Self-organizing map analysis of toxicity-related cell signaling pathways for metal and metal oxide nanoparticles.
The response of a murine macrophage cell line exposed to a library of seven metal and metal oxide nanoparticles was evaluated via High Throughput Screening (HTS) assay employing luciferase-reporters for ten independent toxicity-related signaling pathways. Similarities of toxicity response among the nanoparticles were identified via Self-Organizing Map (SOM) analysis. This analysis, applied to the HTS data, quantified the significance of the signaling pathway responses (SPRs) of the cell population exposed to nanomaterials relative to a population of untreated cells, using the Strictly Standardized Mean Difference (SSMD). Given the high dimensionality of the data and relatively small data set, the validity of the SOM clusters was established via a consensus clustering technique. Analysis of the SPR signatures revealed two cluster groups corresponding to (i) sublethal pro-inflammatory responses to Al2O3, Au, Ag, SiO2 nanoparticles possibly related to ROS generation, and (ii) lethal genotoxic responses due to exposure to ZnO and Pt nanoparticles at a concentration range of 25-100 μg/mL at 12 h exposure. In addition to identifying and visualizing clusters and quantifying similarity measures, the SOM approach can aid in developing predictive quantitative-structure relations; however, this would require significantly larger data sets generated from combinatorial libraries of engineered nanoparticles.
Center for the Environmental Implications of Nanotechnology, California Nanosystems Institute, University of California, Los Angeles, CA 90095, USA.
Robert
R
Rallo
Bryan
B
France
Rong
R
Liu
Sumitra
S
Nair
Saji
S
George
Robert
R
Damoiseaux
Francesc
F
Giralt
Andre
A
Nel
Kenneth
K
Bradley
Yoram
Y
Cohen
D000818:Animals; D002460:Cell Line; D008156:Luciferases / Q000187:drug effects / Q000378:metabolism; D008264:Macrophages; D053768:Metal Nanoparticles / Q000737:chemistry / Q000633:toxicity*; D051379:Mice; D049329:Nanostructures; D010087:Oxides / Q000737:chemistry / Q000633:toxicity; D015398:Signal Transduction / Q000187:drug effects*
D010087:Oxides; D008156:Luciferases
Nat Rev Cancer. 2002 Oct;2(10):764-76
12360279
Curr Med Chem. 2004 May;11(9):1163-82
15134513
Toxicol Lett. 2009 Jan 10;184(1):18-25
19022359
J Biol Chem. 1995 Sep 22;270(38):22129-34
7673190
ACS Nano. 2008 Oct 28;2(10):2121-34
19206459
J Orthop Res. 2006 Jan;24(1):46-54
16419968
Eur J Biochem. 1991 Oct 1;201(1):99-106
1915380
Proc Natl Acad Sci U S A. 1999 Mar 16;96(6):2907-12
10077610
PLoS One. 2010 May 07;5(5):e10522
20479887
J Toxicol Environ Health B Crit Rev. 2006 Jan-Feb;9(1):27-39
16393868
Toxicol Lett. 2009 Mar 28;185(3):211-8
19382294
Clin Immunol Immunopathol. 1987 Aug;44(2):167-86
2440631
Genomics. 2007 Apr;89(4):552-61
17276655
Nanomedicine (Lond). 2010 Jan;5(1):51-64
20025464
ACS Nano. 2010 Oct 26;4(10):5703-12
20857979
Biochem Biophys Res Commun. 2003 May 9;304(3):445-54
12729578
Drug Discov Today. 2006 Aug;11(15-16):694-9
16846796
Syst Biol. 2002 Jun;51(3):492-508
12079646
Proc Natl Acad Sci U S A. 2008 May 27;105(21):7387-92
18492802
Oncogene. 2008 Oct 27;27(50):6462-72
18955973
Annu Rev Public Health. 2009;30:137-50
19705557
Int J Cell Biol. 2010;2010:214074
20182529
ACS Nano. 2010 Jan 26;4(1):15-29
20043640
Environ Sci Technol. 2010 Oct 1;44(19):7309-14
20536146
J Toxicol Environ Health A. 2006 Jul;69(13):1261-84
16754540
Nat Methods. 2009 Aug;6(8):569-75
19644458
Nat Nanotechnol. 2009 Oct;4(10):634-41
19809453
J Toxicol Environ Health B Crit Rev. 2010 Feb;13(2-4):51-138
20574894
Annu Rev Biochem. 2004;73:39-85
15189136
Adv Drug Deliv Rev. 2009 Jun 21;61(6):438-56
19383522