Dataset Information

Metabolome analysis via an HPLC-ESI-MS-based experimental and computational pipeline for chronic nephron toxicity profiling

ABSTRACT: Untargeted metabolomics has the potential to improve the predictivity of in vitro toxicity models and therefore may aid the reduction of expensive and laborious animal models. Here we describe a chronic nephrotoxicity study conducted on a human renal proximal tubular epithelial cell line (RPTEC/TERT1) treated with low (10 µM) and high (35 µM) concentrations of chloroacetaldehyde (CAA) – a known nephrotoxic compound. The presented toxicity study followed two major strategies; the first was to establish an automated and easy to use untargeted metabolomics workflow for HPLC-MS data and second to find time- and dose dependent toxicant-induced cell responses at the metabolite level. The metabolomic changes were integrated with transcriptomics and proteomics data to obtain a more comprehensive picture of the mode of action. Automated data analysis workflows based on open-source software (OpenMS and KNIME) enable a comprehensive and reproducible analysis of the complex and voluminous metabolomics data produced by the profiling approach. For toxicity profiling of CAA, 428 and 317 metabolite features were detectable in positive and negative mode, respectively, after removal of chemical noise and unstable signals. Changes upon treatment were visually explored using principal component analysis and statistically significant differences identified using linear models (LIMMA). The analysis revealed toxic effects only for the high concentration treatment for day 3 and day 14. The most regulated metabolites were glutathione and metabolites related to the oxidative stress response of the cells. These findings are corroborated by proteomics and transcriptomics data, which show, amongst others, an activation of the Nrf2 pathway.

INSTRUMENT(S): Exactive (Thermo Scientific)

SUBMITTER: Marc Rurik

PROVIDER: MTBLS140 | MetaboLights | 2015-09-07

REPOSITORIES: MetaboLights

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Publications

Nephron Toxicity Profiling via Untargeted Metabolome Analysis Employing a High Performance Liquid Chromatography-Mass Spectrometry-based Experimental and Computational Pipeline.

Ranninger Christina C Rurik Marc M Limonciel Alice A Ruzek Silke S Reischl Roland R Wilmes Anja A Jennings Paul P Hewitt Philip P Dekant Wolfgang W Kohlbacher Oliver O Huber Christian G CG

The Journal of biological chemistry 20150608 31

Untargeted metabolomics has the potential to improve the predictivity of in vitro toxicity models and therefore may aid the replacement of expensive and laborious animal models. Here we describe a long term repeat dose nephrotoxicity study conducted on the human renal proximal tubular epithelial cell line, RPTEC/TERT1, treated with 10 and 35 μmol·liter(-1) of chloroacetaldehyde, a metabolite of the anti-cancer drug ifosfamide. Our study outlines the establishment of an automated and easy to use ...[more]

PMID: 26055719

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Project description:The main constituents of electronic cigarette liquids are nicotine, propylene glycol (PG), and vegetable glycerin (VG), together with distilled water and flavors. To assess the toxicity of PG/VG mixtures with and without nicotine as basic components of liquids used in e-cigarettes, a 90-day rat inhalation study according to the Organization for Economic Co-operation and Development test guideline 413 was conducted. Sprague-Dawley (SD) rats were nose-only exposed, 6?h/day, 5 days/week to filtered air, or nebulized vehicle (saline), or three concentrations of PG/VG (0.174 mg PG/l + 0.210 mg VG/l; 0.520 mg PG/l + 0.630 mg VG/l; 1.520 mg PG/l + 1.890 mg VG/l) ï¿½ with (test item) and without (reference item) 23 ï¿½g nicotine/L. Standard toxicological endpoints were complemented by molecular analyses using transcriptomics, proteomics, and lipidomics. Compared to vehicle exposure, the tested PG/VG aerosols showed only very limited biological effects with no signs of toxicity, both for the standard toxicological endpoints (e.g., histopathology, clinical chemistry) and the systems toxicological analyses (transcriptomics, proteomics, and lipidomics). The addition of nicotine to the PG/VG aerosols (23 ï¿½g/l) resulted in effects in line with nicotine effects in previous studies. These included up-regulation of xenobiotic enzymes (Cyp1a1 and Fmo3) in the lung and metabolic effects, e.g., reduction in serum lipid concentrations and changes in the expression of metabolic enzymes in the liver. Signs of a generalized stress response to nicotine exposure such as decreased thymus weights were observed; and likely, a subset of the observed metabolic alterations was interlinked with this generalized stress response. Under the conditions of this 90-day SD rat inhalation study, no toxicologically relevant effects of PG/VG aerosols (up to 1.520 mg PG/l + 1.890 mg VG/l) were observed, and the no observed adverse effect level (NOAEL) for PG/VG/nicotine was determined to be 438/544/6.7 mg/kg/day. Further the study demonstrated how complementary systems toxicology analyses can reveal, also in the absence of observable adverse effects, subtoxic and adaptive responses to pharmacologically active compounds such as nicotine.

Dataset Information

Metabolome analysis via an HPLC-ESI-MS-based experimental and computational pipeline for chronic nephron toxicity profiling

Publications

Nephron Toxicity Profiling via Untargeted Metabolome Analysis Employing a High Performance Liquid Chromatography-Mass Spectrometry-based Experimental and Computational Pipeline.

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