The induction of epigenetic regulation of PROS1 gene in lung fibroblasts by gold nanoparticles and implications for potential lung injury

Department of Anatomy, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117597, Singapore.
Biomaterials (Impact Factor: 8.56). 10/2011; 32(30):7609-15. DOI: 10.1016/j.biomaterials.2011.06.038
Source: PubMed


Advances in nanotechnology have given rise to the rapid development of novel applications in biomedicine. However, our understanding in the risks and health safety of nanomaterials is still not complete and various investigations are ongoing. Here, we show that gold nanoparticles (AuNPs) significantly altered the expression of 19 genes in human fetal lung fibroblasts (using the Affymetrix Human Gene 1.0 ST Array). Among the differentially expressed genes, up-regulation of microRNA-155 (miR-155) was observed concomitant with down-regulation of the PROS1 gene. Silencing of miR-155 established PROS1 as its possible target gene. DNA methylation profiling analysis of the PROS1 gene revealed no changes in the methylation status of this gene in AuNP-treated fibroblasts. At the ultrastructural level, chromatin condensation and reorganization was observed in the nucleus of fibroblasts exposed to AuNPs. The findings provide further insights into the molecular mechanisms underlying toxicity of AuNPs and their impact on epigenetic processes.

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    • "Immortalized epithelial HaCaT cell line Global hypomethylation; dose-dependent decrease in DNMT1, DNMT3a and methyl-CpG binding protein 2 (MBD2) gene and protein expressions Gong et al., 2010 HaCaT cell line PARP-1 hypermethylation and repression of gene expression Gong et al., 2012 CdTe QDs THP1 human monocytic cell line Binding to core histones and stimulation of aggregate formation Conroy et al., 2008 MCF-7 human breast adenocarcinoma cells Histone 3 hypoacetylation and chromatin decondensation leading to reduction in global gene transcription especially for antiapoptotic genes; increase in p53 protein level by its activation via phosphorylation, nuclear and mitochondrial translocation Choi et al., 2008 NIH/3T3 mouse embryonic fibroblast line Global alteration of miRNAs expression patterns resulting in the apoptosis-like cell death Li et al., 2011b Au HeLa cervical cancer cell line Modulation of heterochromatin connections with lamin proteins and core histones Mazumder and Shivashankar, 2007 Enzymatic method Decrease of histone deacetylase activity by NPs binding to sulfhydryl groups on the surface of HDAC8 Sule et al., 2008 MRC5 lung fibroblast line Upregulation of miR-155 with downregulation of PROS1 gene, chromatin condensation Ng et al., 2011 TiO2 HaCaT cells Dysfunction of methylation cycle and methionine deficiency Tucci et al., 2013 MWCNTs NIH/3T3 cell line Changes of various miRNAs expression Li et al., 2011a Super paramagnetic Fe Human prostate cancer cells PC-3 and human breast cancer cells Sk-Br-3 K-182 histone deacetylase inhibitor (HDACI)-coated cationic NPs resulted in an increase in gene expression and core histone hyperacetylation Ishii et al., 2009 Different cancer cell lines (U87, U373, Lipari, DF) "
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    ABSTRACT: Disturbed epigenetic mechanisms, which developmentally regulate gene expression via modifications to DNA, histone proteins, and chromatin, have been hypothesized to play a key role in many human diseases. Recently it was shown that engineered nanoparticles (NPs), that already have a wide range of applications in various fields including food production, coulddramatically affect epigenetic processes, while their ability to induce diseases remains poorly understood. Besides the obvious benefits of the new technologies, it is critical to assess their health effects before proceeding with industrial production. In this article, after surveying the applications of NPs in food technology, we review recent advances in the understanding of epigenetic pathological effects of NPs, and discuss their possible health impact with the aim of avoiding potential health risks posed by the use of nanomaterials in foods and food-packaging. Copyright © 2014. Published by Elsevier Ltd.
    Food and Chemical Toxicology 12/2014; 77. DOI:10.1016/j.fct.2014.12.015 · 2.90 Impact Factor
    • "Epigenetic changes have a role also in several other human diseases, such as obesity, autoimmune disorders, and many others (Rhee et al., 2012; Rodriguez-Cortez et al., 2011). Given the increasing evidence for a contribution of epigenetics to human diseases , current research is focused on the development of the so called " epigenetic drugs " i.e. molecules with epigenetic properties to be used to counteract epigenetic changes occurring with aging, cancer, and other diseases (Schneider-Stock et al., 2012; Song et al., 2011). Moreover " environmental epigenetics " is gathering increasing attention from the scientific community. "
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    ABSTRACT: The term epigenetics includes several phenomena such as DNA methylation, histone tail modifications, and microRNA mediated mechanisms, which are able to mold the chromatin structure and/or gene expression levels, without altering the primary DNA sequence. Environmental agents can exert epigenetic properties and there is increasing evidence of epigenetic deregulation of gene expression in several human diseases, including cancer, cardiovascular diseases, autism spectrum disorders, autoimmune diseases, and neurodegeneration, among others. Given the widespread use and dispersion in the environment of nano-sized materials, this article summarizes the studies performed so far to evaluate their potential epigenetic properties. Those studies highlight the ability of certain nano-sized compounds to induce an impaired expression of genes involved in DNA methylation reactions leading to global DNA methylation changes, as well as changes of gene specific methylation of tumor suppressor genes, inflammatory genes, and DNA repair genes, all potentially involved in cancer development. Moreover, some nano-sized compounds are able to induce changes in the acetylation and methylation of histone tails, as well as microRNA deregulated expression. We also provided a detailed description of currently available methodologies to evaluate epigenetic modifications. Standard protocols are currently available to evaluate cytotoxic and genotoxic effects of nano-sized materials. By contrast, there are at present no available standard protocols to evaluate the epigenetic potential of any given compound. The currently available methodologies offer different, but often complementary information to characterize potential epigenetic changes induced by exposure to nano-sized compounds. Given the widespread use and dispersion in the environment of nano-sized materials, at present and foreseeable in the near future, and in light of the indication of potential epigenetic properties here reviewed, more attention should be paid to unravel the consequences of such effects in future studies.
    Toxicology 12/2012; 313(1). DOI:10.1016/j.tox.2012.12.002 · 3.62 Impact Factor
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    • "Concerns have arisen over exposure to engineered nanomaterials in consumer products and occupational settings . Several in vitro studies have shown that nanoparticle exposure leads to perturbations of miRNA responses [Li et al., 2011a,b; Mahmood et al., 2011; Ng et al., 2011]. Pulmonary exposure to nanotitanium dioxide in *Correspondence to: Carole L. Yauk. "
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    ABSTRACT: MicroRNAs (miRNA) are important noncoding regulatory molecules that bind target messenger RNA (mRNA), primarily affecting their translation into protein. Because miRNAs can simultaneously target hundreds of mRNAs, subtle changes in their expression can elicit important cellular effects. Little is known about the role of miRNAs in pulmonary responses to inhaled particulate matter. We studied pulmonary global miRNA responses to Printex 90 carbon black nanoparticles in (1) nonpregnant C57BL/6 female mice instilled with vehicle or a single dose of 0.162 mg and euthanized 1, 3, and 28 days post-exposure, and (2) C57BL/6Bom Tac dams instilled with vehicle or a cumulative dose of 0.268 mg (four separate instillations of vehicle or 0.067 mg Printex 90 during pregnancy) and euthanized at weaning (26-27 days postexposure). We measured similar expression profiles in both exposure scenarios, with marked increases in miR-135b and subtle changes in miR-21 and miR-146b. All three miRNAs were confirmed in nonpregnant females by RT-PCR, whereas only miR-135b was confirmed in the dams. Target analysis revealed no concomitant changes in established and predicted targets of miR-135b, miR-21, or miR-146b. Analysis of potentially perturbed pathways did not reveal changes that would suggest down-stream miRNA effects. The reasons for the lack of association between miRNA and transcript profiles may be related to the complexity of miRNA function and fate, or to the possibility that targets may differ from those already established or predicted in silico. We hypothesize that changes in the expression of these miRNAs may be associated with resolution of pulmonary inflammation, but future work will be necessary to precisely identify specific targets of these miRNAs in lungs.
    Environmental and Molecular Mutagenesis 07/2012; 53(6):462-8. DOI:10.1002/em.21706 · 2.63 Impact Factor
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