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Metabolomic effects of CeO2, SiO2 and CuO metal oxide nanomaterials on HepG2 cells
Kitchin, K., S. Stirdivant, B. Robinette, B. Castellon, AND X. Liang. Metabolomic effects of CeO2, SiO2 and CuO metal oxide nanomaterials on HepG2 cells. Particle and Fibre Toxicology. BioMed Central Ltd, London, Uk, 14(50):1-16, (2017).
Ingestion of nanomaterials could potentially result in liver toxicity following the systemic absorption of these materials. Information is lacking on the potential hepatotoxicity of nanomaterials. The objective of this study was to examine the metabolomic effects of selected metal oxide nanomaterials on human heptatic cells. Metabolomics is the scientific study of chemical cellular processes involving small molecule metabolites. Regulatory scientists in OPPT would be interested in this study as there is limited information on the toxicological effects of nanomaterials in the liver. The significance is that metal oxide nanomaterials can affect cellular chemical metabolites, particularly the concentratins of several lipid classes , S-adenosylmethionine, UDP-gluronide and others. These alterations in chemical metabolites may perturb higher level cellular processes leading to adverse outcomes.
To better assess potential hepatotoxicity of nanomaterials, human liver HepG2 cells were exposed for 3 days to five different CeO2 (either 30 or 100 μg/ml), 3 SiO2 based (30 μg/ml) or 1 CuO (3 μg/ml) nanomaterials with dry primary particle sizes ranging from 15 to 213 nm. Metabolomic assessment of exposed cells was then performed using four mass spectroscopy dependent platforms (LC and GC), finding 344 biochemicals. Results Four CeO2, 1 SiO2 and 1 CuO nanomaterials increased hepatocyte concentrations of many lipids, particularly free fatty acids and monoacylglycerols but only CuO elevated lysolipids and sphingolipids. In respect to structure-activity, we now know that five out of six tested CeO2, and both SiO2 and CuO, but zero out of four TiO2 nanomaterials have caused this elevated lipids effect in HepG2 cells. Observed decreases in UDP-glucuronate (by CeO2) and S-adenosylmethionine (by CeO2 and CuO) and increased S-adenosylhomocysteine (by CuO and some CeO2) suggest that a nanomaterial exposure increases transmethylation reactions and depletes hepatic methylation and glucuronidation capacity. Our metabolomics data suggests increased free radical attack on nucleotides. There was a clear pattern of nanomaterial-induced decreased nucleotide concentrations coupled with increased concentrations of nucleic acid degradation products. Purine and pyrimidine alterations included concentration increases for hypoxanthine, xanthine, allantoin, urate, inosine, adenosine 3′,5′-diphosphate, cytidine and thymidine while decreases were seen for uridine 5′-diphosphate, UDP-glucuronate, uridine 5′-monophosphate, adenosine 5′-diphosphate, adenosine 5′-monophophate, cytidine 5′-monophosphate and cytidine 3′-monophosphate. Observed depletions of both 6-phosphogluconate, NADPH and NADH (all by CeO2) suggest that the HepG2 cells may be deficient in reducing equivalents and thus in a state of oxidative stress.
Record Details:Record Type: DOCUMENT (JOURNAL/PEER REVIEWED JOURNAL)
Organization:U.S. ENVIRONMENTAL PROTECTION AGENCY
OFFICE OF RESEARCH AND DEVELOPMENT
NATIONAL HEALTH AND ENVIRONMENTAL EFFECTS RESEARCH LABORATORY
INTEGRATED SYSTEMS TOXICOLOGY DIVISION
GENETIC AND CELLULAR TOXICOLOGY BRANCH