Metabonomics evaluations of age-related changes in the urinary compositions of male Sprague Dawley rats and effects of data normalization methods on statistical and quantitative analysis

Schnackenberg, Laura K.; Sun, Jinchun; Espandiari, Parvaneh; Holland, Ricky D.; Hanig, Joseph P.; Beger, Richard D.

doi:10.1186/1471-2105-8-s7-s3

Cited by 49 publications

(40 citation statements)

References 38 publications

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“…Chromatographic tandem mass spectrometry [1,2,3,4,5,6,7,8,9] and NMR spectroscopy [2,8,10,11] have been widely applied to serve the investigation of aging biochemistry. Blood [1,3,7,9], urine samples [2,5,6,8,10,12] and tissues—mostly hepatic tissue samples [1,4]—have been analyzed to study aging. Fecal samples [10,11] have also been used for this purpose.…”

Section: Introductionmentioning

confidence: 99%

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Impact of Exercise and Aging on Rat Urine and Blood Metabolome. An LC-MS Based Metabolomics Longitudinal Study

et al. 2017

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Aging is an inevitable condition leading to health deterioration and death. Regular physical exercise can moderate the metabolic phenotype changes of aging. However, only a small number of metabolomics-based studies provide data on the effect of exercise along with aging. Here, urine and whole blood samples from Wistar rats were analyzed in a longitudinal study to explore metabolic alterations due to exercise and aging. The study comprised three different programs of exercises, including a life-long protocol which started at the age of 5 months and ended at the age of 21 months. An acute exercise session was also evaluated. Urine and whole blood samples were collected at different time points and were analyzed by LC-MS/MS (Liquid Chromatography–tandem Mass Spectrometry). Based on their metabolic profiles, samples from trained and sedentary rats were differentiated. The impact on the metabolome was found to depend on the length of exercise period with acute exercise also showing significant changes. Metabolic alterations due to aging were equally pronounced in sedentary and trained rats in both urine and blood analyzed samples.

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Section: Introductionmentioning

confidence: 99%

“…The findings of these studies could be summarized in the altered metabolism of the associated pathways of amino acids [1,2,4,10], nucleotides [4], glucose [1,2], metabolites of Krebs cycle [2,4,8,10], and lipids [1,2,3,7]. …”

Section: Introductionmentioning

confidence: 99%

Impact of Exercise and Aging on Rat Urine and Blood Metabolome. An LC-MS Based Metabolomics Longitudinal Study

et al. 2017

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“…Because of different overall urine concentration, all spectra were normalized so that the total area of each urine spectrum reached the same value. Schnackenberg et al[ 26] showed that normalization based on the total integral was the most robust approach to normalize metabolite concentrations in rat urine. …”

Section: Methodsmentioning

confidence: 99%

Metabolic Profiles in Urine Reflect Nephrotoxicity of Sirolimus and Cyclosporine following Rat Kidney Transplantation

Schmitz

Klawitter

Bendrick-Peart³

et al. 2009

Nephron Exp Nephrol

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Background: Cyclosporine and/or sirolimus impair recovery of renal transplants. This study examines the changes in urine metabolite profiles as surrogate markers of renal cell metabolism and function after cyclosporine and/or sirolimus treatment employing a rat kidney transplantation model. Methods: Using inbred Lewis rats, kidneys were transplanted into bilaterally nephrectomized recipients followed by treatment with either CsA (cyclosporine) 10, Rapa (sirolimus) 1, CsA10/Rapa1 or CsA25/Rapa1 mg/kg/day for 7 days. On day 7, urine was analyzed by ¹H-NMR spectroscopy. Blood and kidney tissue drug concentrations, tissue high-energy compounds (including ATP, ADP) and oxidative stress markers (15-F_2t-isoprostanes) in urine were measured by HPLC mass spectrometry. Results: Changes in urine metabolites followed the order Rapa1 < CsA10 < CsA10/Rapa1 < CsA25/Rapa1. Compared with controls, CsA25/Rapa1 showed the greatest changes (creatinine –36%, succinate –57%, citrate –89%, α-ketoglutarate –75%, creatine +498%, trimethylamine +210% and taurine +370%). 15-F_2t-isoprostane concentrations in urine increased in the combined immunosuppressant-treated animals ([CsA25/Rapa1]: 795 ± 222, [CsA10/Rapa1]: 475 ± 233 pg/mg/creatinine) as compared with controls (165 ± 78 pg/mg creatinine). Rapa concentration in blood and tissues increased in the combined treatment (blood: 31 ± 8 ng/ml, tissue: 1.3 ± 0.4 ng/mg) as compared with monotherapy (blood: 14 ± 8 ng/ml, tissue: 0.35 ± 0.15 ng/mg). Drug blood concentrations correlated with isoprostane urine concentrations, which correlated negatively with citrate, α-ketoglutarate and creatinine concentrations in urine. Only CsA25/Rapa1 significantly reduced high-energy metabolite concentrations in transplant kidney tissue (ATP –55%, ADP –24%). Conclusion: Immunosuppressant drugs induce changes in urine metabolite patterns, suggesting that immunosuppressant-induced oxidative stress is an early event in the development of nephrotoxicity. Urine 15-F_2t-isoprostane concentrations and metabolite profiles may be sensitive markers of immunosuppressant-induced nephrotoxicity.

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“…The application of metabolomics for the detection of compounds causing hepatotoxicity during preclinical studies has been widely documented (Holmes et al 1992;Robertson et al 2000;Nicholson et al 2002;MortishireSmith et al 2004;Schnackenberg et al 2006Schnackenberg et al , 2007Schnackenberg 2007;Shi et al 2007;Sun et al 2009;Beger et al 2010). It has also been shown that combining metabolomics with transciptomics (Heijne et al 2005;Ferrara et al 2008) or proteomics or by combining metabolomics and proteomics data with metabolic flux measurements ) can provide greater insights into toxicity mechanisms.…”

Section: Introductionmentioning

confidence: 98%

Metabolomic profiling of biomarkers of liver X receptor-induced toxicity in mouse liver tissue

MacIntyre

Zheng

Scullion³

et al. 2010

Metabolomics

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Methods based on matrix-assisted laser desorption/ionisation mass spectrometry (MALDI-MS), liquid chromatography coupled to an LTQ-Orbitrap mass spectrometer (LC-MS) and gas chromatography-mass spectrometry (GC-MS) were used to investigate changes in the small molecule proﬁles of mouse liver in response to administration of an LXR agonist. Mice were treated with either 0.3 mg/kg, 1 mg/kg, 10 mg/kg, 30 mg/kg or 60 mg/kg of an LXR test compound or saline (control) once daily, over a 5 day period, to investigate the effects of the drug on metabolism in the liver. It was possible to detect triacylglycerol accumulation in the livers of animals treated with the drug, even at the lowest concentrations using, in the ﬁrst instance, MALDI MS. There was also an increase in the relative degree of triacylglycerol saturation in the drugtreated samples. Changes in the proﬁles of phosphatidylcholine lipids were also observed. The changes in lipid proﬁles were also conﬁrmed by LC-MS and GC-MS, the latter revealing a large increase in the level of the free fatty acid oleic acid (C18:1) in the treated samples. All of the changes were dose-related. Polar metabolites in the samples were analysed by hydrophilic interaction (HILIC) chromatography in combination with an LTQ-Orbitrap mass spectrometer. There were many changes in the metabolite proﬁles, some of which might simply be related to generalised toxicity. The clearest marker compounds, which showed very marked changes with dose, were methylglutaryl carnitine (MGC) and hydroxymethylglutaryl carnitine (HMGC). Another marker of some interest was uridine diphosphate N-acetylglucosamine (UNGA)

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Metabonomics evaluations of age-related changes in the urinary compositions of male Sprague Dawley rats and effects of data normalization methods on statistical and quantitative analysis

Cited by 49 publications

References 38 publications

Impact of Exercise and Aging on Rat Urine and Blood Metabolome. An LC-MS Based Metabolomics Longitudinal Study

Impact of Exercise and Aging on Rat Urine and Blood Metabolome. An LC-MS Based Metabolomics Longitudinal Study

Metabolic Profiles in Urine Reflect Nephrotoxicity of Sirolimus and Cyclosporine following Rat Kidney Transplantation

Metabolomic profiling of biomarkers of liver X receptor-induced toxicity in mouse liver tissue

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