Gene expression dose-response changes in microarrays after exposure of human peripheral lung epithelial cells to nickel(II).
Occupational exposure to nickel compounds is associated with lung cancer risk; both genotoxic and epigenetic mechanisms have been proposed. For comprehensive examination of the acute effects of nickel(II) acetate on gene expression in cultured human peripheral lung epithelial HPL1D cells, microarray analyses were carried out with cDNA chips (approximately 8000 cDNAs). Cells were exposed for 24 h to nontoxic (50, 100, and 200 microM) or toxic (400, 800, and 1600 microM) nickel(II) concentrations. Cluster analysis was applied to the 868 genes with > or = 2-fold change at any concentration. Two main clusters showed marked up- or down-regulation at the highest, toxic concentrations. The data further subdivided into 10 highly cohesive clusters with high probability, and of these only 2 had the same response trend at low nontoxic as at high concentrations, an observation of clear relevance to the process of high- to low-dose extrapolation in risk assessment. There were 113 genes showing > or = 2-fold change at the three lower nontoxic concentrations, those most relevant to in vivo carcinogenesis. In addition to expected responses of metallothionein, ferritin, and heat-shock proteins, the results revealed for the first time changed expression of some potential cancer-related genes in response to low-dose Ni(II): RhoA, dyskerin, interferon regulatory factor 1, RAD21 homologue, and tumor protein, translationally controlled. Overall, most of the genes impacted by nontoxic concentrations of nickel(II) acetate related to gene transcription, protein synthesis and stability, cytoskeleton, signaling, metabolism, cell membrane, and extracellular matrix.
Cheng
Robert Y S
RY
Laboratory of Comparative Carcinogenesis, National Cancer Institute at Frederick, Bldg. 538, Ft. Detrick, Frederick, MD 21702, USA. rcheng@ncifcrf.gov
Zhao
Ailian
A
Alvord
W Gregory
WG
Powell
Douglas A
DA
Bare
Robert M
RM
Masuda
Akira
A
Takahashi
Takashi
T
Anderson
Lucy M
LM
Kasprzak
Kazimierz S
KS
D000465:Algorithms; D016000:Cluster Analysis; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation / Q000187:drug effects; D004847:Epithelial Cells / Q000378:metabolism / Q000473:pathology*; D005109:Extracellular Matrix / Q000187:drug effects / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D008171:Lung Diseases / Q000139:chemically induced* / Q000378:metabolism / Q000473:pathology*; D008565:Membrane Proteins / Q000096:biosynthesis / Q000235:genetics; D016571:Neural Networks, Computer; D009532:Nickel / Q000633:toxicity*; D009687:Nuclear Proteins / Q000096:biosynthesis / Q000235:genetics; D020411:Oligonucleotide Array Sequence Analysis; D011485:Protein Binding / Q000235:genetics; D014176:Protein Biosynthesis; D011506:Proteins / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012269:Ribosomal Proteins / Q000187:drug effects / Q000235:genetics
D008565:Membrane Proteins; D009687:Nuclear Proteins; D011506:Proteins; D012269:Ribosomal Proteins; D009532:Nickel