 ( v / v ) for further ms analysis . total lipid analysis was performed 
 on an ionkey / ms system composed of an acquity uplc m - class , the ionkey 
 source , and an ikey csh c18 , 130  , 1.7 m ( particle size ) , 
 150 m  100 mm column ( waters corporation , milford , ma , 
 usa ) coupled to a synapt g2-si mass spectrometer ( waters corporation , 
 wilmslow , uk ) . the capillary voltage was 2.8 kv , and the source temperature 
 was 110 c . injections were 0.5 l using the partial - loop 
 mode , and the column temperature and flow rate were 55 c and 
 3 l / min , respectively . mobile phase a consisted of 60:40 acetonitrile / water 
 ( v / v ) with 10 mm ammonium formate + 0.1% formic acid . mobile phase 
 b consisted of 90:10 isopropanol / acetonitrile ( v / v ) with 10 mm ammonium 
 formate + 0.1% formic acid . the gradient was programmed as follows : 
 0.02.0 min from 40% b to 43% b , 2.02.1 min to 50% 
 b , 2.112.0 min to 99% b , 12.012.1 min to 40% b , and 
 12.114.0 min at 40% b. a 3 min re - equilibration time was applied . ms analyses were performed , acquiring from 50 to 1500 m / z in positive electrospray ionization mode with 
 a capillary voltage of 2.8 kv . data were collected in two channels 
 all of the time : low collision energy ( 6.0 v ) , for the molecular ions , 
 and high collision energy ( 1540 v ) , for product ions . the 
 ims gas was nitrogen , and the ims t - wave velocity and height were 
 900 m / s and 40 v , respectively . metabolites were extracted 
 from mice sera using a specific 96-well plate system for protein removal , 
 internal standard normalization , and derivatization using the absolute 
 idq p180 kit ( biocrates life sciences ag , innsbruck , aut ) . the methods 
 have been described in detail , and the preparation 
 was performed according to the user manual included with the kit . briefly , 10 samples ( n = 5 sham - irradiated group 
 and n = 5 irradiated group ) were added to the center 
 of the filter on the upper 96-well kit plate , at 10 l per well , 
 and then dried using a nitrogen evaporator . subsequently , 50 l 
 of a 5% solution of phenylisothiocyanate was added for derivatization 
 of the amino acids and biogenic amines . the metabolites 
 were extracted using 300 l of a 5 mm ammonium acetate solution 
 in methanol and transferred by centrifugation into the lower 96-well 
 plate . the extracts were diluted with 600 l of the ms 
 running solvent for further ms analysis using uplc coupled with the 
 xevo tq - s mass spectrometer ( waters corporation , wilmslow , uk ) . one 
 blank sample ( i.e. , no internal standards and no sample added ) , three 
 water - based zero samples ( phosphate - buffered saline ) , and three quality - control 
 samples were also added to the kit plate . the quality control samples , 
 composed of human serum containing metabolites at several concentration 
 levels , were used to verify the performance of the assay and mass 
 spectrometer . a seven - point serial dilution of calibrators was added 
 to the kit s 96-well plate to generate calibration curves used 
 to quantify biogenic amines and amino acids . the kit included a mixture 
 of internal standards for quantifying the natural metabolites : chemical 
 homologous internal standards were used to quantify glycerophospholipid 
 and sphingomyelin species , whereas stable isotope - labeled internal 
 standards were used to quantify the other compound classes . the amount 
 of internal standards was identical in each well , and the internal - standard 
 intensities of zero sample and sample wells were compared to allow 
 conclusions on ion - suppression effects to be made . acylcarnitines , 
 glycerophospholipids , and sphingolipids were subjected to flow - injection 
 analysis ( fia ) using uplc - xevo tq - s in positive mode . hexose was analyzed 
 using a subsequent fia acquisition in negative electrospray ionization 
 mode . amino acids and biogenic amines were analyzed using an acquity 
 uplc system connected to a xevo tq - s mass spectrometer ( waters corporation , 
 wilmslow , uk ) in positive electrospray ionization mode ( table s1 ) . extraction of oxylipins 
 was performed as previously described . briefly , after thawing on ice , 50 l of serum samples was 
 treated immediately with antioxidants ( 0.2 mg butylated hydroxytoluene 
 ( bht / edta ) ) and spiked with the following internal standards : 6k - pgf1-d4 , txb2-d4 , pgf2-d4 , pge2-d4 , pgd2-d4 , lte4-d3 , ltb4-d4 , 12,13 
 dihome - d4 , 9,10-dihome - d4 , 14,15-dihetre - d11 , 15-deoxy--12,14-pgj2-d4 , 20-hete - d6 , 9s - hode - d4 , 12s - hete - d8 , 5s - hete - d8 , 5-oxo - ete - d7 . serum samples were loaded onto the solid - phase 
 extraction plate and then eluted using 1.5 ml of ethyl acetate after 
 wetting the plate wells with 0.5 ml of methanol . the eluent was reduced 
 under nitrogen and subsequently reconstituted in a 50 l solution 
 of 50:50 methanol / acetonitrile ( v / v ) containing 100 nm 1-cyclohexyluriedo-3-dodecanoic 
 acid , a quality marker for the analysis . oxylipins were analyzed 
 using uplc ( waters corporation , milford , ma , usa ) coupled to electrospray 
 ionization on a xevo tq - s mass spectrometer ( waters corporation , wilmslow , 
 uk ) . the autosampler was cooled to 10 c . for each analysis , 
 3 l of sample was injected onto a beh c18 1.7 m , 2.1 
  100 mm column ( waters corporation , milford , ma , usa ) maintained 
 at 40 c . mobile phases were composed 
 as follows : a = 0.1% acetic acid and b = 90:10 ( v / v ) acetonitrile / isopropanol 
 ( 0.001.00 min from 25% b to 33% b , 1.018.00 min b 
 to 95% , 8.018.50 min to 95% b , 8.5110.00 min to 25% 
 b ) . electrospray ionization was performed in the negative - ion mode 
 applying a capillary voltage of 2 kv , a source temperature of 120 
 c , a desolvation gas temperature of 350 c , a desolvation 
 gas flow of 650 l / h , a cone - gas flow of 150 l / h , a collision voltage 
 of 15 v , and a cone voltage of 35 v. oxylipins were detected by means 
 of multiple reaction monitoring ( mrm ) transitions optimized using 
 synthetic standards ( table s2 ) . for global molecular profiling , 
 samples were acquired as ion maps ( retention time versus m / z ) using data - independent analysis ( ms ) , which provided information for both the intact precursor ions 
 ( at low collision energy ) and the fragment ions ( high collision energy ) . after retention - time alignment , an aggregate run representing the 
 compounds in all samples was generated . this aggregate run was used 
 for peak picking and then propagated to all runs to detect the same 
 ions in each . a combination of analysis of the variance ( anova ) including 
 principal component analysis ( pca ) and partial , least - squares discriminant 
 analysis ( pls - da ) identified metabolites most responsible for differences 
 between sample groups . these searches were performed by the human metabolome database ( hmdb ) and lipidmaps and by fragmentation patterns , 
 retention times , and ion - mobility - derived collision cross sections 
 versus commercially available reference standards , when available . 
 for quantification purposes , mean concentrations and sem values for 
 each group were calculated using mrm transition and appropriate internal 
 standards to normalize for variations in sample preparation and ms 
 detection . univariate analyses ( student s t - test ) were conducted to assess for significance ( p value < 0.05 was considered significant ) , and false - discovery 
 rate ( fdr ) was used to control for multiple comparison . data 
 processing and analysis was conducted using progenesis qi ( nonlinear 
 dynamics , newcastle , uk ) , metabolyzer , and metaboanalyst 2.0 . data quantification 
 was performed using targetlynx software ( waters corporation , milford , 
 ma , usa ) and metidq software ( biocrates life sciences ag , innsbruck , 
 aut ) . to characterize the molecular response associated 
 with exposure 
 to radiation , we phenotyped the metabolomes of irradiated mice ( 8 
 gy , ld50/30 ) and sham control mice using a multiplatform 
 mass spectrometry - based approach ( figure 1 ) . serum metabolomes from sham control and irradiated mice were subjected 
 to global metabolic profiling to screen for major molecular alterations . identification and quantification of bioactive and low - abundance metabolites 
 followed ( figure 1 ) . the overall effects on 
 blood cell levels in combination with various symptoms associated 
 with the acute radiation syndrome following exposure to a ld50/30 have been described extensively in the literature . cb57bl/6 
 mice were irradiated ( 8 gy ; n = 5 ) or subjected to 
 the same treatment minus irradiation ( sham control group ; n = 5 ) . blood was collected , and serum samples were prepared 
 and divided into two aliquots . before extraction , a mixture of internal 
 standards was added to the serum to normalize for variations in sample 
 preparation or ms detection . the 
 results were integrated for the generation of a unique metabolic biosignature , 
 which indicates exposure to radiation . to determine the overall effect of radiation on the molecular 
 phenotype , 
 we compared the serum metabolome of sham control and irradiated mice 
 using a microfluidic device coupled with an electrospray - tof detector , 
 detecting thousands of molecular features in serum samples ( figure s1 ) . pca showed that the -irradiated 
 group was well - separated from the sham control group , underscoring 
 that radiation induces a profound molecular response in blood . significant 
 changes were filtered using anova , highlighting the molecular features 
 that contributed most to the variance between the two groups of mice 
 ( figure s1 ) . among the dysregulated molecular 
 components , we tentatively identified metabolites belonging to the 
 classes of amino acids , carnitines , sphingomyelins , and phosphatidylcholines 
 as discriminators of the sham control and irradiated groups ( table 1 ) . lipids are ranked according to 
 their anova p values . to further investigate these initial findings , in 
 an independent 
 set of experiments , we applied a multiplexed metabolic profiling approach . 
 using stable - isotope - dilution tandem ms , we identified and quantified 
 more than 180 endogenous metabolites from six biochemical classes : 
 biogenic amines , amino acids , glycerophospholipids , sphingolipids , 
 sugars , and acylcarnitines ( table s3 ) . multivariate statistical analyses showed that exposure to  
 radiation induced significant molecular changes in mouse sera ( figure 2a , b and figure s2a ) . in particular , we observed a decrease in the levels of diacyl phosphatidylcholines 
 ( pcs ) containing polyunsaturated fatty acids ( pufas ) ( figure 2c and table s3 ) but a 
 significant increase in the levels of ether pcs in mice exposed to 
 radiation compared with that in their sham - irradiated littermates 
 ( figure 2d and table s3 ) . moreover , in the irradiated animals , the levels of lysophosphatidylcholines 
 and sphingomyelins ( sm ) were also increased ( table 
 s3 ) . such differences were found to be significant after multiple - comparison 
 correction ( fdr < 0.01 ) . other significant differences between 
 sham control and irradiated mice included the levels of serine and 
 carnitines , which increased after irradiation ( figure 2b and table s3 ) . targeted metabolic profiling . 
 ( a ) pls - da analysis showed a marked 
 separation of serum metabolites belonging to irradiated and sham control 
 mice , highlighting the features that contributed most to the variance 
 between the two groups . the colored boxes on the right indicate the relative concentrations 
 of the corresponding metabolite in each group under study . the variable 
 importance in projection ( vip ) , a weighted sum of squares of the pls 
 loadings , takes into account the amount of explained y variation in each dimension . ( c , d ) levels of diacyl pcs ( c ) and 
 ether pcs ( d ) in irradiated and sham control ( n = 
 5 , student s t test ; * * * , p < 0.001 ) . pc species can be hydrolyzed to release pufas that 
 can then be 
 converted into oxylipins by means of enzymatic and nonenzymatic reactions . 
 to measure the levels of such , usually , low - abundance metabolites , 
 we used a tandem ms with multiple reaction monitoring for over 100 
 oxylipins ( figure 1 ) . the overall oxylipins 
 composition was sufficient to discriminate between irradiated and 
 sham control animals ( figure s2b and figure 3a , b ) . we observed a marked increase in the levels 
 of arachidonic acid - derived metabolites ( figure 3b and table 2 ) . in particular , a significant 
 increase after multiple comparison correction was found for hydroxyeicosatetraenoic 
 acids ( 12-hete , 11-hete , 8-hete ) , 14,15 dihydroxy - eicosatrienoic acid 
 ( 14,15-dihetre ) , and 12-hydroxy - heptadecatrienoic acid ( 12-hhtre ) 
 in mice exposed to radiation versus that in the sham control animals 
 ( figure 3c and table 2 ) . our results also highlighted a marked decrease in the levels of 
 diols of epa including 17,18-dihete and 14,15-dihete in the serum 
 of mice exposed to radiation versus that in the serum of sham - treated 
 mice ( figure 3d and table 2 ) . minor decreases were also observed for other ala- or dha - derived 
 metabolites ( figure 3b and table 2 ) ( a ) pls - da analysis showed a marked 
 separation of serum oxylipins belonging to irradiated and sham control 
 mice , highlighting the features that contributed most to the variance 
 between the two groups . the colored boxes on the right indicate the relative concentrations 
 of the corresponding metabolite in each group under study . variable 
 importance in projection ( vip ) , a weighted sum of squares of the pls 
 loadings , takes into account the amount of explained y variation in each dimension . ( c , d ) levels of omega-6 oxylipins 
 ( c ) and omega-3 oxylipins ( d ) in irradiated and sham control mice 
 ( n = 5 , student s t test ; 
 * , p < 0.05 ; * * * , p < 0.001 ) . fdr , false discovery rate . to obtain a metabolic biosignature 
 of mice that would indicate 
 radiation exposure , we combined the quantitative results derived from 
 the multiplexed metabolic profiling analyses , underscoring a significant 
 molecular contrast between sham control and irradiated mice ( figure 4a , b ) . the sham control molecular composition exhibits 
 a decidedly distinct 
 pattern and structure compared with that of the irradiated one , suggesting 
 that radiation elicits a very distinct metabolic response ( figure s3 ) . ( a ) correlation analysis 
 was used to visualize the overall relationships between different 
 features and the irradiated phenotype . ( b ) clustering result shown 
 as a heatmap ( distance measure using pearson ; clustering algorithm 
 using ward ) providing an intuitive visualization of the characteristic 
 lipidomic biosignature found in irradiated mice versus sham control 
 mice . each colored cell on the map corresponds to a concentration 
 value , with samples in rows and features / compounds in columns . in this study , we investigated 
 the molecular response to radiation 
 exposure in mice using a multiplatform mass spectrometry - based strategy . we phenotyped the serum of irradiated and sham control mice , reporting 
 novel metabolic pathways altered after radiation exposure . most of 
 the study s novelty resides in the finding that radiation induces 
 a differential regulation of diacyl pcs and ether pcs as well as omega-6 
 and omega-3 lipid mediators . such radiation - induced changes in lipid 
 composition could have repercussions on ( 1 ) the physicochemical properties 
 of cellular membranes and lipoproteins , ( 2 ) the cellular antioxidant 
 buffering capacity , and ( 3 ) cell signaling . many of these molecular 
 changes may not be specific to the radiation exposure but act instead 
 as general makers of cellular / organism stress and inflammation . limited studies have investigated the effects of ionizing radiation 
 on the blood level of metabolites and lipids in particular . it is reported that treatment of lipid membranes 
 with ionizing radiation leads to lipid degradation , which is mediated 
 by both oxidation and fragmentation processes . such studies , however , aimed to measure the content of 
 a limited number of lipid metabolites in reductionistic models such 
 as synthetic lipid membranes and cellular models . by using a multiplatform 
 mass spectrometry - based approach , we were able to describe in a more 
 comprehensive fashion the alterations in the molecular phenotype of 
 mouse serum following irradiation . in our study , we analyzed metabolites 
 with a wide dynamic range of concentrations : from low - abundance oxylipins , 
 in the picomolar range , to the higher abundance precursor phospholipids , 
 in micromolar amounts . the observed phospholipids rearrangement , 
 a decrease in the levels 
 of diacyl pc species and an increase in ether pcs ( plasmalogens ) , 
 might ultimately have repercussions on the physicochemical properties 
 of the cellular membranes and lipoproteins . the phospholipid 
 class of plasmalogens is indeed ubiquitously found in considerable 
 amounts as a constituent of mammalian cell membranes and of serum 
 lipoproteins . plasmalogens are more susceptible than diacyl pcs to 
 oxidative reactions because of the reactivity of their enol - ether 
 function ; indeed , it is reported that they are effective as endogenous 
 antioxidants . oxidation of the vinyl ether markedly prevents the oxidation of 
 highly polyunsaturated fatty acids , and products of plasmalogen degradation 
 do not propagate lipid oxidation . on the other hand , the oxidation 
 of the vinyl ether bond of plasmalogens leads to the release of fatty 
 aldehydes , which are toxic to cells . the pathological 
 role of plasmalogens and the biochemical pathways underlying their 
 upregulation after radiation exposure remain to be elucidated . the most intriguing observation of our 
 study is that acute exposure 
 to  radiation induced a specific mobilization of bioactive 
 oxylipins ( figure 5a , b ) . these lipid mediators 
 are currently the focus of considerable interest , for they are also 
 key messengers for cellular homeostasis , inflammation , platelet aggregation , 
 and vascularization . oxylipins are produced via enzymatic or nonenzymatic oxygenation 
 of both omega-6 and omega-3 pufas . three major enzymatic pathways 
 are involved in their generation : cyclooxygenase ( cox ) , lipoxygenase 
 ( lox ) , and cytochrome p450 ( cyp450 ) ( figure 5a , b ) . pathway analysis . diet - derived omega-6 linoleic acid ( la ) and omega-3 
 alpha - linolenic acid ( ala ) are transformed into longer chains pufas 
 by the sequential action of desaturases and elongases . pufas can be 
 found in blood as unesterified fatty acids , esterified to phospholipids , 
 or converted into the oxygenated metabolites oxylipins . ( a , b ) the 
 activities of cox , lox , and cyp450 enzymes catalyze the formation 
 of hundreds of oxylipins species with different biological activities 
 starting from the omega-6 pufas precursors ( a ) and the omega-3 pufas 
 ( b ) . the irradiated mice had marked alterations in the lox , cox , and 
 cyp450 pathways , resulting in the increase of omega-6 oxylipins ( red ) 
 and decrease of omega-3 oxylipins ( green ) . significantly , it is reported that ionizing radiation activates 
 cox and lox pathways and that nonsteroidal anti - inflammatory drug 
 treatment reduces radiation - induced expression of pro - inflammatory 
 cytokines ( e.g. , tnf- , tgf- , il-6 , and il-1 / ) . in agreement with these observations , our results further suggest 
 that oxylipins - mediated inflammation might be a critical signaling 
 step for the organism response to radiation . macrophage activation 
 leading to a persistent inflammatory response has been described in 
 radiation therapy for cancer in animals following irradiation and 
 in atomic bomb survivors . like other inflammatory 
 cytokines , , they can be rapidly activated after tissue irradiation 
 as part of the immune response to stress factors and thus they might 
 disrupt cellular homeostasis over time , causing detrimental health 
 effects . it is therefore reasonable to 
 speculate that oxylipins - mediated inflammation could be involved in 
 the bystander and abscopal effects associated with clinical exposures 
 to ionizing radiation in a radiotherapy - type situation . our study 
 indicates that 24 h following irradiation omega-6 pro - inflammatory 
 lipid mediators derived from the cox and lox pathways ( e.g. , hetes , 
 pgf2 , tbx2 ) are upregulated , while the levels of omega-3 anti - inflammatory 
 mediators ( e.g. , 5-hepe , 9-hotre ) are downregulated . notably , some 
 of the most significant oxylipins alterations in the serum of irradiated 
 mice were related to the metabolism of the cyp450 pathway , including 
 14,15-dihetre , 14,15-dihete , and 17,18-dihete ( figure 5 ) . the cyp450 family of enzymes can produce epoxides from 
 pufas , which are subsequently metabolized by the soluble epoxide hydrolase 
 ( seh ) to the corresponding vicinal diols , dihydroxyeicosatrienoic 
 acids . aa - derived cyp metabolites are known to 
 play an important role in renal and cardiovascular function and are 
 linked to the development of hypertension and related disease . omega-3 pufa - derived cyp metabolites are described as possessing 
 anti - inflammatory and analgesic properties , as inhibitors of platelet aggregation , and as pulmonary smooth - muscle relaxants . our results support the hypothesis that cyp450-mediated 
 oxylipins metabolism might represent a major biochemical pathway in 
 response to acute exposure to ionizing radiation . most notably , in 
 human and animal studies , the cyp - dependent metabolite profiles were 
 generally reflective of the pufa intake , suggesting the use therapeutic interventions designed to modulate 
 the levels of oxylipins as a preventive measure or as a countermeasure 
 to cope with the debilitating effects of radiation exposure . oxylipins levels might greatly affect 
 intrinsic cellular radiosensitivity , 
 the incidence and type of radiation - induced tissue complications , 
 and diseases . the balance between omega-6 pro - inflammatory 
 and omega-3 anti - inflammatory lipid mediators may play a key role 
 in the different phases of the response to radiation : a pro - inflammatory 
 phase followed by a pro - resolution phase to restore cellular homeostasis . notably , it is reported that 
 an unbalanced inflammatory response resulting as a consequence of 
 radiation exposure might contribute to both cancer and non - cancer - related 
 diseases , including eye and brain diseases and 
 cardiovascular disease . therefore , the ability to control oxylipin pathways with dietary 
 interventions ( i.e. , omega-3 supplementation ) might alleviate and 
 eventually offset many of the side effects linked to either radiation 
 therapy or accidental exposure . notably , the most significant molecular alterations induced 
 by 
 exposure to radiation affected lipid metabolism . our study , however , 
 also reports a dysregulation of the metabolism of amino acids ( e.g. , 
 serine ) and carnitines ( figure 4 and table s3 ) in mice exposed to radiation . such 
 findings , together with more modest alterations of intermediates of 
 the urea cycle ( e.g. , citrulline , fdr = 0.05 ) , were previously reported 
 and linked to radiation - induced gastrointestinal and liver damage . by offering a bird s eye view of the molecular 
 response to radiation exposure , our study highlights the interplay 
 between lipid metabolism and the network of biochemical pathways for 
 more polar metabolites , which is an object of continued and renewed 
 investigation by the scientific community . using 
 a metabolic phenotyping approach , we identified a novel molecular 
 response in mouse serum following exposure to  radiation . the 
 integration of metabolic profiling information provided a detailed 
 molecular biosignature that might be used as an indicator of radiation 
 exposure and , potentially , as a predictor of radiosensitivity . most 
 important , the molecular components identified in the present study 
 ( i.e. , plasmalogens and oxylipins ) would enable us to modulate their 
 levels using currently available pharmacological treatments or nutritional 
 intervention . if validated in humans , our findings could find 
 applications in 
 personalized medicine . numerous attempts have been made to develop 
 dna - based diagnostic assays to identify cancer patients who might 
 develop severe adverse healthy tissue reactions in response to radiotherapy . we speculate that baseline levels of oxylipins ( e.g. , omega-6/omega-3 
 ratio ) might serve as a companion diagnostic tool for radiation therapy 
 to help differentiate cancer patients who would respond best to radiotherapy 
 treatment from radiosensitive patients who may be unable to tolerate 
 the additional inflammatory response induced by radiotherapy .
exposure 
 to ionizing radiation has dramatically increased in modern 
 society , raising serious health concerns . the molecular response to 
 ionizing radiation , however , is still not completely understood . here , 
 we screened mouse serum for metabolic alterations following an acute 
 exposure to  radiation using a multiplatform mass - spectrometry - based 
 strategy . a global , molecular profiling revealed that mouse serum 
 undergoes a series of significant molecular alterations following 
 radiation exposure . 
 we identified and quantified bioactive metabolites 
 belonging to key biochemical pathways and low - abundance , oxygenated , 
 polyunsaturated fatty acids ( pufas ) in the two groups of animals . 
 exposure to  radiation induced a significant increase in the 
 serum levels of ether phosphatidylcholines ( pcs ) while decreasing 
 the levels of diacyl pcs carrying pufas . in exposed mice , levels of 
 pro - inflammatory , oxygenated metabolites of arachidonic acid increased , 
 whereas levels of anti - inflammatory metabolites of omega-3 pufas decreased . 
 our results indicate a specific serum lipidomic biosignature that 
 could be utilized as an indicator of radiation exposure and as novel 
 target for therapeutic intervention . 
 monitoring such a molecular response 
 to radiation exposure might have implications not only for radiation 
 pathology but also for countermeasures and personalized medicine .