Document Detail


Metabolic response to low-level toxicant exposure in a novel renal tubule epithelial cell system.
MedLine Citation:
PMID:  21103459     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Toxicity testing is vital to protect human health from exposure to toxic chemicals in the environment. Furthermore, combining novel cellular models with molecular profiling technologies, such as metabolomics can add new insight into the molecular basis of toxicity and provide a rich source of biomarkers that are urgently required in a 21st Century approach to toxicology. We have used an NMR-based metabolic profiling approach to characterise for the first time the metabolome of the RPTEC/TERT1 cell line, an immortalised non-tumour human renal epithelial cell line that recapitulates phenotypic characteristics that are absent in other in vitro renal cell models. RPTEC/TERT1 cells were cultured with either the dosing vehicle (DMSO) or with exposure to one of six compounds (nifedipine, potassium bromate, monuron, D-mannitol, ochratoxin A and sodium diclofenac), several of which are known to cause renal effects. Aqueous intracellular and culture media metabolites were profiled by (1)H NMR spectroscopy at 6, 24 and 72 hours of exposure to a low effect dose (IC(10)). We defined the metabolome of the RPTEC/TERT1 cell line and used a principal component analysis approach to derive a panel of key metabolites, which were altered by chemical exposure. By considering only major changes (±1.5 fold change from control) across this metabolite panel we were able to show specific alterations to cellular processes associated with chemical treatment. Our findings suggest that metabolic profiling of RPTEC/TERT1 cells can report on the effect of chemical exposure on multiple cellular pathways at low-level exposure, producing different response profiles for the different compounds tested with a greater number of major metabolic effects observed in the toxin treated cells. Importantly, compounds with established links to chronic renal toxicity produced more diverse and severe perturbations to the cellular metabolome than non-toxic compounds in this model. As these changes can be rationalised with the different pharmacological and toxicity profiles of the chemicals it is suggested that metabolic profiling in the RPTEC/TERT1 model would be useful in investigating the mechanism of action of toxins at a low dose.
Authors:
James Keith Ellis; Toby James Athersuch; Rachel Cavill; Robert Radford; Craig Slattery; Paul Jennings; Tara McMorrow; Michael P Ryan; Timothy Mark David Ebbels; Hector Charles Keun
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2010-11-19
Journal Detail:
Title:  Molecular bioSystems     Volume:  7     ISSN:  1742-2051     ISO Abbreviation:  Mol Biosyst     Publication Date:  2011 Jan 
Date Detail:
Created Date:  2010-12-08     Completed Date:  2011-03-24     Revised Date:  2014-02-20    
Medline Journal Info:
Nlm Unique ID:  101251620     Medline TA:  Mol Biosyst     Country:  England    
Other Details:
Languages:  eng     Pagination:  247-57     Citation Subset:  IM    
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MeSH Terms
Descriptor/Qualifier:
Bromates / toxicity
Cell Line
Diclofenac / toxicity
Environmental Pollutants / toxicity*
Epithelial Cells / drug effects*,  metabolism*
Humans
Kidney Tubules / cytology*
Magnetic Resonance Spectroscopy
Mannitol / toxicity
Methylurea Compounds / toxicity
Microscopy, Fluorescence
Nifedipine / toxicity
Ochratoxins / toxicity
Principal Component Analysis
Toxicity Tests
Grant Support
ID/Acronym/Agency:
G0801056//Medical Research Council
Chemical
Reg. No./Substance:
0/Bromates; 0/Environmental Pollutants; 0/Methylurea Compounds; 0/Ochratoxins; 04MB35W6ZA/potassium bromate; 144O8QL0L1/Diclofenac; 1779SX6LUY/ochratoxin A; 3OWL53L36A/Mannitol; I99GAK5X1D/monuron; I9ZF7L6G2L/Nifedipine

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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