title: Molecular responses of human lung epithelial cells to the toxicity of copper oxide nanoparticles inferred from whole genome expression analysis.
abstract: This study proposes a molecular mechanism for lung epithelial A549 cell response to copper oxide nanoparticles (CuO-NPs) related to Cu ions released from CuO-NPs. Cells that survived exposure to CuO-NPs arrested the cell cycle as a result of the downregulation of proliferating cell nuclear antigen (PCNA), cell division control 2 (CDC2), cyclin B1 (CCNB1), target protein for Xklp2 (TPX2), and aurora kinase A (AURKA) and B (AURKB). Furthermore, cell death was avoided through the induced expression of nuclear receptors NR4A1 and NR4A3 and growth arrest and DNA damage-inducible 45 β and γ (GADD45B and GADD45G, respectively). The downregulation of CDC2, CCNB1, TPX2, AURKA, and AURKB, the expressions of which are involved in cell cycle arrest, was attributed to Cu ions released from CuO-NPs into medium. NR4A1 and NR4A3 expression was also induced by Cu ions released into the medium. The expression of GADD45B and GADD45G activated the p38 pathway that was involved in escape from cell death. The upregulation of GADD45B and GADD45G was not observed with Cu ions released into medium but was observed in cells exposed to CuO-NPs. However, because the expression of the genes was also induced by Cu ion concentrations higher than that released from CuO-NPs into the medium, the expression appeared to be triggered by Cu ions released from CuO-NPs taken up into cells. We infer that, for cells exposed to CuO-NPs, those able to make such a molecular response survived and those unable to do so eventually died.
authors.affiliation: Nanotechnology Innovation Station, National Institute for Materials Science, 1-2-1 Sengen, Tsukuba, Ibaraki 305-0047, Japan. hanagata.nobutaka@nims.go.jp
authors.forename: Nobutaka
authors.initials: N
authors.lastname: Hanagata
authors.forename: Fei
authors.initials: F
authors.lastname: Zhuang
authors.forename: Sarah
authors.initials: S
authors.lastname: Connolly
authors.forename: Jie
authors.initials: J
authors.lastname: Li
authors.forename: Nobuhiro
authors.initials: N
authors.lastname: Ogawa
authors.forename: Mingsheng
authors.initials: M
authors.lastname: Xu
mesh_terms: D002460:Cell Line; D002874:Chromosome Mapping; D003300:Copper / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000187:drug effects*; D006801:Humans; D008168:Lung / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D008422:Materials Testing; D053758:Nanoparticles / Q000633:toxicity*; D020543:Proteome / Q000378:metabolism*
chemical_list: D020543:Proteome; D003300:Copper; C030973:cupric oxide