title: Differential Genomic Effects on Signaling Pathways by Two Different CeO2 Nanoparticles in HepG2 Cells.
abstract: To investigate genomic effects, human liver hepatocellular carcinoma (HepG2) cells were exposed for three days to two different forms of nanoparticles both composed of CeO2 (0.3, 3 and 30 μg/mL). The two CeO2 nanoparticles had dry primary particle sizes of 8 nanometers {(M) made by NanoAmor} and 58 nanometers {(L) made by Alfa Aesar} and differ in various other physical-chemical properties as well. The smaller particle has stronger antioxidant properties, probably because it has higher Ce3+ levels on the particle surface, as well as more surface area per unit weight. Nanoparticle M showed a normal dose-response pattern with 363, 633 and 1273 differentially expressed genes (DEGs) at 0.3, 3 and 30 μg/mL, respectively. In contrast, nanoparticle L showed a puzzling dose-response pattern with the most DEGs found in the lowest exposure group with 1049, 303 and 323 DEGs at 0.3, 3 and 30 μg/mL, respectively. This systems biological genomic study showed that the major altered pathways by these two nano cerium oxides were protein synthesis, stress response, proliferation/cell cycle, cytoskeleton remodeling/actin polymerization and cellular metabolism. Some of the canonical pathways affected were mTOR signaling, EIF2 signaling, fatty acid activation, G2/M DNA damage checkpoint regulation, glycolysis and protein ubiquitination. These two CeO2 nanoparticles differed considerably in their genomic effects. M is more active than L in respect to altering the pathways of mitochondrial dysfunction, acute phase response, apoptosis, 14-3-3 mediated signaling, remodeling of epithelial adherens junction signaling, actin nucleation by ARP-WASP complex, altered TCA cycle and elevated fatty acid concentrations by metabolomics. However, L is more active than M in respect to the pathways of NRF2-mediated stress response and hepatic fibrosis/hepatic stellate cell activation. One major difference in the cell response to nano M and L is that nano M caused the Warburg effect while nano L did not.
authors.forename: Sheau-Fung
authors.initials: SF
authors.lastname: Thai
authors.forename: Kathleen A
authors.initials: KA
authors.lastname: Wallace
authors.forename: Carlton P
authors.initials: CP
authors.lastname: Jones
authors.forename: Hongzu
authors.initials: H
authors.lastname: Ren
authors.forename: Benjamin T
authors.initials: BT
authors.lastname: Castellon
authors.forename: James
authors.initials: J
authors.lastname: Crooks
authors.forename: Eric A
authors.initials: EA
authors.lastname: Grulke
authors.forename: Kirk T
authors.initials: KT
authors.lastname: Kitchin
mesh_terms: D002563:Cerium / Q000737:chemistry*; D056945:Hep G2 Cells; D006801:Humans; D053758:Nanoparticles / Q000737:chemistry*; D010316:Particle Size; D015398:Signal Transduction / Q000187:drug effects*
chemical_list: D002563:Cerium; C030583:ceric oxide