title: Mechanisms of crystalline silica-induced pulmonary toxicity revealed by global gene expression profiling.
abstract: A proper understanding of the mechanisms underlying crystalline silica-induced pulmonary toxicity has implications in the management and potential prevention of the adverse health effects associated with silica exposure including silicosis, cancer and several auto-immune diseases. Human lung type II epithelial cells and rat lungs exposed to crystalline silica were employed as experimental models to determine global gene expression changes in order to understand the molecular mechanisms underlying silica-induced pulmonary toxicity. The differential gene expression profile induced by silica correlated with its toxicity in the A549 cells. The biological processes perturbed by silica exposure in the A549 cells and rat lungs, as identified by the bioinformatics analysis of the differentially expressed genes, demonstrated significant similarity. Functional categorization of the differentially expressed genes identified cancer, cellular movement, cellular growth and proliferation, cell death, inflammatory response, cell cycle, cellular development, and genetic disorder as top ranking biological functions perturbed by silica exposure in A549 cells and rat lungs. Results of our study, in addition to confirming several previously identified molecular targets and mechanisms involved in silica toxicity, identified novel molecular targets and mechanisms potentially involved in silica-induced pulmonary toxicity. Further investigations, including those focused on the novel molecular targets and mechanisms identified in the current study may result in better management and, possibly, reduction and/or prevention of the potential adverse health effects associated with crystalline silica exposure.
authors.affiliation: Toxicology and Molecular Biology Branch, National Institute for Occupational Safety and Health (NIOSH), Morgantown, WV 26505, USA.
authors.forename: Rajendran
authors.initials: R
authors.lastname: Sellamuthu
authors.forename: Christina
authors.initials: C
authors.lastname: Umbright
authors.forename: Shengqiao
authors.initials: S
authors.lastname: Li
authors.forename: Michael
authors.initials: M
authors.lastname: Kashon
authors.forename: Pius
authors.initials: P
authors.lastname: Joseph
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000187:drug effects*; D006801:Humans; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008168:Lung / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D046228:Microarray Analysis; D011791:Quartz / Q000633:toxicity*; D051381:Rats; D011916:Rats, Inbred F344; D060888:Real-Time Polymerase Chain Reaction
chemical_list: D011791:Quartz; D007770:L-Lactate Dehydrogenase
references.citation: Clin Chem. 1999 Jan;45(1):7-17
references.pmid: 9895331
references.citation: FASEB J. 2000 Jan;14(1):6-16
references.pmid: 10627275
references.citation: J Toxicol Environ Health A. 2006 Jul;69(13):1261-84
references.pmid: 16754540
references.citation: J Lipid Res. 2007 Mar;48(3):709-15
references.pmid: 17192422
references.citation: Proc Natl Acad Sci U S A. 2002 Jul 23;99(15):10054-9
references.pmid: 12114539
references.citation: Inhal Toxicol. 2002 Apr;14(4):349-67
references.pmid: 12028809
references.citation: Cell Biol Toxicol. 2004 Mar;20(2):97-108
references.pmid: 15242185
references.citation: Cell Tissue Res. 2004 Nov;318(2):325-33
references.pmid: 15459768
references.citation: Free Radic Biol Med. 2008 Apr 1;44(7):1246-58
references.pmid: 18226603
references.citation: Toxicol Sci. 2004 Oct;81(2):480-90
references.pmid: 15240896
references.citation: Int Immunopharmacol. 2002 Feb;2(2-3):303-13
references.pmid: 11811933
references.citation: J Cell Physiol. 1999 Aug;180(2):158-66
references.pmid: 10395285
references.citation: N Engl J Med. 1997 Apr 10;336(15):1066-71
references.pmid: 9091804
references.citation: Free Radic Biol Med. 2004 Oct 1;37(7):916-25
references.pmid: 15336307
references.citation: Toxicol Sci. 2011 Aug;122(2):253-64
references.pmid: 21602193
references.citation: Toxicol Sci. 2008 May;103(1):28-34
references.pmid: 18281259
references.citation: J Immunol. 2006 Dec 1;177(11):7497-504
references.pmid: 17114416
references.citation: FEBS J. 2008 Jun;275(11):2795-806
references.pmid: 18422650
references.citation: J Biol Chem. 2001 Mar 23;276(12):9108-14
references.pmid: 11096084
references.citation: Environ Health Perspect. 2004 Mar;112(4):465-79
references.pmid: 15033597
references.citation: Curr Colorectal Cancer Rep. 2008 Apr;4(2):59-64
references.pmid: 18504508
references.citation: Free Radic Biol Med. 2003 Jun 15;34(12):1507-16
references.pmid: 12788471
references.citation: Genome Biol. 2004;5(10):R80
references.pmid: 15461798
references.citation: J Toxicol Environ Health A. 1998 Sep 11;55(1):31-44
references.pmid: 9747602
references.citation: Mol Cell Biochem. 2002 May-Jun;234-235(1-2):177-84
references.pmid: 12162431
references.citation: J Biol Chem. 1999 Dec 10;274(50):35591-5
references.pmid: 10585435
references.citation: Int J Cancer. 2009 Oct 15;125(8):1859-67
references.pmid: 19588488
references.citation: Toxicol Sci. 2004 Jun;79(2):370-80
references.pmid: 15056817
references.citation: Mutat Res. 2004 May 18;549(1-2):241-53
references.pmid: 15120974
references.citation: Environ Health Perspect. 1994 Dec;102 Suppl 10:165-71
references.pmid: 7705292
references.citation: Toxicol Appl Pharmacol. 2001 Aug 15;175(1):28-42
references.pmid: 11509024
references.citation: Toxicol Pathol. 2002 Jul-Aug;30(4):470-82
references.pmid: 12187938
references.citation: Cell Death Differ. 2007 Mar;14(3):436-46
references.pmid: 16990849
references.citation: Environ Health Perspect. 1997 Feb;105 Suppl 1:165-77
references.pmid: 9114285
references.citation: J Biol Chem. 1997 May 23;272(21):13731-7
references.pmid: 9153226
references.citation: Environ Health Perspect. 1997 Sep;105 Suppl 5:1121-5
references.pmid: 9400710
references.citation: Toxicol In Vitro. 2008 Jun;22(4):844-53
references.pmid: 18282682
references.citation: Mol Cancer Res. 2009 Aug;7(8):1390-8
references.pmid: 19671674