Metabolomic effects of CeO(2), SiO(2) and CuO metal oxide nanomaterials on HepG2 cells

BACKGROUND: To better assess potential hepatotoxicity of nanomaterials, human liver HepG2 cells were exposed for 3 days to five different CeO(2) (either 30 or 100 μg/ml), 3 SiO(2) 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 CeO(2), 1 SiO(2) 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 CeO(2), and both SiO(2) and CuO, but zero out of four TiO(2) nanomaterials have caused this elevated lipids effect in HepG2 cells. Observed decreases in UDP-glucuronate (by CeO(2)) and S-adenosylmethionine (by CeO(2) and CuO) and increased S-adenosylhomocysteine (by CuO and some CeO(2)) 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 CeO(2)) suggest that the HepG2 cells may be deficient in reducing equivalents and thus in a state of oxidative stress. CONCLUSIONS: Metal oxide nanomaterial exposure may compromise the methylation, glucuronidation and reduced glutathione conjugation systems; thus Phase II conjugational capacity of hepatocytes may be decreased. This metabolomics study of the effects of nine different nanomaterials has not only confirmed some observations of the prior 2014 study (lipid elevations caused by one CeO(2) nanomaterial) but also found some entirely new effects (both SiO(2) and CuO nanomaterials also increased the concentrations of several lipid classes, nanomaterial induced decreases in S-adenosylmethionine, UDP-glucuronate, dipeptides, 6-phosphogluconate, NADPH and NADH). ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1186/s12989-017-0230-4) contains supplementary material, which is available to authorized users.