PubMed

Related Articles Anti-CTLA-4 immunotherapy: uncoupling toxicity and efficacy. Cell Res. 2018 Mar 28;: Authors: Pol J, Kroemer G PMID: 29593340 [PubMed - as supplied by publisher]

Related Articles Nonhuman primate breath volatile organic compounds associate with developmental programming and cardio-metabolic status. J Breath Res. 2018 Mar 29;: Authors: Bishop AC, Libardoni M, Choudary A, Misra BB, Lange K, Bernal J, Nijland M, Li C, Olivier M, Nathanielsz PW, Cox LA Abstract Rodent and nonhuman primate (NHP) studies indicate that developmental programming by reduced perinatal nutrition negatively impacts life course cardio-metabolic health. We have developed a baboon model in which we feed control mothers (CON) ad libitum while nutrient restricted mothers are fed 70% of ad libitum global feed in pregnancy and lactation. Offspring of nutrient restricted mothers are intrauterine growth restricted (IUGR) at term. By 3.5 years IUGR baboons showed signs of insulin resistance, indicating a pre-diabetic phenotype, in contrast to healthy CON offspring. We hypothesized that a novel breath analysis approach would provide markers of the altered cardio-metabolic state in a non-invasive manner. Here we assess whether exhaled breath volatile organic compounds (VOCs) collected from this unique cohort of juvenile baboons with documented cardio-metabolic dysfunction resulting from in utero programming can be detected from their breath signatures. Breath was collected from male and female CON and IUGR baboons at 4.8±0.2 years (human equivalent ~13 years). Breath VOCs were quantified using a two-dimensional gas chromatography mass spectrometer (2D GC-MS). Two-way ANOVA, on 76 biologically relevant VOCs identified 27 VOCs (p<0.05) with altered abundances between groups (sex, birthweight, and sex x birthweight). The 27 VOCs included 2-pentanone, 2-octanone, 2,5,5 trimethyl-1-hexene and 2,2-dimethyl-undecane, which have not previously been associated with cardio-metabolic disease. Unsupervised principal component analysis of these VOCs could discriminate the four defined clusters defining males, females, CON and IUGR. This study, which is the first to assess quantifiable breath signatures associated with cardio-metabolic programing for any model of IUGR, demonstrates the translational value of this unique model to identify metabolites of programmed cardio-metabolic dysfunction in breath signatures. Future studies are required to validate the translatability of these findings to humans. PMID: 29593130 [PubMed - as supplied by publisher]

Related Articles Genetic defects in SAPK signalling, chromatin regulation, vesicle transport and CoA-related lipid metabolism are rescued by rapamycin in fission yeast. Open Biol. 2018 Mar;8(3): Authors: Sajiki K, Tahara Y, Villar-Briones A, Pluskal T, Teruya T, Mori A, Hatanaka M, Ebe M, Nakamura T, Aoki K, Nakaseko Y, Yanagida M Abstract Rapamycin inhibits TOR (target of rapamycin) kinase, and is being used clinically to treat various diseases ranging from cancers to fibrodysplasia ossificans progressiva. To understand rapamycin mechanisms of action more comprehensively, 1014 temperature-sensitive (ts) fission yeast (Schizosaccharomyces pombe) mutants were screened in order to isolate strains in which the ts phenotype was rescued by rapamycin. Rapamycin-rescued 45 strains, among which 12 genes responsible for temperature sensitivity were identified. These genes are involved in stress-activated protein kinase (SAPK) signalling, chromatin regulation, vesicle transport, and CoA- and mevalonate-related lipid metabolism. Subsequent metabolome analyses revealed that rapamycin upregulated stress-responsive metabolites, while it downregulated purine biosynthesis intermediates and nucleotide derivatives. Rapamycin alleviated abnormalities in cell growth and cell division caused by sty1 mutants (Δsty1) of SAPK. Notably, in Δsty1, rapamycin reduced greater than 75% of overproduced metabolites (greater than 2× WT), like purine biosynthesis intermediates and nucleotide derivatives, to WT levels. This suggests that these compounds may be the points at which the SAPK/TOR balance regulates continuous cell proliferation. Rapamycin might be therapeutically useful for specific defects of these gene functions. PMID: 29593117 [PubMed - in process]

Related Articles Dilated Cardiomyopathy and Premature Ovarian Failure Unveiling Propionic Aciduria. Clin Chem. 2018 Apr;64(4):752-754 Authors: Grotto S, Sudrié-Arnaud B, Drouin-Garraud V, Nafeh-Bizet C, Chadefaux-Vekemans B, Gobin S, Bekri S, Tebani A PMID: 29592908 [PubMed - in process]

Related Articles Serum apolipoprotein A2 isoforms in autoimmune pancreatitis. Biochem Biophys Res Commun. 2018 03 11;497(3):903-907 Authors: Kobayashi T, Sato Y, Nishiumi S, Yagi Y, Sakai A, Shiomi H, Masuda A, Okaya S, Kutsumi H, Yoshida M, Honda K Abstract Recently, apolipoprotein A2 (apoA2) isoforms have been reported as candidate serum/plasma biomarkers of pancreatic cancer. However, the distribution of apoA2 isoforms in patients with autoimmune pancreatitis (AIP) has not been investigated yet. In this study, we evaluated the distribution of serum apoA2 isoforms; i.e., homodimer apoA2-ATQ/ATQ, heterodimer apoA2-ATQ/AT, and homodimer apoA2-AT/AT, in AIP patients and healthy volunteers (HV) using enzyme-linked immunosorbent assays, and the clinical characteristics and serum levels of each apoA2 isoform in 32 AIP patients and 38 HV were investigated. The calculated apoA2-ATQ/AT levels of the AIP patients were significantly lower than those of the HV, which agreed with results obtained for patients with pancreatic cancer. Interestingly, most of the AIP patients exhibited high levels of apoA2-ATQ along with low levels of apoA2-AT, indicating that the processing of the C-terminal regions of apoA2 dimer was inhibited in the AIP patients. This specific distribution of serum apoA2 isoforms might provide important information about the disease states of AIP patients and aid the differential diagnosis of AIP versus pancreatic cancer. PMID: 29481802 [PubMed - indexed for MEDLINE]

Related Articles Genome-wide methylome and chromatin interactome identify abnormal enhancer to be risk factor of breast cancer. Oncotarget. 2017 Jul 04;8(27):44705-44719 Authors: Wang Y, Hao DP, Li JJ, Wang L, Di LJ Abstract Enhancer is critical cis regulatory elements in gene expression. To understand whether and how the aberrant enhancer activation may contribute to cancer risk, the differentially methylated enhancers (eDMRs) in normal and malignant breast tissues were identified and analyzed. By incorporating genome-wide chromatin interaction, integrated analysis of eDMRs and target gene expression identified 1,272 enhancer-promoter pairs. Surprisingly, two functionally distinct groups of genes were identified in these pairs, one showing better correlation to enhancer methylation (eRGs) and the other showing better correlation to promoter methylation (pRGs), and the former group is functionally enriched with cancer related genes. Moreover, enhancer methylation based clustering of breast cancer samples is capable of discriminating basal breast cancer from other subtypes. By correlating enhancer methylation status to patient survival, 345 enhancers show the impact on the disease outcome and the majority of their target genes are important regulators of cell survival pathways including known cancer related genes. Together, these results suggest reactivation of enhancers in cancer cells has the add-on effect and contributes to cancer risk in combination. PMID: 28621677 [PubMed - indexed for MEDLINE]

Related Articles BioContainers: an open-source and community-driven framework for software standardization. Bioinformatics. 2017 Aug 15;33(16):2580-2582 Authors: da Veiga Leprevost F, Grüning BA, Alves Aflitos S, Röst HL, Uszkoreit J, Barsnes H, Vaudel M, Moreno P, Gatto L, Weber J, Bai M, Jimenez RC, Sachsenberg T, Pfeuffer J, Vera Alvarez R, Griss J, Nesvizhskii AI, Perez-Riverol Y Abstract Motivation: BioContainers (biocontainers.pro) is an open-source and community-driven framework which provides platform independent executable environments for bioinformatics software. BioContainers allows labs of all sizes to easily install bioinformatics software, maintain multiple versions of the same software and combine tools into powerful analysis pipelines. BioContainers is based on popular open-source projects Docker and rkt frameworks, that allow software to be installed and executed under an isolated and controlled environment. Also, it provides infrastructure and basic guidelines to create, manage and distribute bioinformatics containers with a special focus on omics technologies. These containers can be integrated into more comprehensive bioinformatics pipelines and different architectures (local desktop, cloud environments or HPC clusters). Availability and Implementation: The software is freely available at github.com/BioContainers/. Contact: yperez@ebi.ac.uk. PMID: 28379341 [PubMed - indexed for MEDLINE]

Serine Availability Influences Mitochondrial Dynamics and Function through Lipid Metabolism. Cell Rep. 2018 Mar 27;22(13):3507-3520 Authors: Gao X, Lee K, Reid MA, Sanderson SM, Qiu C, Li S, Liu J, Locasale JW Abstract Cell proliferation can be dependent on the non-essential amino acid serine, and dietary restriction of serine inhibits tumor growth, but the underlying mechanisms remain incompletely understood. Using a metabolomics approach, we found that serine deprivation most predominantly impacts cellular acylcarnitine levels, a signature of altered mitochondrial function. Fuel utilization from fatty acid, glucose, and glutamine is affected by serine deprivation, as are mitochondrial morphological dynamics leading to increased fragmentation. Interestingly, these changes can occur independently of nucleotide and redox metabolism, two known major functions of serine. A lipidomics analysis revealed an overall decrease in ceramide levels. Importantly, supplementation of the lipid component of bovine serum or C16:0-ceramide could partially restore defects in cell proliferation and mitochondrial fragmentation induced by serine deprivation. Together, these data define a role for serine in supporting mitochondrial function and cell proliferation through ceramide metabolism. PMID: 29590619 [PubMed - in process]

1H-NMR-based metabolomics approach reveals metabolic mechanism of (-)-5-hydroxy-equol against hepatocellular carcinoma cells in vitro. J Proteome Res. 2018 Mar 28;: Authors: Gao L, Wang KX, Zhang NN, Li JQ, Qin XM, Wang XL Abstract 1H-NMR-based metabolomics can rapidly detect metabolic shift under various stimulus, thus it facilitated the dissection of the therapeutic mechanisms of compounds. (-)-5-hydroxy-equol is an isoflavone metabolite that be obtained by microbial biotransformation. In the current work, the effect of (‒)-5-hydroxy-equol on hepatocellular carcinoma cells and its mechanism have been explored based on 1H-NMR-based metabolomics approach. Our results revealed that (-)-5-hydroxy-equol can significantly inhibit the proliferation, migration and invasion of SMMC-7721 cells, and inhibit the proliferation of HepG2 cells. Metabolomics revealed that 17 differential metabolites involving in amino acid metabolism and energy metabolism were significantly changed inside and outside of the cells after treatment of (-)-5-hydroxy-equol. Specifically, (-)-5-hydroxy-equol at concentration of 30 μM significantly decreased the concentrations of pyruvate, glutamate and glucose. As glycometabolism is a crucial feature of cancer-specific metabolism, we further verified enzymes and proteins that closely relevant to glycometabolism. Our results indicated that (-)-5-hydroxy-equol modulated glycolysis in HCC through inhibition of activities of hexokinase, phosphofructokinase and pyruvate kinase, and the expression of pyruvate kinase M2. This study revealed that metabolomic analysis integrating with further verifications at the biochemical level can facilitate understanding the anti-HCC mechanisms of (-)-5-hydroxy-equol. PMID: 29589762 [PubMed - as supplied by publisher]

Related Articles Influence of Nutritional Status on the Absorption of Polyphyllin I, an Anticancer Candidate from Paris polyphylla in Rats. Eur J Drug Metab Pharmacokinet. 2018 Mar 28;: Authors: Yu FL, Gong WL, Xu FJ, Wu JW, Shakya S, Zhu H Abstract BACKGROUND AND OBJECTIVES: Protein-calorie malnutrition (PCM) is one of the most suffered complications in cancer patients. Polyphyllin I (PPI), a saponin isolated from rhizome of Paris polyphylla, is a potential candidate in cancer therapy. In this study, the influence of nutritional status on the absorption of PPI in rats was explored after oral administration. METHODS: PCM rats, namely mal-nourished (MN) rats, were induced from well-nourished (WN) rats by caloric restriction protocol. Intestinal absorption of PPI in WN and MN rats was evaluated by pharmacokinetic and intestinal perfusion methods. The potential mechanisms between two groups were investigated on the basis of intestinal permeability, intestinal efflux and PPI's depletions in vivo. The intestinal permeability was analyzed by determining the concentration of paracellular marker transport in serum and the expression of junction proteins in intestine. The intestinal efflux was evaluated through comparing the protein level of P-glycoprotein (P-gp) in intestine, and the depletions of PPI and/or generation of its metabolites in liver and intestines were analyzed by liquid chromatography triple quadrupole mass spectrometry (LC-MS/MS) method. RESULTS: Compared to WN rats, the oral systemic exposure of PPI was significantly increased in MN rats, evidenced by significant enhancement of maximum plasma concentration (Cmax) and area under the plasma concentration-time curve (AUC0-60h) by more than 2.51- and 3.71-folds as well as terminal elimination half-life (t1/2) prolonged from to 7.3 to 14.1 h. Further studies revealed that the potential mechanism might be associated with combined contribution of improved intestinal absorption and depressed deglycosylation of PPI in MN rats. Furthermore, enhanced intestinal absorption of PPI was benefited from increased intestinal permeability and decreased intestinal efflux in MN rats. Meanwhile, the former manifested as increased transport of paracellular marker and decreased junction proteins levels, while the later evidenced by reduced P-gp expression. CONCLUSIONS: The oral exposure of PPI was enhanced in MN rats, which suggested that nutritional status alters the absorption of PPI, and thus the dosage of PPI should be modified during the treatment of cancer patient with PCM. PMID: 29589340 [PubMed - as supplied by publisher]

Related Articles Colorectal Cancer Detection Using Targeted LC-MS Metabolic Profiling. Methods Mol Biol. 2018;1765:229-240 Authors: Djukovic D, Zhang J, Raftery D Abstract Colorectal cancer (CRC) is one of the most commonly diagnosed malignancies and causes of cancer death. While the mortality rates from CRC have steadily declined, 50,000 individuals in the USA (and many times this number worldwide) still succumb to this illness every year. Early detection of CRC is the most critical need for improving 5-year survival and cure rates. Currently available CRC diagnostic techniques often miss early stage disease such that only 40% of newly diagnosed CRC patients are treated for local disease, Therefore, development of new screening methods that are highly sensitive, specific, noninvasive and easily accessible are critically desired for the early diagnosis and significant reduction in death rate from CRC. In this chapter we describe a targeted LC-MS based metabolic profiling approach used for the discovery of CRC metabolite biomarker candidates, based on highly reproducible hydrophilic interaction liquid chromatography coupled to triple-quadrupole mass spectrometry (HILIC-LC-QQQ-MS). A partial least squares-discriminant analysis (PLS-DA) model was able to differentiate CRC patients from both healthy controls and polyp patients, as well as to distinguish CRC patients based on the cancer stage. PMID: 29589312 [PubMed - in process]

Related Articles Identifying and correcting epigenetics measurements for systematic sources of variation. Clin Epigenetics. 2018;10:38 Authors: Perrier F, Novoloaca A, Ambatipudi S, Baglietto L, Ghantous A, Perduca V, Barrdahl M, Harlid S, Ong KK, Cardona A, Polidoro S, Nøst TH, Overvad K, Omichessan H, Dollé M, Bamia C, Huerta JM, Vineis P, Herceg Z, Romieu I, Ferrari P Abstract Background: Methylation measures quantified by microarray techniques can be affected by systematic variation due to the technical processing of samples, which may compromise the accuracy of the measurement process and contribute to bias the estimate of the association under investigation. The quantification of the contribution of the systematic source of variation is challenging in datasets characterized by hundreds of thousands of features.In this study, we introduce a method previously developed for the analysis of metabolomics data to evaluate the performance of existing normalizing techniques to correct for unwanted variation. Illumina Infinium HumanMethylation450K was used to acquire methylation levels in over 421,000 CpG sites for 902 study participants of a case-control study on breast cancer nested within the EPIC cohort. The principal component partial R-square (PC-PR2) analysis was used to identify and quantify the variability attributable to potential systematic sources of variation. Three correcting techniques, namely ComBat, surrogate variables analysis (SVA) and a linear regression model to compute residuals were applied. The impact of each correcting method on the association between smoking status and DNA methylation levels was evaluated, and results were compared with findings from a large meta-analysis. Results: A sizeable proportion of systematic variability due to variables expressing 'batch' and 'sample position' within 'chip' was identified, with values of the partial R2 statistics equal to 9.5 and 11.4% of total variation, respectively. After application of ComBat or the residuals' methods, the contribution was 1.3 and 0.2%, respectively. The SVA technique resulted in a reduced variability due to 'batch' (1.3%) and 'sample position' (0.6%), and in a diminished variability attributable to 'chip' within a batch (0.9%). After ComBat or the residuals' corrections, a larger number of significant sites (k = 600 and k = 427, respectively) were associated to smoking status than the SVA correction (k = 96). Conclusions: The three correction methods removed systematic variation in DNA methylation data, as assessed by the PC-PR2, which lent itself as a useful tool to explore variability in large dimension data. SVA produced more conservative findings than ComBat in the association between smoking and DNA methylation. PMID: 29588806 [PubMed - in process]

Related Articles Approaches in studying the pharmacology of Chinese Medicine formulas: bottom-up, top-down-and meeting in the middle. Chin Med. 2018;13:15 Authors: Huang T, Zhong LLD, Lin CY, Zhao L, Ning ZW, Hu DD, Zhang M, Tian K, Cheng CW, Bian ZX, for MZRW Research Group Abstract Investigating the pharmacology is key to the modernization of Chinese Medicine (CM) formulas. However, identifying which are the active compound(s) of CM formulas, which biological entities they target, and through which signaling pathway(s) they act to modify disease symptoms, are still difficult tasks for researchers, even when equipped with an arsenal of advanced modern technologies. Multiple approaches, including network pharmacology, pharmaco-genomics, -proteomics, and -metabolomics, have been developed to study the pharmacology of CM formulas. They fall into two general categories in terms of how they tackle a problem: bottom-up and top-down. In this article, we compared these two different approaches in several dimensions by using the case of MaZiRenWan (MZRW, also known as Hemp Seed Pill), a CM herbal formula for functional constipation. Multiple hypotheses are easy to be proposed in the bottom-up approach (e.g. network pharmacology); but these hypotheses are usually false positives and hard to be tested. In contrast, it is hard to suggest hypotheses in the top-down approach (e.g. pharmacometabolomics); however, once a hypothesis is proposed, it is much easier to be tested. Merging of these two approaches could results in a powerful approach, which could be the new paradigm for the pharmacological study of CM formulas. PMID: 29588653 [PubMed]

Related Articles Metabolomics and biomarker discovery in Traumatic Brain Injury. J Neurotrauma. 2018 Mar 27;: Authors: Banoei MM, Casault C, Metwaly SM, Winston BW Abstract Traumatic brain injury (TBI) is one of the leading cause of disability and mortality worldwide. The TBI pathogenesis can induce broad pathophysiological consequences and clinical outcomes due to the brain complexity. Thus, the diagnosis and prognosis of outcome are important issues for the management of mild, moderate and severe forms of TBI. Metabolomics of readily accessible biofluids is a promising tool for establishing more useful and reliable biomarkers of TBI than using clinical findings alone. Metabolites are an integral part of all biochemical and pathophysiological pathways. Metabolomic processes respond to the internal and external stimuli resulting in an alteration of metabolite concentrations. Current high throughput and highly sensitive analytical tools are capable of detecting and quantifying the small concentrations of metabolites allowing us to measure metabolite alterations following a pathological event when compared to a normal state or a different pathological process. Further, these metabolites biomarkers could be used for the assessment of injury severity as well as discovering of mechanisms of injury and defining structural damage in brain in TBI. Metabolite biomarkers can also be used for the prediction of outcome, monitoring treatment response, in the assessment of or prognosis of post-injury recovery and potentially in the use of neuroplasticity procedures. Metabolomics can also enhance our understanding of the pathophysiological mechanisms of TBI, both in primary and secondary injury. Thus, this review presents the promising application of metabolomics for the assessment of TBI as a stand alone platform or in association with proteomics in the clinical setting. PMID: 29587568 [PubMed - as supplied by publisher]

Related Articles Bile Acids as Potential Biomarkers to Assess Liver Impairment in Polycystic Kidney Disease. Int J Toxicol. 2018 Mar/Apr;37(2):144-154 Authors: Brock WJ, Beaudoin JJ, Slizgi JR, Su M, Jia W, Roth SE, Brouwer KLR Abstract Polycystic kidney disease is characterized by the progressive development of kidney cysts and declining renal function with frequent development of cysts in other organs including the liver. The polycystic kidney (PCK) rat is a rodent model of polycystic liver disease that has been used to study hepatorenal disease progression and evaluate pharmacotherapeutic interventions. Biomarkers that describe the cyst progression, liver impairment, and/or hepatic cyst burden could provide clinical utility for this disease. In the present study, hepatic cyst volume was measured by magnetic resonance imaging in PCK rats at 12, 16, and 20 weeks. After 20 weeks, Sprague Dawley (n = 4) and PCK (n = 4) rats were sacrificed and 42 bile acids were analyzed in the liver, bile, serum, and urine by liquid chromatography coupled to tandem mass spectrometry. Bile acid profiling revealed significant increases in total bile acids (molar sum of all measured bile acids) in the liver (13-fold), serum (6-fold), and urine (3-fold) in PCK rats, including those speciated bile acids usually associated with hepatotoxicity. Total serum bile acids correlated with markers of liver impairment (liver weight, total liver bile acids, total hepatotoxic liver bile acids, and cyst volume [ r > 0.75; P < 0.05]). Based on these data, serum bile acids may be useful biomarkers of liver impairment in polycystic hepatorenal disease. PMID: 29587557 [PubMed - in process]

Related Articles Surface fitting for calculating the second dimension retention index in comprehensive two-dimensional gas chromatography mass spectrometry. J Chromatogr A. 2018 Mar 02;1539:62-70 Authors: Prodhan MAI, Yin X, Kim S, McClain C, Zhang X Abstract Comprehensive two-dimensional gas chromatography mass spectrometry (GC × GC-MS) has been widely used for analysis of volatile compounds. However, the second dimension retention index (I) of each compound is not widely used to aid compound identification owing to the limited accuracy of I calculation. We report a surface fitting approach to the calculation of I using n-alkanes (C7-C30) as references, where the second dimension retention time (2tR) and the second dimension column temperature (2Te) formed the X-Y plane and the I was the Z-axis to form the I surface. Compared to the conventional approach for calculating I using isovolatility curves, the surface fitting approach eliminated the construction of isovolatility curves for the reference compounds and gives better reproducibility. The goodness of the proposed surface fitting achieved R2 = 0.9999 and RMSE = 6.1 retention index units (iu). Ten-fold cross validation demonstrated the surface fitting approach had a good predictability with average R2 = 0.9999 and RMSE = 6.6 iu. The developed method was also applied to calculate the second dimension retention indices of compound standards in two commercial mixtures MegaMix A and MegaMix B. The mean standard deviation of the calculated I was only 1.6 iu for compounds in MegaMix A and 3.4 iu for compounds in MegaMix B. Compared with the literature results, the small value of standard deviation in the calculated retention index using surface fitting method shows that the surface fitting method has less measurement variability than the conventional isovolatility curve approach. PMID: 29395161 [PubMed - indexed for MEDLINE]

19 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results: metabolomics These pubmed results were generated on 2018/03/28PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

34 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results: metabolomics These pubmed results were generated on 2018/03/27PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

34 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results: metabolomics These pubmed results were generated on 2018/03/27PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

Metabolomic analysis of short-term sulfamethazine exposure on marine medaka (Oryzias melastigma) by comprehensive two-dimensional gas chromatography-time-of-flight mass spectrometry. Aquat Toxicol. 2018 Mar 08;198:269-275 Authors: Liu Y, Wang X, Li Y, Chen X Abstract Toxicological effects of sulfamethazine (SM2) have garnered increasing concern due to its wide applications in aquaculture and persistence in the aquatic environment. Most studies have main focused on freshwater fish (i.e. zebrafish), while information regarding effects of SM2 on marine species is still scarce. Here, the hepatotoxicities in marine medaka (Oryzias melastigma) with an increasing SM2 concentration exposures (0.01 mg/L, 0.1 mg/L and 1 mg/L) were assessed by comprehensive two-dimensional gas chromatography-time-of-flight mass spectrometry (GC × GC-TOF/MS) based metabolomics. Significant metabolites belonging to different metabolites classes were identified by multivariate statistical analysis. The increases levels of amino acids including alanine, asparagine, ornithine, proline, threonine, glutamic acid, lysine, tyrosine and phenylalanine were found in at least two exposure levels. Pathway analysis revealed that amino acids played important biological roles during SM2 exposure: up-regulation of high energy-related amino acids for energy alteration; immune function disorder, oxidative stress and corresponding toxicities defenses. The down regulations of sugar and fatty acid metabolism were observed with an increasing level of SM2 exposure, suggesting that extra energy for cellular defense and detoxification was demanded in terms of different stress request. This study provided an innovative perspective to explore possible SM2 induced hepatic damages at three exposure levels on a nontarget aquatic specie. PMID: 29573603 [PubMed - as supplied by publisher]