Differential regulation of intracellular factors mediating cell

Páginas: 41 (10173 palabras) Publicado: 6 de septiembre de 2012
AshaRani et al. Genome Integrity 2012, 3:2 http://www.genomeintegrity.com/content/3/1/2

Open Access


Differential regulation of intracellular factors mediating cell cycle, DNA repair and inflammation following exposure to silver nanoparticles in human cells
PV AshaRani1,2, Swaminathan Sethu2, Hui Kheng Lim2, Ganapathy Balaji1, Suresh Valiyaveettil1* and MPrakash Hande2,3*

Background: Investigating the cellular and molecular signatures in eukaryotic cells following exposure to nanoparticles will further our understanding on the mechanisms mediating nanoparticle induced effects. This study illustrates the molecular effects of silver nanoparticles (Ag-np) in normal human lung cells, IMR-90 and human brain cancer cells, U251 withemphasis on gene expression, induction of inflammatory mediators and the interaction of Ag-np with cytosolic proteins. Results: We report that silver nanoparticles are capable of adsorbing cytosolic proteins on their surface that may influence the function of intracellular factors. Gene and protein expression profiles of Ag-np exposed cells revealed up regulation of many DNA damage response genessuch as Gadd 45 in both the cell types and ATR in cancer cells. Moreover, down regulation of genes necessary for cell cycle progression (cyclin B and cyclin E) and DNA damage response/repair (XRCC1 and 3, FEN1, RAD51C, RPA1) was observed in both the cell lines. Double strand DNA damage was observed in a dose dependant manner as evidenced in gH2AX foci assay. There was a down regulation of p53and PCNA in treated cells. Cancer cells in particular showed a concentration dependant increase in phosphorylated p53 accompanied by the cleavage of caspase 3 and PARP. Our results demonstrate the involvement of NFB and MAP kinase pathway in response to Ag-np exposure. Up regulation of pro-inflammatory cytokines such as interleukins (IL-8, IL-6), macrophage colony stimulating factor,macrophage inflammatory protein in fibroblasts following Ag-np exposure were also observed. Conclusion: In summary, Ag-np can modulate gene expression and protein functions in IMR-90 cells and U251 cells, leading to defective DNA repair, proliferation arrest and inflammatory response. The observed changes could also be due to its capability to adsorb cytosolic proteins on its surface. Keywords: DNAdamage, Isothermal titration calorimetry, inflammation

Background Wide spread use of nanoparticles has increased the risk of nanoparticle induced toxic effects in the environment and in humans. The rate of exposure increased progressively over the years when engineered nanomaterials
* Correspondence: chmsv@nus.edu.sg; phsmph@nus.edu.sg 1 Department of Chemistry, Faculty of Science, 3 ScienceDrive 3, National University of Singapore, 117543, Singapore 2 Department of Physiology, Yong Loo Lin School of Medicine, 2, Medical Drive, National University of Singapore, 117597, Singapore Full list of author information is available at the end of the article

were extensively used in a variety of industries. Intentional manipulation of nanoparticle surfaces with biomolecules andchemicals to cater various applications resulted in nanomaterials with unforeseeable activity. Large scale production and improper waste disposal may elevate human exposure to them and subsequent accumulation of these nanomaterials in nature [1]. To add on to the complexity, most of the metal nanomaterials seem to be non-biodegradable and survive in nature and tissues for years [2]. Dermal orintravenous injections of

© 2012 AshaRani et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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