Article Cite This: Environ. Sci. Technol. 2018, 52, 7996−8004
pubs.acs.org/est
Molecular Toxicity of Metal Oxide Nanoparticles in Danio rerio Jing Hou,† Haiqiang Liu,† Luyao Wang,† Linshuai Duan,† Shiguo Li,*,‡ and Xiangke Wang*,† †
College of Environmental Science and Engineering, North China Electric Power University, Beijing 102206, China Research Center for Eco-Environmental Sciences, Chinese Academy of Science, Beijing 100085, China
‡
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S Supporting Information *
ABSTRACT: Metal oxide nanoparticles can exert adverse effects on humans and aquatic organisms; however, their toxic mechanisms are still unclear. We investigated the toxic effects and mechanisms of copper oxide, zinc oxide, and nickel oxide nanoparticles in Danio rerio using microarray analysis and the comet assay. Copper oxide nanoparticles were more lethal than the other metal oxide nanoparticles. Gene ontology analysis of genes that were differentially expressed following exposure to all three metal oxide nanoparticles showed that the nanoparticles mainly affected nucleic acid metabolism in the nucleus via alterations in nucleic acid binding. KEGG analysis classified the differentially expressed genes to the genotoxicity-related pathways “cell cycle”, “Fanconi anemia”, “DNA replication”, and “homologous recombination”. The toxicity of metal oxide nanoparticles may be related to impairments in DNA synthesis and repair, as well as to increased production of reactive oxygen species.
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INTRODUCTION With the rapid development of nanotechnology, a wide range of metal oxide nanoparticles (MO-NPs) have been incorporated into various commercial products such as food, sunscreen, and electronic and medical devices because of their superior magnetism, conductivity, reactivity, and optical properties.1,2 Inevitably, MO-NPs are released into the aquatic environment, especially through sewage.3,4 Small MO-NPs (27 nm TiO2 and 24 nm CeO2) can easily enter the tissues and cells of aquatic organisms,5 and thereby accumulate up the food chain, with human beings as the ultimate reservoir.6 Multiple studies have demonstrated that MO-NPs can impair biological systems, causing cytotoxicity, inflammation, and cell membrane leakage.7−9 A thorough understanding of the toxicity of MO-NPs, from molecular mechanisms to physiology and morphology, is required to mitigate their adverse effects. However, the study on the molecular mechanisms of MO-NPs is not clear, which is not conducive to the scientific assessment and prediction of the ecological risk of NPs. Many of the published studies have been devoted to assessing the environmental risk of NPs by observing responses at the whole-organism level, including growth inhibition,10 reproduction,11 and mortality.12 These traditional toxicological end points are time-consuming and generally require higher exposure doses, when low doses not causing large-scale damage may in fact induce effects sufficient to disrupt normal function.13 In this context, microarray technology is a powerful experimental tool for assessing cellular alterations at the transcriptional level.14 Gene expression analysis can provide © 2018 American Chemical Society
information on low-level toxic effects at lower concentrations and elucidate the underlying molecular mechanisms.15,16 Moreover, the complex constituents of contaminants discharged into the aqueous environment render research with traditional end points unsuited. As a sensitive high-throughput genomic technology,17 expression profiling with microarrays can screen multiple contaminants rapidly.18 The responses of fish to environmental toxicants have been studied in the fathead minnow Pimephales promelas,19 Etheostoma caeruleum,20 Cyprinus carpio,18 Gasterosteus aculeatus,21 Salmo trutta,22 and Oryzias latipes.23 Understanding the toxic effects and mechanisms of MO-NPs requires the use of representative research species. Fish are a preferred model in the study of NP toxicity to aquatic organisms.24 Danio rerio has long been used as a model organism of vertebrate molecular developmental biology.25 As a model organism recommended by the Organization for Economic Co-operation and Development (OECD),26 D. rerio is gaining recognition in the fields of aquatic toxicology,27,28 drug discovery, and disease research29 because of its characteristics.30 The D. rerio genome is 70% homologous to the human genome, permitting some extrapolations to humans.31 D. rerio adults are highly fecund, and embryos are transparent and easy to handle,32 allowing the study of embryonic toxicity and malformation.13 Received: Revised: Accepted: Published: 7996
March 19, 2018 June 21, 2018 June 26, 2018 June 26, 2018 DOI: 10.1021/acs.est.8b01464 Environ. Sci. Technol. 2018, 52, 7996−8004
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Environmental Science & Technology
(Qiagen, Hilden, Germany) was used to purify the labeled cRNA, which was then fragmented and hybridized on a D. rerio microarray. A 15 μg sample of the fragmented cRNA were hybridized to each microarray at 45 °C for 15 h in an Affymetrix GeneChip Hybridization Oven 640 (Affymetrix, Santa Clara, CA, USA). The microarray was washed after hybridization. Streptavidin phycoerythrinonan was used to stain the microarray on an Affymetrix Fluidics Station 450 (Affymetrix), and a GeneChip Scanner 3000 7G (Affymetrix) was used to scan the microarray. Three replicate experiments were conducted using cRNA prepared independently from individual D. rerio. Microarray data were further analyzed with Microarray Suite version 5.0 at the default settings, and global scaling was used as the normalization method. Genes with a false discovery rate adjusted fold-change of ≥2 and p-value of 13) was added onto the slides. The slides were incubated for 20 min and then subjected to horizontal electrophoresis at 10 °C and 200 mA for 25 min. Finally, the slides were neutralized in a solution of 0.4 mol/L Tris-HCl
The aim of this study was to investigate the transcriptional toxicity of MO-NPs on D. rerio and to explore its toxicity mechanisms of various MO-NPs in the same valence state. We used microarrays to identify differentially expressed genes (DEGs) common to copper oxide (CuO), zinc oxide (ZnO), and nickel oxide (NiO) NP exposure. Next, we used bioinformatics approaches to suggest the molecular mechanism of toxicity. These findings contribute to our understanding of the toxicity of MO-NPs to aquatic organisms and are of significance in evaluating the ecological risk of MO-NPs.
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MATERIALS AND METHODS D. rerio Maintenance. All experimental D. rerio were kindly provided by the Chinese Research Academy of Environmental Sciences. D. rerio were 5 months old and had an average length of 2.8 cm and an average weight of 12.5 g. Fish were healthy and free of any signs of disease. During the acclimation period (not less than 14 days), D. rerio were housed in 60 L tanks (40 cm height ×30 cm width ×50 cm length) at a maximum density of 7 D. rerio per liter. The tanks were filled with water previously treated by aeration and kept under filtration at a temperature of 24 ± 2 °C and pH of 7.0− 8.0. Fish were fed commercially available dry flakes twice a day. Dead fish were removed in a timely manner, and the cumulative mortality did not exceed 2%. Preparation of NPs. CuO NPs ( NiO NPs. Particle size is one of the factors that affect its toxicity. The negative charge on the surface of NPs increases as the zeta potential increases, leading to greater electrostatic repulsive force between NPs and to reduce aggregation. The 96 h zeta potential of CuO NPs was higher than that of ZnO and NiO NPs, indicating that CuO NPs were more stable and could resist aggregation, resulting in smaller particles. NiO NPs had the lowest zeta potential, indicating a tendency to coagulate or aggregate, resulting in larger particles. Aggregation can reduce the toxicity of NPs,35,36 and the lowest toxicity was indeed observed for NiO NPs. The expression of multiple genes involved in nucleic acid metabolism was dysregulated, which may lead to impairments in the synthesis and/or degradation of nucleic acids. The nucleotide is the basic nucleic acid unit, and nucleotide synthesis generally includes the chemical reaction of pentose sugar, phosphate, and nitrogenous base in the nucleus. In contrast, degradation of nucleic acid is a catabolic nuclear reaction, whereby partial nucleobases and nucleotides can be recycled to create new nucleotides, suggesting a complex relationship between degradation and synthesis. The expression of multiple genes involved in nucleic acid binding was also dysregulated by exposure to MO-NPs. Studies have demonstrated that DNA or RNA binding to proteins affects 7999
DOI: 10.1021/acs.est.8b01464 Environ. Sci. Technol. 2018, 52, 7996−8004
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Environmental Science & Technology
Figure 3. Gene ontology (GO) enrichment analysis of differentially expressed genes (DEGs). The top 30 GO terms were sorted by p-value. The xaxis represents p-value on a log10 scale, and the y-axis is the GO functional classification. The GO enrichment analysis is divided into three categories: biological processes, cellular components, and molecular functions.
protein structure and function, leading to dysregulation of transcription, translation, DNA replication, DNA repair and chromosomal recombination, and RNA processing and translocation.37−39 Therefore, the GO enrichment analysis provided insights into the effects of MO-NPs on D. rerio. KEGG pathway analysis indicated that cell cycle, Fanconi anemia, DNA replication, and homologous recombination may be involved in the toxicity induced by MO-NPs. These four pathways are closely linked. The cell cycle in D. rerio incorporates several successive events, including the S phase (DNA replication), M phase (mitosis), and G1 and G2 phases. Cyclin-dependent kinases (CDKs) are important regulators of the cell cycle and typically contain two subunits, the activating cyclin subunit and the catalytic CDK subunit. CDKs can control the cell cycle phases by regulating the activities of their key substrates. Targets downstream of CDKs include multiple proteins such as origin recognition complex (ORC),
minichromosome maintenance (MCM), cell division control (CDC), transcription factor E2F, and its regulator Rb. Cyclins usually form a complex with CDKs prior to involvement in the cell cycle process. Therefore, orderly cell division requires regular inactivation and activation of CDKs at specific points in the cell cycle process. We found that MO-NPs inhibited the expression of CDK1, CDK2, and CDK7 and their downstream target genes ORC, CDC6, CDC4, CDC5, CDC7, and MCM but had no significant effect on the expression of CDK4, CDK6, E2F, or Rb. While MO-NPs are selective for the CDK gene family, they can inhibit key regulatory enzymes in the cell cycle, affecting DNA synthesis. These enzymes are involved in all phases of the cell cycle, suggesting that the effect of MONPs on D. rerio would not be isolated to one phase. In particular, the CycA-CDK2-Cdc6-ORC process has a more direct inhibitory effect on DNA synthesis. 8000
DOI: 10.1021/acs.est.8b01464 Environ. Sci. Technol. 2018, 52, 7996−8004
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Environmental Science & Technology
Figure 4. Three-dimensional principal component analysis score plot of Danio rerio exposure to copper oxide (CuO), zinc oxide (ZnO), and nickel oxide (NiO) nanoparticles (NPs). Each color represents an exposure and each point represents a replicate sample.
Figure 6. Effects of copper oxide (CuO), zinc oxide (ZnO), and nickel oxide (NiO) nanoparticles (NPs) on DNA damage in Danio rerio cells, detected by the comet assay.
DNA replication is mainly accomplished during the S phase and is termed “semi-conservative replication” because it contains both newly synthesized and original DNA. Both strands of the original DNA serve as templates for the opposite strands. DNA polymerases are enzyme families involved in DNA replication and are the rate-limiting factor in DNA replication. These enzymes synthesize DNA molecules from deoxyribonucleotides to create uniform DNA strands. Three DNA polymerase complexes have been identified in eukaryotes. The genes encoding DNA polymerases were downregulated following exposure to MO-NPs, indicating that enzyme production decreased, reducing the efficiency of DNA replication and leading to a blocked S phase.
Numerous studies have reported that NPs penetrating the nucleus through a nuclear pore may interact directly with chromosomal DNA. During interphase, NPs can bind or interact with DNA molecules, interrupting DNA replication and transcription.40−42 During DNA replication, carbon NPs can bind to single-stranded DNA and then merge into a double-strand structure43 In addition, NPs can disrupt mitosis or chromosomes by mechanical or chemical binding, leading to some vertebrate diseases. NPs can also induce primary genotoxicity by indirect contact with DNA, via interaction with nuclear proteins involved in DNA replication, transcription, and repair processes, or by interfering with cell cycle checkpoint functions and generating mitochondrial reactive oxygen species. Oxidative stress has been proposed as a
Figure 5. Fifteen genes that were differentially expressed following exposure to (A) copper oxide, (B) zinc oxide, and (C) nickel oxide nanoparticles were selected at random for RT-qPCR analysis to verify the accuracy of microarray data. Each dot represents a gene. 8001
DOI: 10.1021/acs.est.8b01464 Environ. Sci. Technol. 2018, 52, 7996−8004
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Environmental Science & Technology mechanism of MO-NP toxicity in various organisms.44 Studies have shown that MO-NPs can cross the cell membrane of respiratory epithelial cells.45 MO-NPs entering the cell will be transported to the lysosome, an organelle with acidic conditions (pH 4.5) that can dissolve MOs and release them as metal ions.46 It is possible that CuO NPs may easily cross the cell membrane, and once inside the cell, the may release Cu2+ and induce the production of reactive oxygen species or directly affect intracellular proteins. Cu2+ may also decrease cell viability by binding to DNA directly, resulting in DNA damage and cell death.47 Several studies have suggested that the toxicity of MO-NPs is associated with oxidative stress, leading to DNA damage48−50 and constant activation of DNA repair processes. DNA damage from environmental stressors typically includes double-strand breaks (DSBs). Homologous recombination is critical for the accurate repair of DSBs and is a process of nucleotide sequence exchange between two identical or similar DNA molecules. Cells usually repair DSBs rapidly by homologous recombination. Recombinases are key ratelimiting enzymes in the homologous recombination process, and the RecA recombinase protein family is thought to have been inherited from a common ancestral recombinase. RecA is a 38 KDa recombinase necessary for repairing DNA damage and maintaining DNA integrity, and a functional and structural homologue of RecA has been identified in multiple species. Investigations into the evolutionary relationships between these recombinases in bacteria, eukaryotes, and archaea have indicated that they are monophyletic and may have originated from a common ancestor. Several recA-like genes have been identified in D. rerio, and all are essential for cell division, differentiation, and proliferation. In the present study, the RecA-like genes RAD51B, RAD52, RAD54, and XRCC2 were significantly down-regulated following exposure to MO-NPs. The protein encoded by RAD51B is a member of the RAD51 family, evolutionarily conserved proteins responsible for homologous recombination in DNA damage repair. RAD51B can interact with RAD51C to form a stable heterodimer, which can interact with other members of this protein family to effect DNA single-strand invasion. Moreover, RAD54 can closely interact with RAD51s to form a complex that participates in homologous recombination and DNA damage repair. Alterations in the expression of these genes are known to delay the G1 phase and cell apoptosis, suggesting a role for these proteins in DNA damage-sensing. RAD52 is a key regulator in DSB repair and homologous recombination via binding to the ends of single-stranded DNA, a process crucial to annealing complementary DNA strands. RAD52 can also interact with the DNA recombination protein RAD51, suggesting an underlying role of this complex in RAD51-related DNA recombination and repair. Downregulating the expression of these genes can reduce the levels of the response proteins, affect the stability of the DNA strand and the single-strand invasion process during repair, and prevent efficient repair of damaged DNA. The comet assay results showed that the DNA tail moment increased significantly following exposure to MONPs, indicating that DNA damage occurred. DNA damage from environmental stressors can often be repaired effectively by homologous recombination. In this study, the MO-NPs not only influenced the cell cycle and DNA replication processes but also suppressed homologous recombination, amplifying the effects on DNA replication and the cell cycle because the DSBs
could not be effectively repaired by homologous recombination. Our analysis indicated effects on the Fanconi anemia pathway, suggesting that in addition to DSB damage, MONP exposure may also lead to DNA cross-link damage in D. rerio. DNA cross-link damage can block the formation of the DNA replication fork and affect the replication process. The DNA cross-link repair process is relatively complex, and the Fanconi anemia pathway is one effective repair method. Fanconi anemia is a rare genetic disease that can cause an impaired response to DNA damage, and each of its subtypes corresponds to a gene mutation. At least 12 protein families encoded by Fanconi anemia genes have been described. In the present study, the proteins FANCB, FANCC, FANCF, FANCG, and FANCI, as well as their interacting centromere protein MHF, core complex-associated protein FAAP24, and downstream target replication protein RPA, were downregulated following exposure to MO-NPs. This indicates that the Fanconi anemia pathway was significantly inhibited by the exposure, hindering the repair of DNA cross-link damage. In particular, the decrease in RPA expression can establish a relationship between the Fanconi anemia pathway and homologous recombination or the repair of DSBs. DSBs in Fanconi anemia have been shown to occur in response to cross-linking agents,36 indicating that the Fanconi anemia pathway is involved in repairing DSBs by homologous recombination. The Fanconi anemia, DNA replication, cell cycle, and homologous recombination pathways may therefore be closely related to the normal physiological processes in D. rerio, and impairment of these pathways may explain the toxic effects of MO-NPs at the molecular level. In this study, MO-NPs mainly affected nucleic acid metabolism in the nucleus via alterations in nucleic acid binding. The DEGs were mainly classified into the genotoxicity-related pathways “cell cycle”, “Fanconi anemia”, “DNA replication”, and “homologous recombination”. These results will help us to understand the nature of aquatic toxicity of NPs with different properties and have important scientific significance. In order to reduce the toxicity, the interaction and integration of NPs should be paid more attention in the future research.
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ASSOCIATED CONTENT
S Supporting Information *
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.est.8b01464. File S1: Differentially expressed genes for CuO NPs, ZnO NPs, and NiO NPs (XLSX) File S2: Lists of 4792 differentially expressed genes coexpressed in CuO NPs, ZnO NPs, and NiO NPs treatments (XLSX) File S3: Lists of enrichment GO terms for CuO NPs, ZnO NPs, and NiO NPs (XLSX) File S4: Lists of enriched KEGG pathways for CuO NPs, ZnO NPs, and NiO NPs (XLSX) Primer sequences, cell cycle pathway, Fanconi anemia pathway, DNA replication pathway, and homologous recombination pathway (PDF)
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AUTHOR INFORMATION
Corresponding Authors
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DOI: 10.1021/acs.est.8b01464 Environ. Sci. Technol. 2018, 52, 7996−8004
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[email protected]. Tel. (Fax): +86-1061772890.
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ORCID
Jing Hou: 0000-0003-0244-1398 Shiguo Li: 0000-0002-1578-8844 Xiangke Wang: 0000-0002-3352-1617 Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS Financial support from NSFC (21607043), the Youth Innovation Promotion Association, Chinese Academy of Sciences (2018054), the Open Project of Key Laboratory of Environmental Biotechnology, CAS (kf2016009), the Fundamental Research Funds for the Central Universities (2016ZZD06, 2018ZD11) are acknowledged.
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