Genome-wide DNA methylome and transcriptome changes induced by inorganic nanoparticles in human kidney cells after chronic exposure (original) (raw)
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NanoMiner — Integrative Human Transcriptomics Data Resource for Nanoparticle Research
PLoS ONE, 2013
The potential impact of nanoparticles on the environment and on human health has attracted considerable interest worldwide. The amount of transcriptomics data, in which tissues and cell lines are exposed to nanoparticles, increases year by year. In addition to the importance of the original findings, this data can have value in broader context when combined with other previously acquired and published results. In order to facilitate the efficient usage of the data, we have developed the NanoMiner web resource (http://nanominer.cs.tut.fi/), which contains 404 human transcriptome samples exposed to various types of nanoparticles. All the samples in NanoMiner have been annotated, preprocessed and normalized using standard methods that ensure the quality of the data analyses and enable the users to utilize the database systematically across the different experimental setups and platforms. With NanoMiner it is possible to 1) search and plot the expression profiles of one or several genes of interest, 2) cluster the samples within the datasets, 3) find differentially expressed genes in various nanoparticle studies, 4) detect the nanoparticles causing differential expression of selected genes, 5) analyze enriched Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways and Gene Ontology (GO) terms for the detected genes and 6) search the expression values and differential expressions of the genes belonging to a specific KEGG pathway or Gene Ontology. In sum, NanoMiner database is a valuable collection of microarray data which can be also used as a data repository for future analyses.
An ancestral molecular response to nanomaterial particulates
Nature Nanotechnology
The varied transcriptomic response to nanoparticles has hampered the understanding of the mechanism of action. Here, by performing a meta-analysis of a large collection of transcriptomics data from various engineered nanoparticle exposure studies, we identify common patterns of gene regulation that impact the transcriptomic response. Analysis identifies deregulation of immune functions as a prominent response across different exposure studies. Looking at the promoter regions of these genes, a set of binding sites for zinc finger transcription factors C2H2, involved in cell stress responses, protein misfolding and chromatin remodelling and immunomodulation, is identified. The model can be used to explain the outcomes of mechanism of action and is observed across a range of species indicating this is a conserved part of the innate immune system.
Current Genomics, 2008
Engineered nanomaterials are commonly defined as materials with at least one dimension of 100 nanometers or less. Such materials typically possess nanostructure-dependent properties (e.g., chemical, mechanical, electrical, optical, magnetic, biological), which make them desiderable for commercial or medical application. However, these same properties may potentially lead to nanostructure-dependent biological activity that differs from and is not directly predicted by the bulk properties of the constitutive chemicals and compounds. Nanoparticles and nanomaterials can be on the same scale of living cells components, including proteins, nucleic acids, lipids and cellular organelles. When considering nanoparticles it must be asked how man-made nanostructures can interact with or influence biological systems. Carbon nanotubes (CNTs) are an example of carbon-based nanomaterial, which has won a huge spreading in nanotechnology. The incorporation of CNTs in living systems has raised many concerns because of their hydrophobicity and tendency to aggregate and accumulate into cells, organs, and tissues with dangerous effects. Applications of toxicogenomics to both investigative and predictive toxicology will contribute to the in-depth investigation of molecular mechanisms or the mode of nanomaterials action that is achieved by using conventional toxicological approaches. Parallel toxicogenomic technologies will promote a valuable platform for the development of biomarkers, in order to predict possible nanomaterial's toxicity. The potential of characteristic gene expression profiles ("fingerprint") of exposure or toxicological response to nanoparticles will be discussed in the review to enhance comprehension of the molecular mechanism of in vivo and in vitro system exposed to nanomaterials.
Short-term exposure to engineered nanomaterials affects cellular epigenome
Nanotoxicology, 2015
Extensive incorporation of engineered nanomaterials (ENMs) into industrial and biomedical applications increases the risks of exposure to these potentially hazardous materials. While the geno-and cytotoxic effects of ENMs have been investigated, the potential of ENMs to target the cellular epigenome remains largely unknown. Our goal was to determine whether industry relevant ENMs can affect the epigenome at low cytotoxic doses. A panel of cells relevant to inhalation exposures such as human and murine macrophages (THP-1 and RAW264.7, respectively) and human small airway epithelial cells (SAEC) were exposed to printer-emitted engineered nanoparticles (PEPs), mild steel welding fumes (MS-WF), copper oxide (CuO) and titanium dioxide nanoparticles. Toxicological effects, including cytotoxicity, oxidative stress and inflammatory responses were assessed, taking into consideration in vitro dosimetry. The effects of ENMs on cellular epigenome were determined by addressing the global and transposable elements (TEs)-associated DNA methylation and expression of DNA methylation machinery and TEs. The percentage of ENMs-induced cytotoxicity for all cell lines was in the range of 0-15%. Oxidative stress was evident in SAEC after exposure to PEPs and in THP-1 when exposed to CuO. In addition, exposure to ENMs resulted in modest alterations in DNA methylation of two most abundant TEs in mammalian genomes, LINE-1 and Alu/SINE, their transcriptional reactivation, and decreased expression of DNA methylation machinery in a cell-, dose-and ENM-dependent manner. These results indicate that exposure to ENMs at environmentally relevant concentrations, aside from the geno-and cytotoxic effects, can also affect the epigenome of target cells.
Epigenetic Toxicity of Nanoparticles
2020
Nanoparticles (NPs) are being used in an increasingly wide range of fields which leads to increased human exposure. It is evident from mounting data that exposure to NPs leads to cell toxicity, immunotoxicity, genotoxicity, non-genotoxic carcinogenicity, reproductive toxicity, etc. Recently there is abundant proof available to link sublethal NP toxicity to epigenetic variations, which may lead to reprogramming of variety of gene expression. Being the most sensitive and first retort, epigenetic modifications are extensively studied and used as potential biomarkers in several disease conditions. The early NP exposure biomarker may go unnoticed by traditional toxicity assays, but epigenetic variations being more sensitive can be used as fingerprint for nanotoxicity and provide guidance for creating safe nanomaterials. This review collates the literate on “nanoepigenetic toxicity” and its contribution to both genotoxicity and cytotoxicity experienced by cell. Even at concentration at wh...
Kidney nanotoxicity studied in human renal proximal tubule epithelial cell line TH1
Mutation Research/Genetic Toxicology and Environmental Mutagenesis
Progressive expansion of nanomaterials in our everyday life raises concerns about their safety for human health. Although kidneys are the primary organs of xenobiotic elimination, little attention has been paid to the kidneys in terms of nanotoxicological studies up to now. Here we investigate the cytotoxic and genotoxic potential of four solid-core uncoated inorganic nanoparticles (TiO 2 NPs, SiO 2 NPs, Fe 3 O 4 NPs and AuNPs) using the human renal proximal tubule epithelial TH1 cells. To mimic the in vivo conditions more realistic, TH1 cells were exposed in vitro to inorganic NPs under static as well as dynamic conditions for 3 h and 24 h. The medium throughput alkaline comet assay (12 minigels per slide) was employed to evaluate the impact of these NPs on genome integrity and their capacity to produce oxidative lesions to DNA. The accumulation and localization of studied inorganic NPs inside the cells was monitored by transmission electron microscopy (TEM) and the efficacy of internalization of particular NPs was determined by atomic absorption spectroscopy (AAS) and inductively coupled plasma mass spectrometry (ICP-MS). From all the tested NPs, only Fe 3 O 4 NPs induced a slight cytotoxicity in TH1 cells exposed to high concentrations (> 700 μg/ml) for 24 h. On the other hand, the inorganic NPs did not increase significantly the level of DNA strand breaks or oxidative DNA damage regardless of the treatment mode (static vs. dynamic conditions). Interestingly, substantial differences were observed in the internalized amount of inorganic NPs in TH1 cells exposed to equivalent (2.2 μg/ml) concentration. Fe 3 O 4 NPs were most efficiently taken up while the lowest quantity of particles was determined in TiO 2 NPs-treated cells. As the particle size and shape of individual inorganic NPs in culture medium was nearly identical, it is reasonable to suppose that the chemical composition may contribute to the differences in the efficacy of NPs uptake.
Food and Chemical Toxicology
The unique properties of nanomaterials (NMs) are beneficial in numerous industrial and medical applications. However, they could also induce unintended effects. Thus, a proper strategy for toxicity testing is essential in human hazard and risk assessment. Toxicity can be tested in vivo and in vitro; in compliance with the 3Rs, alternative strategies for in vitro testing should be further developed for NMs. Robust, standardized methods are of great importance in nanotoxicology, with comprehensive material characterization and uptake as an integral part of the testing strategy. Oxidative stress has been shown to be an underlying mechanism of possible toxicity of NMs, causing both immunotoxicity and genotoxicity. For testing NMs in vitro, a battery of tests should be performed on cells of human origin, either cell lines or primary cells, in conditions as close as possible to an in vivo situation. Novel toxicity pathways, particularly epigenetic modification, should be assessed along with conventional toxicity testing methods. However, to initiate epigenetic toxicity screens for NM exposure, there is a need to better understand their adverse effects on the epigenome, to identify robust and reproducible causal links between exposure, epigenetic changes and adverse phenotypic endpoints, and to develop improved assays to monitor epigenetic toxicity.
Use of whole genome expression analysis in the toxicity screening of nanoparticles
Toxicol Appl Pharmacol, 2014
The use of nanoparticles (NPs) offers exciting new options in technical and medical applications provided they do not cause adverse cellular effects. Cellular effects of NPs depend on particle parameters and exposure conditions. In this study, whole genome expression arrays were employed to identify the influence of particle size, cytotoxicity, protein coating, and surface functionalization of polystyrene particles as model particles and for short carbon nanotubes (CNTs) as particles with potential interest in medical treatment. Another aim of the study was to find out whether screening by microarray would identify other or additional targets than commonly used cell-based assays for NP action. Whole genome expression analysis and assays for cell viability, interleukin secretion, oxidative stress, and apoptosis were employed. Similar to conventional assays, microarray data identified inflammation, oxidative stress, and apoptosis as affected by NP treatment. Application of lower particle doses and presence of protein decreased the total number of regulated genes but did not markedly influence the top regulated genes. Cellular effects of CNTs were small; only carboxyl-functionalized single-walled CNTs caused appreciable regulation of genes. It can be concluded that regulated functions correlated well with results in cellbased assays. Presence of protein mitigated cytotoxicity but did not cause a different pattern of regulated processes.
Toxicogenomics aims at characterising the mechanism of action (MOA) of environmental exposures, and often relies on transcriptomics to investigate the responses of exposed biological systems. However, the identification of shared toxicogenomics-derived signatures across exposed biological systems is hampered by the complexity and heterogeneity of transcriptomics data. Given the lack of a clear transcriptomic signature of exposure, we hypothesise that common patterns of gene regulation could explain the response to engineered nanomaterials (ENM) across biological systems, disentangling the complexity of their MOA. We performed meta-analysis of a large collection of transcriptomics data from various ENM exposure studies and identified deregulation of immune functions as a prominent response across different ENM exposures. This pattern of transcriptional deregulation differed significantly from exposure to drugs. By investigating the promoter regions of genes frequently altered both in...