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  • Graphene onto medical grade titanium: an atom-thick multimodal coating that promotes osteoblast maturation and inhibits biofilm formation from distinct species
    Nanotoxicology (IF 6.428) Pub Date : 2018-02-06
    Nileshkumar Dubey, Kassapa Ellepola, Fanny E. D. Decroix, Julien L. P. Morin, AH Castro Neto, Chaminda J. Seneviratne, Vinicius Rosa

    The time needed for the osseointegration of titanium implants is deemed too long. Moreover, the bacterial colonization of their surfaces is a major cause of failure. Graphene can overcome these issues but its wet transfer onto substrates employs hazardous chemicals limiting the clinical applications. Alternatively, dry transfer technique has been developed, but the biological properties of this technique remain unexplored. Here, a dry transfer technique based on a hot-pressing method allowed to coat titanium substrates with high-quality graphene and coverage area >90% with a single transfer. The graphene-coated titanium is cytocompatible, did not induce cell membrane damage, induced human osteoblast maturation (gene and protein level), and increased the deposition of mineralized matrix compared to titanium alone. Moreover, graphene decreased the formation of biofilms from Streptococcus mutans, Enterococcus faecalis and even from whole saliva on titanium without killing the bacteria. These findings confirm that coating of titanium with graphene via a dry transfer technique is a promising strategy to improve osseointegration and prevent biofilm formation on implants and devices.

  • Impact of acute and subchronic inhalation exposure to PbO nanoparticles on mice
    Nanotoxicology (IF 6.428) Pub Date : 2018-02-15
    J. Lebedová, Z. Nováková, Z. Večeřa, M. Buchtová, J. Dumková, B. Dočekal, L. Bláhová, P. Mikuška, I. Míšek, A. Hampl, K. Hilscherová

    Lead nanoparticles (NPs) are released into air from metal processing, road transport or combustion processes. Inhalation exposure is therefore very likely to occur. However, even though the effects of bulk lead are well known, there is limited knowledge regarding impact of Pb NPs inhalation. This study focused on acute and subchronic exposures to lead oxide nanoparticles (PbO NPs). Mice were exposed to PbO NPs in whole body inhalation chambers for 4–72 h in acute experiment (4.05 × 106 PbO NPs/cm3), and for 1–11 weeks in subchronic experiment (3.83 × 105 particles/cm3 in lower and 1.93 × 106 particles/cm3 in higher exposure group). Presence of NPs was confirmed in all studied organs, including brain, which is very important considering lead neurotoxicity. Lead concentration gradually increased in all tissues depending on the exposure concentration and duration. The most burdened organs were lung and kidney, however liver and brain also showed significant increase of lead concentration during exposure. Histological analysis documented numerous morphological alterations and tissue damage, mainly in lung, but also in liver. Mild pathological changes were observed also in kidney and brain. Levels of glutathione (reduced and oxidized) were modulated mainly in lung in both, acute and subchronic exposures. Increase of lipid peroxidation was observed in kidney after acute exposure. This study characterized impacts of short to longer-term inhalation exposure, proved transport of PbO NPs to secondary organs, documented time and concentration dependent gradual increase of Pb concentration and histopathological damage in tissues.

  • The fate of silver nanoparticles in authentic human saliva
    Nanotoxicology (IF 6.428) Pub Date : 2018-02-16
    Kamonwad Ngamchuea, Christopher Batchelor-McAuley, Richard G. Compton

    The physicochemical properties of silver nanoparticles (AgNPs) in human whole saliva are investigated herein. In authentic saliva samples, AgNPs exhibit a great stability with over 70% of the nanomaterial remaining intact after a 24-h incubation in the presence of ∼0.3 mM dissolved oxygen. The small loss of AgNPs from the saliva sample has been demonstrated to be a result of two processes: agglomeration/aggregation (not involving oxygen) and oxidative dissolution of AgNPs (assisted by oxygen). In authentic saliva, AgNPs are also shown to be more inert both chemically (silver oxidative dissolution) and electrochemically (electron transfer at an electrode) than in synthetic saliva or aqueous electrolytes. The results thus predict based on the chemical persistence (over a 24-h study) of AgNPs in saliva and hence the minimal release of hazardous Ag+ and reactive oxygen species that the AgNPs are less likely to cause serious harm to the oral cavity but this persistence may enable their transport to other environments.

  • Airborne particulate matter impairs corneal epithelial cells migration via disturbing FAK/RhoA signaling pathway and cytoskeleton organization
    Nanotoxicology (IF 6.428) Pub Date : 2018-02-20
    Yu-Hong Cui, Zi-Xuan Hu, Zi-Xun Gao, Xi-Ling Song, Qing-Yang Feng, Guang Yang, Zhi-Jie Li, Hong-Wei Pan

    Background: Cornea is the outmost structure of the eye and exposed directly to the air pollution. However, little is known about the effect of PM2.5 on corneal epithelium, which is critical for maintenance of cornea homeostasis and visual function.

  • High-throughput tool to discriminate effects of NMs (Cu-NPs, Cu-nanowires, CuNO3, and Cu salt aged): transcriptomics in Enchytraeus crypticus
    Nanotoxicology (IF 6.428) Pub Date : 2018-03-05
    Susana I. L. Gomes, Carlos P. Roca, Natália Pegoraro, Tito Trindade, Janeck J. Scott-Fordsmand, Mónica J. B. Amorim

    The current testing of nanomaterials (NMs) via standard toxicity tests does not cover many of the NMs specificities. One of the recommendations lays on understanding the mechanisms of action, as these can help predicting long-term effects and safe-by-design production. In the present study, we used the high-throughput gene expression tool, developed for Enchytraeus crypticus (4 × 44k Agilent microarray), to study the effects of exposure to several copper (Cu) forms. The Cu treatments included two NMs (spherical and wires) and two copper-salt treatments (CuNO3 spiked and Cu salt field historical contamination). To relate gene expression with higher effect level, testing was done with reproduction effect concentrations (EC20, EC50), using 3 and 7 days as exposure periods. Results showed that time plays a major role in the transcriptomic response, most of it occurring after 3 days. Analysis of gene expression profiles showed that Cu-salt-aged and Cu-nanowires (Nwires) differed from CuNO3 and Cu-nanoparticles (NPs). Functional analysis revealed specific mechanisms: Cu-NPs uniquely affected senescence and cuticle pattern formation, which can result from the contact of the NPs with the worms’ tegument. Cu-Nwires affected reproduction via male gamete generation and hermaphrodite genitalia development. CuNO3 affected neurotransmission and locomotory behavior, both of which can be related with avoidance response. Cu salt-aged uniquely affected phagocytosis and reproductive system development (via different mechanisms than Cu-Nwires). For the first time for Cu (nano)materials, the adverse outcome pathways (AOPs) drafted here provide an overview for common and unique effects per material and linkage with apical effects.

  • RNA sequencing analysis shows that titanium dioxide nanoparticles induce endoplasmic reticulum stress, which has a central role in mediating plasma glucose in mice
    Nanotoxicology (IF 6.428) Pub Date : 2018-03-06
    Hailong Hu, Li Li, Qian Guo, He Zong, Yuheng Yan, Yao Yin, Yu Wang, Yuri Oh, Yujie Feng, Qiong Wu, Ning Gu

    Titanium dioxide nanoparticles (TiO2 NPs) constitute the top five NPs in use today. In this study, oral administration of 50, 100, and 200 mg/kg body weight (b.w.) TiO2 NPs increases plasma glucose in mice, whereas 10 and 20 mg/kg b.w. TiO2 NPs did not. RNA sequencing (RNA-seq) technology was used to investigate genome-wide effects of TiO2 NPs. Clustering analysis of the RNA-seq data showed the most significantly enriched gene ontology terms and KEGG pathways related to the endoplasmic reticulum (ER) and ER stress. Molecular biology verification showed that 50 mg/kg b.w. and higher doses TiO2 NPs activated a xenobiotic biodegradation response and increased expression of cytochrome P450 family genes in mouse livers, thus inducing ER stress in mice. ER stress-activated MAPK and NF-κB pathways and induced an inflammation response, resulting in phosphorylation of the insulin receptor substrate 1 and, consequently, insulin resistance. This was the main mechanism by which TiO2 NPs increased plasma glucose in mice. Meanwhile, ER stress disturbed the monooxygenase system, and thus generated reactive oxygen species (ROS). Relief of ER stress with 4-phenylbutyric acid inhibited all the above effects of TiO2 NPs, including the generation of ROS. Therefore, TiO2 NP-induced ER stress was a decisive factor with a central role in plasma glucose disturbance in mice.

  • Assessment of the in vitro genotoxicity of TiO2 nanoparticles in a regulatory context
    Nanotoxicology (IF 6.428) Pub Date : 2018-03-19
    Sandrine Charles, Stéphane Jomini, Valérie Fessard, Emilie Bigorgne-Vizade, Christophe Rousselle, Cécile Michel

    A review of in vitro genotoxicity studies on titanium dioxide nanoparticles (TiO2-NPs) published between 2010 and 2016 was performed by France in the framework of the CLP Regulation 1272/2008/EC. Neither the few in vivo studies of low quality nor the larger number of acceptable in vitro studies available for genotoxicity allowed France to conclude on the genotoxicity of TiO2-NPs. Based on this work, it was decided to compare the acceptable in vitro studies to understand the reasons for the diverging results observed, such as the materials tested or of the protocols used and their inherent interferences. The systematic review performed on in vitro genotoxicity data for TiO2-NPs was then restricted to studies with the highest level of confidence among studies following OECD guidelines and the largely applied comet assay. Indeed, the aim of this article is to understand why, even if judged of good quality, the 36 publications selected and analyzed did not lead to a clear picture. Some recommendations to be taken into account before performing new in vitro genotoxicity assays for insoluble particles such as TiO2-NPs are proposed. Although secondary genotoxic effects consequent to oxidative stress seem to be the major mechanism responsible for the genotoxicity of TiO2-NPs reported in some studies, primary genotoxic effects cannot be excluded. Further studies are needed to clarify the exact mode of action of TiO2-NPs and to highlight which physicochemical properties lead to their genotoxicity in vitro to ultimately identify a specific combination of parameters that could represent a risk in vivo.

  • Comparative toxicity of three differently shaped carbon nanomaterials on Daphnia magna: does a shape effect exist?
    Nanotoxicology (IF 6.428) Pub Date : 2018-02-01
    Renato Bacchetta, Nadia Santo, Irene Valenti, Daniela Maggioni, Mariangela Longhi, Paolo Tremolada

    The acute toxicity of three differently shaped carbon nanomaterials (CNMs) was studied on Daphnia magna, comparing the induced effects and looking for the toxic mechanisms. We used carbon nano-powder (CNP), with almost spherical primary particle morphology, multi-walled carbon nanotubes (CNTs), tubes of multi-graphitic sheets, and cubic-shaped carbon nanoparticles (CNCs), for which no ecotoxicological data are available so far. Daphnids were exposed to six suspensions (1, 2, 5, 10, 20 and 50 mg L−1) of each CNM, and then microscopically analyzed. Ultrastructural analyses evidenced cellular uptake of nanoparticle in CNP and CNT exposed groups, but not in samples exposed to CNCs. Despite this difference, very similar effects were observed in tissues exposed to the three used CNMs: empty spaces between cells, cell detachment from the basal lamina, many lamellar bodies and autophagy vacuoles. These pathological figures were qualitatively similar among the three groups, but they differed in frequency and severity. CNCs caused the most severe effects, such as partial or complete dissolution of the brush border and thinning of the digestive epithelium. Being the cubic shape not allowed to be internalized into cells, but more effective than others in determining physical damages, we can conclude that shape is an important factor for driving nanoparticle uptake by cells and for determining the acute toxicological endpoints. Shape also plays a key role in determining the kind and the severity of pathologies, which are linked to the physical interactions of CNMs with the exposed tissues.

  • Short-term inhalation study of graphene oxide nanoplates
    Nanotoxicology (IF 6.428) Pub Date : 2018-02-01
    Young Hun Kim, Mi Seong Jo, Jin Kwon Kim, Jae Hoon Shin, Jin Ee Baek, Hye Seon Park, Hyo Jin An, Jong Seong Lee, Boo Wook Kim, Hoi Pin Kim, Kang Ho Ahn, KiSoo Jeon, Seung Min Oh, Ji Hyun Lee, Tomomi Workman, Elaine M. Faustman, Il Je Yu

    Graphene oxides possess unique physicochemical properties with important potential applications in electronics, pharmaceuticals, and medicine. However, the toxicity following inhalation exposure to graphene oxide has not yet been clarified. Therefore, this study conducted a short-term graphene oxide inhalation toxicity analysis using a nose-only inhalation exposure system and male Sprague–Dawley rats. A total of four groups (15 rats per group) were exposed: (1) control (fresh air), (2) low concentration (0.76 ± 0.16 mg/m3), (3) moderate concentration (2.60 ± 0.19 mg/m3), and (4) high concentration (9.78 ± 0.29 mg/m3). The rats were exposed to graphene oxide for 6 h/day for 5 days, followed by recovery for 1, 3, and 21 days. No significant body or organ weight changes were noted after the short-term exposure or during the recovery period. Similarly, no significant systemic effects of toxicological importance were noted in the hematological assays, bronchoalveolar lavage fluid (BAL) inflammatory markers, BAL fluid cytokines, or blood biochemical assays following the graphene oxide exposure or during the post-exposure observation period. Moreover, no significant differences were observed in the BAL cell differentials, such as lymphocytes, macrophages, or polymorphonuclear cells. Graphene oxide-ingested alveolar macrophages as a spontaneous clearance reaction were observed in the lungs of all the concentration groups from post 1 day to post 21 days. Histopathological examination of the liver and kidneys did not reveal any significant test-article-relevant histopathological lesions. Importantly, similar to previously reported graphene inhalation data, this short-term nose-only inhalation study found only minimal or unnoticeable graphene oxide toxicity in the lungs and other organs.

  • Copper oxide nanoparticles induce collagen deposition via TGF-β1/Smad3 signaling in human airway epithelial cells
    Nanotoxicology (IF 6.428) Pub Date : 2018-01-31
    Je-Won Ko, Na-Rae Shin, Ji-Won Park, Sung-Hyeuk Park, In-Chul Lee, Joong-Sun Kim, Jong-Choon Kim, Kyung-Seop Ahn, In-Sik Shin

    Use and application of nanoparticles has increased in recent years. Copper oxide nanoparticles (CuONPs) are one of the most common types of nanoparticles, and they are mainly used as catalysts and preservatives. However, limited toxicity data are available on the toxicity of CuONPs to the respiratory system. We investigated fibrotic responses induced by CuONPs in the respiratory tract and elucidated its underlying mechanism of action in vivo and in vitro experiments. In the mouse model, CuONPs exposure markedly increased transforming growth factor-β1 (TGF-β1) and collagen I expression and Smad3 phosphorylation, combined with elevation of inflammatory mediators including interleukin (IL)-1β, IL-6, and tumor necrosis factor-α (TNF-α). These alterations were also observed in histological analysis of lung tissue. CuONPs markedly increased inflammatory responses and collagen deposition, accompanied by the elevation of TGF-β1 and collagen I expression in lung tissue. In addition, CuONPs-treated H292 cells showed significantly increased mRNA and protein production of TGF-β1, collagen I, IL-6, and TNF-α; this response was markedly decreased by treatment of a TGF-β1 inhibitor (SB-431542). Taken together, CuONPs induced fibrotic responses in the respiratory tract, closely related to TGF-β1/Smad3 signaling. Therefore, our results raise the necessity of further investigation for the present state of its risk by providing useful information of the toxicity of CuONPs.

  • Metabolomics reveals the depletion of intracellular metabolites in HepG2 cells after treatment with gold nanoparticles
    Nanotoxicology (IF 6.428) Pub Date : 2018-02-02
    Jeremie Zander Lindeque, Alnari Matthyser, Shayne Mason, Roan Louw, Cornelius Johannes Francois Taute

    Studies on the safety of gold nanoparticles (GNPs) are plentiful due to their successful application in drug delivery and treatment of diseases in trials. Cytotoxicity caused by GNPs has been studied on the physiological and biochemical level; yet, the effect of GNPs (particularly gold nano-spheres) on the metabolome of living organisms remains understudied. In this investigation, metabolomics was used to comprehensively study the metabolic alterations in HepG2 cells caused by GNPs; and to investigate the role of representative GNP coatings. GNPs were synthesized, coated and characterized before use on HepG2 cell cultures. Cells were treated for 3 h with citrate-, poly-(sodiumsterene sulfunate)-, and poly-vinylpyrrolidone (PVP)-capped GNPs, respectively. The internalization of the different GNPs and their effect on mitochondrial respiration and the metabolome were studied. Results indicated that the PVP-capped GNPs internalized more and also caused a more observable effect on the metabolome. Conversely, it was the citrate- and poly-(sodiumsterene sulfunate) coated particles that influenced ATP production in addition to the metabolomic changes. A holistic depletion of intracellular metabolites was observed regardless of GNP coating, which hints to the binding of certain metabolites to the particles.

  • Nanosilver and the microbiological activity of the particulate solids versus the leached soluble silver
    Nanotoxicology (IF 6.428) Pub Date : 2018-02-15
    Merisa B. Faiz, Rose Amal, Christopher P. Marquis, Elizabeth J. Harry, Georgios A. Sotiriou, Scott A. Rice, Cindy Gunawan

    Nanosilver (Ag NPs) is currently one of the most commercialized antimicrobial nanoparticles with as yet, still unresolved cytotoxicity origins. To date, research efforts have mostly described the antimicrobial contribution from the leaching of soluble silver, while the undissolved solid Ag particulates are often considered as being microbiologically inert, serving only as source of the cytotoxic Ag ions. Here, we show the rapid stimulation of lethal cellular oxidative stress in bacteria by the presence of the undissolved Ag particulates. The cytotoxicity characteristics are distinct from those arising from the leached soluble Ag, the latter being locked in organic complexes. The work also highlights the unique oxidative stress-independent bacterial toxicity of silver salt. Taken together, the findings advocate that future enquiries on the antimicrobial potency and also importantly, the environmental and clinical impact of Ag NPs use, should pay attention to the potential bacterial toxicological responses to the undissolved Ag particulates, rather than just to the leaching of soluble silver. The findings also put into question the common use of silver salt as model material for evaluating bacterial toxicity of Ag NPs.

  • Dendritic polyglycerol nanoparticles show charge dependent bio-distribution in early human placental explants and reduce hCG secretion
    Nanotoxicology (IF 6.428) Pub Date : 2018-01-15
    Herbert Juch, Liudmila Nikitina, Sabine Reimann, Martin Gauster, Gottfried Dohr, Barbara Obermayer-Pietsch, Denise Hoch, Karin Kornmueller, Rainer Haag

    A thorough understanding of nanoparticle bio-distribution at the feto-maternal interface will be a prerequisite for their diagnostic or therapeutic application in women of childbearing age and for teratologic risk assessment. Therefore, the tissue interaction of biocompatible dendritic polyglycerol nanoparticles (dPG-NPs) with first- trimester human placental explants were analyzed and compared to less sophisticated trophoblast-cell based models. First-trimester human placental explants, BeWo cells and primary trophoblast cells from human term placenta were exposed to fluorescence labeled, ∼5 nm dPG-NPs, with differently charged surfaces, at concentrations of 1 µM and 10 nM, for 6 and 24 h. Accumulation of dPGs was visualized by fluorescence microscopy. To assess the impact of dPG-NP on trophoblast integrity and endocrine function, LDH, and hCG releases were measured. A dose- and charge-dependent accumulation of dPG-NPs was observed at the early placental barrier and in cell lines, with positive dPG-NP-surface causing deposits even in the mesenchymal core of the placental villi. No signs of plasma membrane damage could be detected. After 24 h we observed a significant reduction of hCG secretion in placental explants, without significant changes in trophoblast apoptosis, at low concentrations of charged dPG-NPs. In conclusion, dPG-NP’s surface charge substantially influences their bio-distribution at the feto-maternal interface, with positive charge facilitating trans-trophoblast passage, and in contrast to more artificial models, the first-trimester placental explant culture model reveals potentially hazardous influences of charged dPG-NPs on early placental physiology.

  • Silver nanoparticles induce neurotoxicity in a human embryonic stem cell-derived neuron and astrocyte network
    Nanotoxicology (IF 6.428) Pub Date : 2018-01-15
    Neza Repar, Hao Li, Jose S. Aguilar, Qingshun Quinn Li, Damjana Drobne, Yiling Hong

    Silver nanoparticles (AgNPs) are among the most extensively used nanoparticles and are found in a variety of products. This ubiquity leads to inevitable exposure to these particles in everyday life. However, the effects of AgNPs on neuron and astrocyte networks are still largely unknown. In this study, we used neurons and astrocytes derived from human embryonic stem cells as a cellular model to study the neurotoxicity that is induced by citrate-coated AgNPs (AgSCs). Immunostaining with the astrocyte and neuron markers, glial fibrillary acidic protein and microtubule-associated protein-2 (MAP2), respectively, showed that exposure to AgSCs at the concentration of 0.1 µg/mL increased the astrocyte/neuron ratio. In contrast, a higher concentration of AgSCs (5.0 µg/ml) significantly changed the morphology of astrocytes. These results suggest that astrocytes are sensitive to AgSC exposure and that low concentrations of AgSCs promote astrogenesis. Furthermore, our results showed that AgSCs reduced neurite outgrowth, decreased the expression of postsynaptic density protein 95 and synaptophysin, and induced neurodegeneration in a concentration-dependent manner. Our findings additionally suggest that the expression and phosphorylation status of MAP2 isoforms, as modulated by the activation of the Akt/glycogen synthase kinase-3/caspase-3 signaling pathway, may play an important role in AgSC-mediated neurotoxicity. We also found that AgNO3 exposure only slightly reduced neurite outgrowth and had little effect on MAP2 expression, suggesting that AgSCs and AgNO3 have different neuronal toxicity mechanisms. In addition, most of these effects were reduced when the cell culture was co-treated with AgSCs and the antioxidant ascorbic acid, which implies that oxidative stress is the major cause of AgSC-mediated astrocytic/neuronal toxicity and that antioxidants may have a neuroprotective effect.

  • Graphene oxide regulates cox2 in human embryonic kidney 293T cells via epigenetic mechanisms: dynamic chromosomal interactions
    Nanotoxicology (IF 6.428) Pub Date : 2018-01-16
    Yuxiang Sun, Hui Dai, Shaopeng Chen, Ming Xu, Xuanyu Wang, Yajun Zhang, Shengmin Xu, An Xu, Jian Weng, Sijin Liu, Lijun Wu

    To extend the applications of engineered nanomaterials, such as graphene oxide (GO), it is necessary to minimize cytotoxicity. However, the mechanisms underlying this cytotoxicity are unclear. Dynamic chromosomal interactions have been used to illustrate the molecular bases of gene expression, which offers a more sensitive and cutting-edge technology to elucidate complex biological processes associated with epigenetic regulations. In this study, the role of GO-triggered chromatin interactions in the activation of cox2, a hallmark of inflammation, was investigated in normal human cells. Using chromosome conformation capture technology, we showed that GO triggers physical interactions between the downstream enhancer and the cox2 promoter in human embryonic kidney 293T (293T) via p65 and p300 complex-mediated dynamic chromatin looping, which was required for high cox2 expression. Moreover, tumor necrosis factor-α (TNF-α), located upstream of the p65 signaling pathway, contributed to the regulation of cox2 activation through dynamic chromatin architecture. Compared with pristine GO and aminated GO (GO-NH2), poly (acrylic acid)-functionalized GO (GO-PAA) induced a weaker inflammatory response and a weaker effect on chromatin architecture. Our results mechanistically link GO-mediated chromatin interactions with the regulation of cox2 and suggest that GO derivatives may minimize toxicity in practical applications.

  • Characterization of the proteome and lipidome profiles of human lung cells after low dose and chronic exposure to multiwalled carbon nanotubes
    Nanotoxicology (IF 6.428) Pub Date : 2018-01-19
    Santosh Phuyal, Mayes Kasem, Oskar Knittelfelder, Animesh Sharma, Davi de Miranda Fonseca, Vaineta Vebraite, Sergey Shaposhnikov, Geir Slupphaug, Vidar Skaug, Shanbeh Zienolddiny

    The effects of long-term chronic exposure of human lung cells to multi-walled carbon nanotubes (MWCNT) and their impact upon cellular proteins and lipids were investigated. Since the lung is the major target organ, an in vitro normal bronchial epithelial cell line model was used. Additionally, to better mimic exposure to manufactured nanomaterials at occupational settings, cells were continuously exposed to two non-toxic and low doses of a MWCNT for 13-weeks. MWCNT-treatment increased ROS levels in cells without increasing oxidative DNA damage and resulted in differential expression of multiple anti- and pro-apoptotic proteins. The proteomic analysis of the MWCNT-exposed cells showed that among more than 5000 identified proteins; more than 200 were differentially expressed in the treated cells. Functional analyses revealed association of these differentially regulated proteins to cellular processes such as cell death and survival, cellular assembly, and organization. Similarly, shotgun lipidomic profiling revealed accumulation of multiple lipid classes. Our results indicate that long-term MWCNT-exposure of human normal lung cells at occupationally relevant low-doses may alter both the proteome and the lipidome profiles of the target epithelial cells in the lung.

  • Macrophage polarization and activation at the interface of multi-walled carbon nanotube-induced pulmonary inflammation and fibrosis
    Nanotoxicology (IF 6.428) Pub Date : 2018-01-16
    Jie Dong, Qiang Ma

    Pulmonary exposure to carbon nanotubes (CNTs) induces fibrosing lesions in the lungs that manifest rapid-onset inflammatory and fibrotic responses, leading to chronic fibrosis in animals and health concerns in exposed humans. The mechanisms underlying CNT-induced fibrogenic effects remain undefined. Macrophages are known to play important roles in immune regulation and fibrosis development through their distinct subsets. Here we investigated macrophage polarization and activation in mouse lungs exposed to multi-walled CNTs (MWCNTs). Male C57BL/6J mice were treated with MWCNTs (XNRI MWNT-7) at 40 μg per mouse (∼1.86 mg/kg body weight) by oropharyngeal aspiration. The treatment stimulated prominent acute inflammatory and fibrotic responses. Moreover, it induced pronounced enrichment and polarization of macrophages with significantly increased M1 and M2 populations in a time-dependent manner. Induction of M1 polarization was apparent on day 1 with a peak on day 3, but declined rapidly thereafter. On the other hand, the M2 polarization was induced on day 1 modestly, but was remarkably elevated on day 3 and maintained at a high level through day 7. M1 and M2 macrophages were functionally activated by MWCNTs as indicated by the expression of their distinctive functional markers, such as iNOS and ARG1, with time courses parallel to M1 and M2 polarization, respectively. Molecular analysis revealed MWCNTs boosted specific STAT and IRF signaling pathways to regulate M1 and M2 polarization in the lungs. These findings suggest a new mechanistic connection between inflammation and fibrosis induced by MWCNTs through the polarization and activation of macrophages during MWCNT-induced lung pathologic response.

  • Cardiopulmonary effects induced by occupational exposure to titanium dioxide nanoparticles
    Nanotoxicology (IF 6.428) Pub Date : 2018-01-11
    Lin Zhao, Yifang Zhu, Zhangjian Chen, Huadong Xu, Jingwen Zhou, Shichuan Tang, Zhizhen Xu, Fanling Kong, Xinwei Li, Yifei Zhang, Xianzuo Li, Ji Zhang, Guang Jia

    Although some toxicological studies have reported that exposure to titanium dioxide nanoparticles (nano-TiO2) may elicit adverse cardiopulmonary effects, related data collected from human are currently limited. The purpose of this study is to explore cardiopulmonary effects among workers who were exposed to nano-TiO2 and to identify biomarkers associated with exposure. A cross-sectional study was conducted in a nano-TiO2 manufacturing plant in eastern China. Exposure assessment and characterization of TiO2 particles were performed in a packaging workshop. Physical examination and possible biomarkers for cardiopulmonary effects were examined among 83 exposed workers and 85 controls. In packaging workshop, the total mass concentration of particles was 3.17 mg/m3. The mass concentration of nanoparticles was 1.22 mg/m3 accounting for 39% of the total mass. Lung damage markers (SP-D and pulmonary function), cardiovascular disease markers (VCAM-1, ICAM-1, LDL, and TC), oxidative stress markers (SOD and MDA), and inflammation markers (IL-8, IL-6, IL-1β, TNF-α, and IL-10) were associated with occupational exposure to nano-TiO2. Among those markers, SP-D showed a time (dose)–response pattern within exposed workers. The data strongly suggest that nano-TiO2 could contribute, at least in part, to the cardiopulmonary effects observed in workers. The studied markers and pulmonary function tests may be useful in health surveillance for workers exposed to nanomaterials.

  • Inhibition of the proteasome activity by graphene oxide contributes to its cytotoxicity
    Nanotoxicology (IF 6.428) Pub Date : 2018-01-16
    Xiaochuan Ma, Sangyun Lee, Xingshu Fei, Ge Fang, Tien Huynh, Yu Chong, Zhifang Chai, Cuicui Ge, Ruhong Zhou

    Due to its hydrophobicity and other unique physicochemical properties, graphene oxide (GO) has been extensively utilized in various biological applications. However, introducing nanomaterials into the biological environment may raise serious risk in terms of nanotoxicity, leading to some unintended changes to the structure and the function of other biomolecules. This study investigates the interaction of GO with the ubiquitin–proteasome system, one of the essential machineries in the cellular metabolism, using a combination of experimental and computational approaches. The experimental results show that GO could adsorb the 20S proteasome, causing a dose-dependent suppression of the proteolytic activity of proteasome. This adverse effect eventually disturbed other important cellular activities relevant to cell cycle and survival. Meanwhile, the molecular dynamics simulations revealed that when 20S proteasome was adsorbed onto the graphene surface, the central gate in the outer ring (α-subunit) for the entry and the exit of the peptide ligand to the protease active site was effectively blocked. These findings of GO induced functional disturbance of 20S proteasome provides a novel perspective to understand the molecular mechanism of GO’s cytotoxicity, which might further promote applications of GO in potential therapies for various cancers due to the abnormal elevation of the relevant proteasome activities.

  • Decision tree models to classify nanomaterials according to the DF4nanoGrouping scheme
    Nanotoxicology (IF 6.428) Pub Date : 2017-12-18
    Agnieszka Gajewicz, Tomasz Puzyn, Katarzyna Odziomek, Piotr Urbaszek, Andrea Haase, Christian Riebeling, Andreas Luch, Muhammad A. Irfan, Robert Landsiedel, Meike van der Zande, Hans Bouwmeester

    To keep pace with its rapid development an efficient approach for the risk assessment of nanomaterials is needed. Grouping concepts as developed for chemicals are now being explored for its applicability to nanomaterials. One of the recently proposed grouping systems is DF4nanoGrouping scheme. In this study, we have developed three structure-activity relationship classification tree models to be used for supporting this system by identifying structural features of nanomaterials mainly responsible for the surface activity. We used data from 19 nanomaterials that were synthesized and characterized extensively in previous studies. Subsets of these materials have been used in other studies (short-term inhalation, protein carbonylation, and intrinsic oxidative potential), resulting in a unique data set for modeling. Out of a large set of 285 possible descriptors, we have demonstrated that only three descriptors (size, specific surface area, and the quantum-mechanical calculated property ‘lowest unoccupied molecular orbital’) need to be used to predict the endpoints investigated. The maximum number of descriptors that were finally selected by the classification trees (CT) was very low– one for intrinsic oxidative potential, two for protein carbonylation, and three for NOAEC. This suggests that the models were well-constructed and not over-fitted. The outcome of various statistical measures and the applicability domains of our models further indicate their robustness. Therefore, we conclude that CT can be a useful tool within the DF4nanoGrouping scheme that has been proposed before.

  • Research on the hepatotoxicity mechanism of citrate-modified silver nanoparticles based on metabolomics and proteomics
    Nanotoxicology (IF 6.428) Pub Date : 2017-12-18
    Jiabin Xie, Wenying Dong, Rui Liu, Yuming Wang, Yubo Li

    Citrate-modified silver nanoparticles (AgNP-cit) have received extensive attention due to their excellent antimicrobial properties. However, these particles tend to migrate in vivo, thereby entering the blood circulatory system in granular form and accumulating in the liver, causing toxic reactions. However, the mechanism underlying AgNP-cit toxicity is not yet clear. Thus, we adopted a tandem mass tag (TMT)-labeled quantitative proteomics and metabolomics approach to identify proteins and small molecule metabolites associated with AgNP-cit-induced liver damage and constructed interaction networks between the differentially expressed proteins and metabolites to explain the AgNP-cit toxicity mechanism. AgNP-cit resulted in abnormal purine metabolism mainly by affecting xanthine and other key metabolites along with pyruvate kinase and other bodily proteins, leading to oxidative stress. AgNP-cit regulated the metabolism of amino acids and glycerol phospholipids through glycerol phospholipids, CYP450 enzymes and other key proteins, causing liver inflammation. Via alanine, isoleucine, L-serine dehydratase/L-threonine deaminase and other proteins, AgNP-cit altered the metabolism of glycine, serine and threonine, cysteine and methionine, affecting oxidation and deamination, and ultimately leading to liver damage. This work clearly explains toxic reactions induced by AgNP-cit from three perspectives, oxidative stress, inflammatory response, and oxidation and deamination, thus providing an experimental basis for the safe application of nanomaterials.

  • Reactive oxygen species damage drives cardiac and mitochondrial dysfunction following acute nano-titanium dioxide inhalation exposure
    Nanotoxicology (IF 6.428) Pub Date : 2017-12-15
    Cody E. Nichols, Danielle L. Shepherd, Quincy A. Hathaway, Andrya J. Durr, Dharendra Thapa, Alaeddin Abukabda, Jinghai Yi, Timothy R. Nurkiewicz, John M. Hollander

    Nanotechnology offers innovation in products from cosmetics to drug delivery, leading to increased engineered nanomaterial (ENM) exposure. Unfortunately, health impacts of ENM are not fully realized. Titanium dioxide (TiO2) is among the most widely produced ENM due to its use in numerous applications. Extrapulmonary effects following pulmonary exposure have been identified and may involve reactive oxygen species (ROS). The goal of this study was to determine the extent of ROS involvement on cardiac function and the mitochondrion following nano-TiO2 exposure. To address this question, we utilized a transgenic mouse model with overexpression of a novel mitochondrially-targeted antioxidant enzyme (phospholipid hydroperoxide glutathione peroxidase; mPHGPx) which provides protection against oxidative stress to lipid membranes. MPHGPx mice and littermate controls were exposed to nano-TiO2 aerosols (Evonik, P25) to provide a calculated pulmonary deposition of 11 µg/mouse. Twenty-four hours following exposure, we observed diastolic dysfunction as evidenced by E/A ratios greater than 2 and increased radial strain during diastole in wild-type mice (p < 0.05 for both), indicative of restrictive filling. Overexpression of mPHGPx mitigated the contractile deficits resulting from nano-TiO2 exposure. To investigate the cellular mechanisms associated with the observed cardiac dysfunction, we focused our attention on the mitochondrion. We observed a significant increase in ROS production (p < 0.05) and decreased mitochondrial respiratory function (p < 0.05) following nano-TiO2 exposure which were attenuated in mPHGPx transgenic mice. In summary, nano-TiO2 inhalation exposure is associated with cardiac diastolic dysfunction and mitochondrial functional alterations, which can be mitigated by the overexpression of mPHGPx, suggesting ROS contribution in the development of contractile and bioenergetic dysfunction.

  • Fluorescent nanoparticles present in Coca-Cola and Pepsi-Cola: physiochemical properties, cytotoxicity, biodistribution and digestion studies
    Nanotoxicology (IF 6.428) Pub Date : 2017-12-20
    Shen Li, Chengkun Jiang, Haitao Wang, Shuang Cong, Mingqian Tan

    Foodborne nanoparticles (NPs) have drawn great attention due to human health concerns. This study reports the detection of the presence of fluorescent NPs, about 5 nm, in two of the most popular beverages, Coca-Cola (Coke) and Pepsi-Cola (Pepsi). The NPs contain H, C and O, three elements with a tunable emission and with a quantum yield of 3.3 and 4.3% for Coke and Pepsi, respectively. The presence of sp3-hybridized carbon atoms of alcohols and ethers bonds was confirmed by NMR analysis. The NPs can be taken up by living cells and accumulate within cell membrane and cytoplasm. Evaluation of the acute toxicity of the NPs revealed that the BALB/c mice appeared healthy after administration of a single dose of 2 g kg−1 body weight. Analysis of glutamate pyruvate transaminase (GPT), glutamic oxaloacetic transaminase (GOT), urea and creatinine showed that there were statistically, but not biologically, significant differences in some of these biochemical parameters between the test and control groups. No obvious organ damage or apparent histopathological abnormality was observed in the tested mice. The biodistribution study in major organs indicated that the NPs were easily accumulated in the digestive tract, and they were able to cross the blood–brain barrier and dispersed in the brain. In vitro digestion of the NPs showed a significant fluorescence quenching of the NPs. This work represents the first report of foodborne fluorescent NPs present in Coke and Pepsi, and provides valuable insights into physicochemical properties of these NPs and their toxicity characteristics both in vitro and in vivo.

  • Dissolution and bandgap paradigms for predicting the toxicity of metal oxide nanoparticles in the marine environment: an in vivo study with oyster embryos
    Nanotoxicology (IF 6.428) Pub Date : 2017-12-20
    Seta Noventa, Christian Hacker, Darren Rowe, Christine Elgy, Tamara Galloway

    Dissolution and bandgap paradigms have been proposed for predicting the ability of metal oxide nanoparticles (NPs) to induce oxidative stress in different in vitro and in vivo models. Here, we addressed the effectiveness of these paradigms in vivo and under conditions typical of the marine environment, a final sink for many NPs released through aquatic systems. We used ZnO and MnO2 NPs as models for dissolution and bandgap paradigms, respectively, and CeO2 NPs to assess reactive oxygen radical (ROS) production via Fenton-like reactions in vivo. Oyster embryos were exposed to 0.5–500 μM of each test NP over 24 h and oxidative stress was determined as a primary toxicity pathway across successive levels of biological complexity, with arrested development as the main pathological outcome. NPs were actively ingested by oyster larvae and entered cells. Dissolution was a viable paradigm for predicting the toxicity of NPs in the marine environment, whereas the surface reactivity based paradigms (i.e. bandgap and ROS generation via Fenton-like reaction) were not supported under seawater conditions. Bio-imaging identified potential cellular storage-disposal sites of solid particles that could ameliorate the toxicological behavior of non-dissolving NPs, whilst abiotic screening of surface reactivity suggested that the adsorption-complexation of surface active sites by seawater ions could provide a valuable hypothesis to explain the quenching of the intrinsic oxidation potential of MnO2 NPs in seawater.

  • Long-term effects of tungsten carbide (WC) nanoparticles in pelagic and benthic aquatic ecosystems
    Nanotoxicology (IF 6.428) Pub Date : 2018-01-15
    Mikael T. Ekvall, Jonas Hedberg, Inger Odnevall Wallinder, Lars-Anders Hansson, Tommy Cedervall

    As the production and usage of nanomaterials are increasing so are the concerns related to the release of the material into nature. Tungsten carbide (WC) is widely used for its hard metal properties, although its use, in for instance tyre studs, may result in nano-sized particles ending up in nature. Here, we evaluate the potential long-term exposure effects of WC nanoparticles on a pelagic (Daphnia magna) and a benthic (Asellus aquaticus) organism. No long-term effects were observed in the benthic system with respect to population dynamics or ecosystem services. However, long-term exposure of D. magna resulted in increased time to first reproduction and, if the particles were resuspended, strong effects on survival and reproductive output. Hence, the considerable differences in acute vs. long-term exposure studies revealed here emphasize the need for more long-term studies if we are to understand the effects of nanoparticles in natural systems.

  • Potential impact of inorganic nanoparticles on macronutrient digestion: titanium dioxide nanoparticles slightly reduce lipid digestion under simulated gastrointestinal conditions
    Nanotoxicology (IF 6.428) Pub Date : 2017-11-21
    Qian Li, Ti Li, Chengmei Liu, Glen DeLoid, Georgios Pyrgiotakis, Philip Demokritou, Ruojie Zhang, Hang Xiao, David Julian McClements

    Titanium dioxide (TiO2) particles are used in some food products to alter their optical properties, such as whiteness or brightness. These additives typically contain a population of TiO2 nanoparticles (d < 100 nm), which has led to concern about their potential toxicity. The objective of this study was to examine the impact of TiO2 particles on the gastrointestinal fate of oil-in-water emulsions using a simulated gastrointestinal tract (GIT) that includes mouth, stomach, and small intestine phases. Theoretical predictions suggested that TiO2 nanoparticles might inhibit lipid digestion through two physicochemical mechanisms: (i) a fraction of the lipase adsorbs to TiO2 particle surfaces, thereby reducing the amount available to hydrolyze lipid droplets; (ii) some TiO2 particles adsorb to the surfaces of lipid droplets, thereby reducing the lipid surface area exposed to lipase. The importance of these mechanisms was tested by passing protein-coated lipid droplets (2%, w/w) through the simulated GIT in the absence and presence of TiO2 (0.5%, w/w) nanoparticles (18 nm) and fine particles (167 nm). Changes in particle characteristics (size, organization, and charge) and lipid digestion were then measured. Both TiO2 nanoparticles and fine particles had little impact on the aggregation state and charge of the lipid droplets in the different GIT regions, as well as on the rate and extent of lipid digestion. This suggests that the theoretically predicted impact of particle size on lipid digestion was not seen in practice.

  • Graphene oxide significantly inhibits cell growth at sublethal concentrations by causing extracellular iron deficiency
    Nanotoxicology (IF 6.428) Pub Date : 2017-11-09
    Qilin Yu, Bing Zhang, Jianrong Li, Tingting Du, Xiao Yi, Mingchun Li, Wei Chen, Pedro J. J. Alvarez

    Graphene oxide (GO)-based materials are increasingly being used in medical materials and consumer products. However, their sublethal effects on biological systems are poorly understood. Here, we report that GO (at 10 to 160 mg/L) induced significant inhibitory effects on the growth of different unicellular organisms, including eukaryotes (i.e. Saccharomyces cerevisiae, Candida albicans, and Komagataella pastoris) and prokaryotes (Pseudomonas fluorescens). Growth inhibition could not be explained by commonly reported cytotoxicity mechanisms such as plasma membrane damage or oxidative stress. Based on transcriptomic analysis and measurement of extra- and intracellular iron concentrations, we show that the inhibitory effect of GO was mainly attributable to iron deficiency caused by binding to the O-functional groups of GO, which sequestered iron and disrupted iron-related physiological and metabolic processes. This inhibitory mechanism was corroborated with supplementary experiments, where adding bathophenanthroline disulfonate—an iron chelating agent—to the culture medium exerted similar inhibition, whereas removing surface O-functional groups of GO decreased iron sequestration and significantly alleviated the inhibitory effect. These findings highlight a potential indirect detrimental effect of nanomaterials (i.e. scavenging of critical nutrients), and encourage research on potential biomedical applications of GO-based materials to sequester iron and enhance treatment of iron-dependent diseases such as cancer and some pathogenic infections.

  • Distinct toxic interactions of TiO2 nanoparticles with four coexisting organochlorine contaminants on algae
    Nanotoxicology (IF 6.428) Pub Date : 2017-11-07
    Shuai Zhang, Rui Deng, Daohui Lin, Fengchang Wu

    Engineered nanoparticles are increasingly discharged into the environment. After discharge, these nanoparticles can interact with co-existing organic contaminants, resulting in a phenomena referred to as ‘joint toxicity’. This study evaluated joint toxicities of TiO2 nanoparticles (TiO2NPs) with four different (atrazine, hexachlorobenzene, pentachlorobenzene, and 3,3′,4,4′-tetrachlorobiphenyl) organochlorine contaminants (OCs) toward algae (Chlorella pyrenoidosa). The potential mechanisms underlying the joint toxicity were discussed, including TiO2NPs–OC interactions, effects of TiO2NPs and OCs on biophysicochemical properties of algae and effects of TiO2NPs and OCs on each other’s bioaccumulation in algae. The results indicate that coexposure led to a synergistic effect on the joint toxicity for TiO2NPs–atrazine, antagonistic effect for TiO2NPs–hexachlorobenzene and TiO2NPs–3,3',4,4'-tetrachlorobiphenyl, and an additive effect for TiO2NPs–pentachlorobenzene. There was nearly no adsorption of OCs by TiO2NPs, and the physicochemical properties of TiO2NPs were largely unaltered by the presence of OCs. However, both OCs and NPs affected the biophysicochemical properties of algal cells and thereby influenced the cell surface binding and/or internalization. TiO2NPs significantly increased the bioaccumulation of each OC. However, with the exception of atrazine, the bioaccumulation of TiO2NPs decreased when used with each OC. The distinct joint toxicity outcomes were a result of the balance between the increased toxicities of OCs (increased bioaccumulations) and the altered toxicity of TiO2NPs (bioaccumulation can either increase or decrease). These results can significantly improve our understanding of the potential environmental risks associated with NPs.

  • Comparison of acute to chronic ratios between silver and gold nanoparticles, using Ceriodaphnia dubia
    Nanotoxicology (IF 6.428) Pub Date : 2017-12-01
    Ashley R. Harmon, Alan J. Kennedy, Jennifer G. Laird, Anthony J. Bednar, Jeffery A. Steevens

    As integration of nanoparticles (NPs) into products becomes more common, the need to address the paucity of chronic hazard information for aquatic environments required to determine risk potential increases. This study generated acute and chronic toxicity reference values for Ceriodaphnia dubia exposed to 20 and 100 nm silver nanoparticles (AgNPs) and gold nanoparticles (AuNPs) to generate and evaluate potential differences in acute-to-chronic ratios (ACR) using two different feeding methods. A modified feeding procedure was employed alongside the standard procedures to investigate the influence of food on organism exposure. An 8-h period before food was added allowed direct organism exposure to NP dispersions (and associated ions) without food-to-NP interactions. The AgNPs [chronic lethal median concentrations (LC50) between 18.7 and 31.9 µg/L] were substantially more toxic than AuNPs (LC50 = 21 507 to >26 384 µg/L). The modified chronic testing method resulted in greater sensitivity in AgNPs exposures. However, the modified feeding ration had less of an effect in exposures to the larger (100 nm) AgNPs compared to smaller particles (20 nm). The ACRs for AgNPs using the standard feeding ration were 1.6 and 3.5 for 20 nm and 100 nm, respectively. The ACRs for AgNPs using the modified feeding ration were 3.4 and 7.6 for 20 nm and 100 nm NPs, respectively. This supports that the addition of the standard feeding ration decreases C. dubia chronic sensitivity to AgNPs, although it must also be recognized organisms may be sensitized due to less access to food. The ACRs for 20 nm and 100 nm AuNPs (standard ration only) were 4.0 and 3.0, respectively. It is important to also consider that dissolved Ag+ ions are more toxic than AgNPs, based on both acute toxicity values in the cited literature and chronic toxicity thresholds generated in this study that support existing thresholds that Ag+ are likely protective of AgNPs effects.

  • Impact of TiO2 and ZnO nanoparticles on an aquatic microbial community: effect at environmentally relevant concentrations
    Nanotoxicology (IF 6.428) Pub Date : 2017-11-10
    Nathalia Londono, Ariel R. Donovan, Honglan Shi, Matthew Geisler, Yanna Liang

    To investigate effects of engineered nanoparticles (ENPs) at environmentally relevant concentrations to aquatic microbial communities, TiO2 at 700 µg/L and ZnO at 70 µg/L were spiked to river water samples either separately or combined. Compared to controls where no ENPs were added, the addition of TiO2 ENPs alone at the tested concentration had no statistically significant effect on both the bacterial and eukaryotic communities. The presence of added ENPs: ZnO or ZnO + TiO2 led to significant shift of the microbial community structure and genus distribution. This shift was more obvious for the bacteria than the eukaryotes. Based on results from single particle – inductively coupled plasma – mass spectrometry (SP-ICP-MS), all ENPs aggregated rapidly in water and resulted in much larger particles sizes than the original counterparts. “Dissolved” (including particles smaller than the size detection limits and dissolved ions) concentrations of Ti and Zn increased, too in treatment groups vs. the controls.

  • Bacterial endotoxin (lipopolysaccharide) binds to the surface of gold nanoparticles, interferes with biocorona formation and induces human monocyte inflammatory activation
    Nanotoxicology (IF 6.428) Pub Date : 2017-12-01
    Yang Li, Zhenzhen Shi, Isabella Radauer-Preiml, Ancuela Andosch, Eudald Casals, Ursula Luetz-Meindl, Macarena Cobaleda, Zhoumeng Lin, Majid Jaberi-Douraki, Paola Italiani, Jutta Horejs-Hoeck, Martin Himly, Nancy A. Monteiro-Riviere, Albert Duschl, Victor F. Puntes, Diana Boraschi

    Nanoparticles (NPs) are easily contaminated by bacterial endotoxin (lipopolysaccharide [LPS]). The presence of LPS can be responsible for many immune/inflammatory effects attributed to NPs. In this study, we examined the effects of LPS adsorption on the NP surface on the formation of a biocorona in biological fluids and on the subsequent inflammation-inducing activity of NPs. Different gold (Au) NPs with sizes ranging from 10 to 80 nm and with different surface functionalization (sodium citrate, lipoic acid, and branched polyethyleneimine (BPEI), or polyethylene glycol (PEG)) were exposed to E. coli LPS under different conditions. The binding capacity of LPS to the surface of AuNPs was dose- and time-dependent. LPS attached to sodium citrate and lipoic acid coatings, but did not adhere to BPEI- or PEG-coated NPs. By computational simulation, the binding of LPS to AuNPs seems to follow the Langmuir absorption isotherm. The presence of LPS on AuNP surface interfered and caused a decrease in the formation of the expected biomolecular corona upon incubation in human plasma. LPS-coated AuNPs, but not the LPS-free NPs, induced significant inflammatory responses in vitro. Notably, while free LPS did also induce an anti-inflammatory response, LPS bound to NPs appeared unable to do so. In conclusion, the unintentional adsorption of LPS onto the NP surface can affect the biocorona formation and the inflammatory properties of NPs. Thus, for an accurate interpretation of NP interactions with cells, it is extremely important to be able to distinguish the intrinsic NP biological effects from those caused by biologically active contaminants such as endotoxin.

  • Amorphous silica nanoparticles induce malignant transformation and tumorigenesis of human lung epithelial cells via P53 signaling
    Nanotoxicology (IF 6.428) Pub Date : 2017-11-22
    Caixia Guo, Ji Wang, Man Yang, Yang Li, Shuxiang Cui, Xianqing Zhou, Yanbo Li, Zhiwei Sun

    Rapid development and deployment of engineered nanomaterials, such as amorphous silica nanoparticles (SiNPs) in various commercial and biomedical applications have raised concerns about their potential adverse health effects, especially their chronic effects which have not been well addressed. In this study, human lung epithelial cells, BEAS-2B were continuously exposed to amorphous SiNPs, 5 μg/mL for 40 passages. We demonstrated here that prolonged exposure of BEAS-2B cells to amorphous SiNPs induced malignant transformation as indicated by enhanced cellular proliferation, anchorage-independent cell growth, and increased cell migration. The transformed cells induced tumorigenesis in nude mice. Furthermore, a comprehensive understanding of genome-wide transcriptional analysis was performed to clarify the molecular mechanisms based on microarray and bioinformatics analysis. Microarray data analysis demonstrated that chronic exposure of SiNPs affected expression of 821 genes, including 5 up-regulated and 816 down-regulated genes. Gene ontology and pathway analysis showed that SiNPs caused significant changes in gene expression patterns related to many important functions and pathways, mainly including response to cellular processes, oxidative stress, DNA damage, and cancer. In addition, Signal-net analysis indicated the most prominent significant role of tumor protein p53 in amorphous SiNPs-induced transformation. Further, data confirmed the inactivated p53 and aberrant p53 signaling under chronic amorphous SiNPs exposure. In summary, our data firstly demonstrated chronically low-dose amorphous SiNPs exposure resulted in malignant transformation of human lung epithelial cell via p53 signaling, which provides new in vitro evidence for the carcinogenicity of amorphous SiNPs.

  • Changes in DNA methylation induced by multi-walled carbon nanotube exposure in the workplace
    Nanotoxicology (IF 6.428) Pub Date : 2017-11-30
    Manosij Ghosh, Deniz Öner, Katrien Poels, Ali M. Tabish, Jelle Vlaanderen, Anjoeka Pronk, Eelco Kuijpers, Qing Lan, Roel Vermeulen, Bram Bekaert, Peter HM Hoet, Lode Godderis

    This study was designed to assess the epigenetic alterations in blood cells, induced by occupational exposure to multi-wall carbon nanotubes (MWCNT). The study population comprised of MWCNT-exposed workers (n=24) and unexposed controls (n=43) from the same workplace. We measured global DNA methylation/hydroxymethylation levels on the 5th cytosine residues using a validated liquid chromatography tandem-mass spectrometry (LC-MS/MS) method. Sequence-specific methylation of LINE1 retrotransposable element 1 (L1RE1) elements, and promoter regions of functionally important genes associated with epigenetic regulation [DNA methyltransferase-1 (DNMT1) and histone deacetylase 4 (HDAC4)], DNA damage/repair and cell cycle pathways [nuclear protein, coactivator of histone transcription/ATM serine/threonine kinase (NPAT/ATM)], and a potential transforming growth factor beta (TGF-β) repressor [SKI proto-oncogene (SKI)] were studied using bisulfite pyrosequencing. Analysis of global DNA methylation levels and hydroxymethylation did not reveal significant difference between the MWCNT-exposed and control groups. No significant changes in Cytosine-phosphate-Guanine (CpG) site methylation were observed for the LINE1 (L1RE1) elements. Further analysis of gene-specific DNA methylation showed a significant change in methylation for DNMT1, ATM, SKI, and HDAC4 promoter CpGs in MWCNT-exposed workers. Since DNA methylation plays an important role in silencing/regulation of the genes, and many of these genes have been associated with occupational and smoking-induced diseases and cancer (risk), aberrant methylation of these genes might have a potential effect in MWCNT-exposed workers.

  • Metal load assessment in patient pulmonary lavages: towards a comprehensive mineralogical analysis including the nano-sized fraction
    Nanotoxicology (IF 6.428) Pub Date : 2017-11-25
    Valérie Forest, Jean-Michel Vergnon, Cyril Guibert, Dimitrios Bitounis, Lara Leclerc, Gwendoline Sarry, Jérémie Pourchez

    Mineralogical analyses of clinical samples have been proved useful to identify causal relationship between exposure to airborne particles and pulmonary diseases. The most striking example is asbestosis where the assessment of asbestos bodies in patient lung samples has allowed defining values specific of pathologies. However, this type of analyses only considers the micro-sized fraction of the particles, neglecting the specific impact of nano-sized particles which have been otherwise shown to be reactive and able to induce biological effects. Similarly, in nanotoxicology, the mineralogical analysis of pulmonary fluids could be used as an indicator of exposure to inhaled nanoparticles and could help investigations on the relationship between exposure to these nanoparticles and lung diseases. We designed this study first to demonstrate the technical feasibility of this approach, then to get a clear picture of the metals present, and in what form, in patient lungs and finally to determine if indeed it is worth investigating separately the micro, sub-micro and nano fractions. Broncho-alveolar lavages were recovered from 100 patients suffering from interstitial lung diseases. A protocol was specifically developed to isolate three fractions containing respectively microparticles, sub-microparticles and nanoparticles with ions. The metal content in each fraction was qualitatively and quantitatively characterized. Results showed significant differences between the three fractions in terms of metal load confirming that the separate analysis of the fractions is relevant. It also means that the assessment of the micro-sized fraction alone, as commonly done in clinical practice, only gives a partial view of the mineralogical analysis.

  • The elemental changes occurring in the rat liver after exposure to PEG-coated iron oxide nanoparticles: total reflection x-ray fluorescence (TXRF) spectroscopy study
    Nanotoxicology (IF 6.428) Pub Date : 2017-11-29
    Katarzyna Matusiak, Agnieszka Skoczen, Zuzanna Setkowicz, Aldona Kubala-Kukus, Ilona Stabrawa, Małgorzata Ciarach, Krzysztof Janeczko, Aleksandra Jung, Joanna Chwiej

    The main goal of this study was to evaluate in vivo effects of low dose of PEG-coated magnetic iron oxide nanoparticles (IONPs) on the rat liver. The IONPs was intravenously injected into rats at a dose equaled to 0.03 mg of Fe per 1 kg of an animal body weight. The elemental composition of liver tissue in rats subjected to IONPs action and controls were compared. Moreover, in order to determine the dynamics of nanoparticles (NPs) induced elemental changes, the tissues taken from animals 2 hours, 24 hours, and 7 days from IONPs injection were examined. The analysis of subtle elemental anomalies occurring as a result of IONPs action required application of highly sensitive analytical method. The total reflection X-ray fluorescence spectroscopy perfectly meets such requirements and therefore it was used in this study. The obtained results showed increasing trend of Fe level within liver occurring 2 hours from IONPs injection. One day after NPs administration, the liver Fe content presented the baseline level what suggests only the short-term accumulation of nanoparticles in the organ. The Ca, Cu, and Zn levels changed significantly as a result of NPs action. Moreover, the anomalies in their accumulation were still observed 7 days after IONPs injection. The level of Cu decreased while those of Ca and Zn increased in the liver of NPs-treated animals. The reduced liver Cu, followed by elevated serum level of this element, might be related in triggering the mechanisms responsible for Fe metabolism in the organism.

  • Assessment of evidence for nanosized titanium dioxide-generated DNA strand breaks and oxidatively damaged DNA in cells and animal models
    Nanotoxicology (IF 6.428) Pub Date : 2017-11-27
    Peter Møller, Ditte Marie Jensen, Regitze Sølling Wils, Maria Helena Guerra Andersen, Pernille Høgh Danielsen, Martin Roursgaard

    Nanosized titanium dioxide (TiO2) has been investigated in numerous studies on genotoxicity, including comet assay endpoints and oxidatively damaged DNA in cell cultures and animal models. The results have been surprisingly mixed, which might be attributed to physico-chemical differences of the tested TiO2. In the present review, we assess the role of certain methodological issues and publication bias. The analysis shows that studies on DNA strand breaks without proper assay controls or very low intra-group variation tend to show statistically significant effects. Levels of oxidatively damaged DNA, measured by the enzyme-modified comet assay, tend to show no effect in studies that have not included proper assay controls or they have uncertainty about the measurement. In addition, there are indications of publication and reporting bias. Nevertheless, the analysis shows that Aeroxide P25 generates DNA strand breaks in a concentration-dependent manner, which is not dependent on the duration of exposure. The standard comet assay seems to be able to discriminate between the genotoxicity of different types of TiO2, where anatase TiO2 seems to be the form with strongest genotoxic potential. Cell culture studies also demonstrate increased levels of oxidatively damaged DNA after exposure to TiO2. There are relatively few studies on animal models where DNA strand breaks and oxidatively damaged DNA have been tested with reliable methods. Collectively, this review shows that exposure to nanosized TiO2 is associated with genotoxicity in cells, whereas there are still too few reliable studies to assess the genotoxic potential in animal models.

Some contents have been Reproduced with permission of the American Chemical Society.
Some contents have been Reproduced by permission of The Royal Society of Chemistry.
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