- Email: [email protected]
Recent progress in studies of metallic nickel and nickel-based nanoparticles’ genotoxicity and carcinogenicity
e n v i r o n m e n t a l t o x i c o l o g y a n d p h a r m a c o l o g y 3 4 ( 2 0 1 2 ) 644–650
Available online at www.sciencedirect.com
journal homepage: www.elsevier.com/locate/etap
Mini-review
Recent progress in studies of metallic nickel and nickel-based nanoparticles’ genotoxicity and carcinogenicity Ruth Magaye, Jinshun Zhao ∗ Department of Preventive Medicine of the Medical School, Zhejiang Provincial Key Laboratory of Pathological and Physiological Technology, Ningbo University, Ningbo, Zhejiang 315211, PR China
a r t i c l e
i n f o
a b s t r a c t
Article history:
Recently, nanoparticles have been the focus of many research and innovation. Metallic nickel
Received 28 April 2012
and nickel-based nanoparticles are among those being exploited. Nickel fine particles are
Received in revised form
known to be genotoxic and carcinogenic. It has been discovered that many properties of
9 August 2012
nano sized elements and materials are not present in their bulk states. The nano size of
Accepted 24 August 2012
these particles renders them the ability to be easily transported into biological systems, thus
Available online 6 September 2012
raising the question of their effects on the susceptible system. Therefore scientific research
Keywords:
the current knowledge on the genotoxicity and carcinogenicity potential of metallic nickel
Genotoxicity
and nickel-based nanoparticles implicated in in vitro and in vivo mammalian studies.
on the effects of nickel nanoparticles is important. This mini-review intends to summarize
Carcinogenicity
© 2012 Elsevier B.V. All rights reserved.
Nickel Nanoparticles
Contents 1. 2.
3.
∗
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Metallic nickel nanoparticles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1. Genotoxicity of metallic nickel nanoparticles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1.1. In vitro studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1.2. In vivo studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2. Carcinogenicity of metallic nickel nanoparticles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2.1. Experimental studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2.2. Epidemiological studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Nickel-based nanoparticles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1. Genotoxicity of nickel-based nanoparticles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1.1. In vitro studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Corresponding author. E-mail address: [email protected] (J. Zhao). 1382-6689/$ – see front matter © 2012 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.etap.2012.08.012
645 645 645 645 646 646 646 646 646 646 646
e n v i r o n m e n t a l t o x i c o l o g y a n d p h a r m a c o l o g y 3 4 ( 2 0 1 2 ) 644–650
3.1.2. In vivo studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Carcinogenicity of nickel-based nanoparticles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2.1. Experimental studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2.2. Epidemiological studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conflicts of interest statement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2.
1.
Introduction
In the new millennium, nanotechnology has broadened the horizon for innovators, producers and consumers in nearly all sectors, by enabling the engineering of functional systems at the molecular level. Nanoparticles are the raw materials used in nanotechnology, which have at least one of their dimensions in the range of 1–100 nm (Morimoto et al., 2010a). However, they do occur in our natural environments (Swidwinska-Gajewska, 2007) and also as the by-products of industrial processes (Swidwinska-Gajewska, 2007; Buffle, 2006; Anon., 2005). Although human beings and the environment have been able to tolerate, avoid or adapt to the naturally occurring nanoparticles, what is of relevance now is the intentional production of nanoparticles (Magaye et al., 2012). Nickel nanoparticles are new products. Some of the unique characteristics of nickel nanoparticles include a high level of surface energy, high magnetism, low melting point, high surface area, and low burning point. These characteristics are only present at the nanoscale level and have thus led to its heightened experimentation and use in industry (Zhang et al., 2003; Kyono et al., 1992). For example, researchers have explored the potential for nickel nanoparticles in the form of nanorings as memory cells (Zhu et al., 2006). Alloys of copper and nickel at the nanometer scale are being investigated for use in controlled magnetic hyperthermia applications (Ban et al., 2011), and metallic nickel nanoparticles are also showing potential for use as electrode materials in multilayer ceramic capacitors (MLCC) (Chou et al., 2007). However, concerns have been expressed that these same properties of nickel-based nanoparticles may present unique bioactivity and challenges to human health (Maynard and Kuempel, 2005), since the size of the particles in combination with the properties attained at this scale make nanoparticles unpredictable. The key factor in nanoparticle toxicity is their minute sizes, apart from the chemical composition, shape, particle aging and surface charge. Being smaller than cellular organelles and cells, it allows them to penetrate basic biological structures, which may in-turn disrupt their normal function (Buzae et al., 2007). In addition to this, the physical and chemical properties of a nanoparticle cannot be simply predicted from the properties of a fine particle with the same chemical composition. This is supported by studies which have shown that nanoparticles are more toxic than their fine particles (Oberdorster, 2001; Oberdorster et al., 1994; Zhang et al., 2010). There is evidence of adverse effects such as skin allergies, lung fibrosis and lung cancer following exposure to nickel fine particles (Kasprzak et al., 2003; Zhao et al., 2009a; Bajpai et al., 1994). Many experimental and epidemiological studies as well as reviews have also shown metallic nickel and nickel compounds in their fine state to be carcinogenic (Tang
645
647 647 647 648 648 648 648
et al., 2010; Oller, 2002; Seilkop and Oller, 2003; Grimsrud et al., 2000; Goodman et al., 2011; Costa et al., 2003; Salnikow and Zhitkovich, 2008; Salnikow and Costa, 2000; Johnson et al., 2011). Based on these evidences, the IARC classed nickel compounds as group 1: carcinogenic to humans. While, metallic nickel is classed as group 2B: possibly carcinogenic to humans. Nickel was also voted as allergen of the year by the American Contact Dermatitis Society in 2008 following an article by Kornick and Zug (2008). Recently, among the studies evaluating the potential for genotoxicity and carcinogenicity of metal-based nanoparticles, nickel based nanoparticles have also emerged. Similar to the bulk nickel and nickel compounds, inhalation is also the major route of exposure for nickel and nickel-based nanoparticles. Due to their very small size, they may also be ingested or absorbed through the gastrointestinal tract or skin. This paper will focus mainly on current knowledge concerning the potential for genotoxicity and carcinogenicity of nickel-based (metallic nickel and nickel compounds) nanoparticles implicated in in vitro and in vivo mammalian studies.
2.
Metallic nickel nanoparticles
Here we have defined metallic nickel nanoparticles as those that are used as the primary raw material without combining them with other metals, compounds or elements. Such as that which is mentioned above (Chou et al., 2007). The term nickel nanoparticle as used in this review, also refers to metallic nickel nanoparticle.
2.1.
Genotoxicity of metallic nickel nanoparticles
Many studies have examined the genotoxicity of nickel and it’s compounds by using different toxicological test systems in the past 30 years (Zhao et al., 2009a). The common test systems that are used for genotoxicity studies include comet assay, micronucleus test, Ames test, and mammalian cell mutagenicity assays. However, there have been few studies that have utilized these same systems to demonstrate genotoxicity of metallic nickel nanoparticles. Most studies have concentrated on cytotoxicity rather than genotoxicity.
2.1.1.
In vitro studies
Flow cytometry and DNA fragmentation studies showed that A549 cells exposed to nickel nanoparticles (100 nm) had greater apoptotic damage than silica and titanium oxide fine particles (Park et al., 2007). The increase in DNA fragmentation was about 20–24%. They suggested that these effects were attributable to reactive oxygen species (ROS) generation. DNA fragmentation is a key feature of apoptosis, where DNA is cleaved into internucleosomal fragments of 180 bp
646
e n v i r o n m e n t a l t o x i c o l o g y a n d p h a r m a c o l o g y 3 4 ( 2 0 1 2 ) 644–650
(Nagata, 2000). Nickel’s ability to bind with amino acids, peptides and proteins facilitates the production of ROS (Cameron et al., 2011). Another study using western blot analysis of pro-apoptotic factors such as fas (CD95), fas-associated protein with death domain (FADD), caspase-8, death receptor 3 (DR3) and BID demonstrated that metallic nickel nanoparticles (92 nm) induced higher apoptotic damage in mouse epithelial (JB6) cells (Zhao et al., 2009b). They observed that metallic nickel nanoparticles caused higher cytotoxicity and apoptotic induction than fine particles (3 m) after 24 h exposure of JB6 cells to 0.1–20 g/m2 of metallic nickel fine or nanoparticles. Taken together, cell apoptosis induced by nickel nanoparticles seems to be a common finding, which has been demonstrated to be related to genotoxicity. DNA damage can occur as a result of metal-induced generation of oxygen radicals.
2.1.2.
In vivo studies
So far there is no data on in vivo studies available regarding genotoxicity of metallic nickel nanoparticles.
2.2.
et al., 2005), it can be implied that the HIF-1␣ pathway may have been activated in their study. However, this can only be confirmed with further studies that incorporate these two molecular processes. Zhao et al. (2009b) used the activation of Bcl-2 and the antiapoptotic factor Akt as endpoints in their study on metallic nickel nano and fine particle. They concluded that activation of Bcl-2 and Akt may play an important role in preventing the release of cytochrome c from the mitochondria into the cytoplasm. Over activation of Bcl-2 and Akt can give rise to the development of cancers. In addition, cytochrome c is a functional apoptosis-initiating protein for cancer cells. Another study demonstrated that nickel nanoparticles also caused approximately the same amount of morphological damage in cultured cells as zinc, silver and aluminum-based nanoparticles (Park et al., 2007). In summary, metallic nickel nanoparticles are capable of inducing cancers as shown by only one animal study. Most other in vitro experimental evidence lies in the activation or up-regulation of cell signal pathways which are related to carcinogenicity.
Carcinogenicity of metallic nickel nanoparticles 2.2.2.
The mechanisms of metal-induced carcinogenesis are not well understood. Enhanced oxidative stress, inflammatory response and abnormal apoptosis are non-genetic factors that are elicited by nanoparticles in cells that may predispose to carcinogenicity. Many studies involving metallic nickel nanoparticles have demonstrated the induction of one or all of these non-genetic factors.
2.2.1.
Experimental studies
In an animal study (Hansen et al., 2006), the development of rhabdomyosarcomas in rats that were intramuscularly implanted with metallic nickel nanoparticles at the vertebral column were observed. Their result showed that both nickel nano and fine particles caused the formation of rhabdomyosarcomas. Pietruska et al. (2011) reported that metallic nickel nanoparticles, in contrast to fine particles, activated a toxicity pathway characteristic of carcinogenic nickel compounds (Salnikow et al., 1999, 2000, 2002, 2003) in human lung epithelial cells (H460). They showed that nickel nanoparticles caused a rapid and prolonged activation of the hypoxia inducible factor-1alpha (HIF-1␣) pathway, which was stronger than that induced by soluble nickel (II) in human lung epithelial cells. They concluded that moderate cytotoxicity and sustained activation of the HIF-1␣ pathway by metallic nickel nanoparticles could promote cell transformation and tumor progression, by tricking the cell to think that hypoxic conditions exist. The normal function of the HIF-1␣ pathway is to help trigger genes that support a cell during hypoxia and is also known to encourage tumor cell growth. In an inhalation study that utilized C57BL/6 mice to quantify bone marrow (BM) resident endothelial progenitor cells (EPCs) using flow cytometry, EPCs were found to be functionally impaired and the numbers were reduced in the bone marrow (Liberda et al., 2010). They suggested that this may lead to progression of atherosclerosis. Since hypoxic conditions encourage the proliferation of EPCs and the organization of cell clusters (Bagley et al., 2008; Tepper
Epidemiological studies
Even though evidence exists of systemic and pulmonary pathology in a human after accidental exposure to nickel nanoparticles (Phillip et al., 2010), most epidemiological studies concerning carcinogenicity of metallic nickel were done on metallic nickel fine particles. In a case study reported by Iannitti et al. (2010), nickel nanoparticles including other heavy metals were indicated as the causative agents in Hodgkin’s lymphoma. This case study showed the presence of heavy metal nanoparticles in cells, and their involvement in the onset of Hodgkin’s disease. However, as noted by Oberdorster et al. (1994), the epidemiological studies on the carcinogenicity of metallic nickel is in itself limited by; inadequate exposure information, low exposures, short follow-up periods and low number of cases. Even though there is a lack of epidemiological data, the cases cited above do show possible evidence of nickel nanoparticle involvement in the initiation of carcinogenic processes. Thus, further well designed epidemiological studies are needed to confirm the involvement of nickel nanoparticles in carcinogenicity related to occupational exposures.
3.
Nickel-based nanoparticles
Among the studies on nickel nanoparticles, most have used nickel-based nanoparticles. This is due to the fact that nickel nanoparticle compounds are widely used in industry than metallic nickel nanoparticles. Here we define nickel-based nanoparticles as nickel nanoparticles that have been combined with other compounds, metals or elements.
3.1.
Genotoxicity of nickel-based nanoparticles
3.1.1.
In vitro studies
Nickel oxide (NiO) nanoparticle (20 nm) was shown to increase the gene expression of Hemeoxygenase-1 (HO-1) and surfactant protein-D (SP-D) in A549 cells (Horie et al., 2011). This
e n v i r o n m e n t a l t o x i c o l o g y a n d p h a r m a c o l o g y 3 4 ( 2 0 1 2 ) 644–650
study highlighted that an increase in gene expression of stress responsive enzymes such as HO-1 and SP-D and translocations of the transcription factor HIF-1␣ are effects of NiO nanoparticles. Pietruska et al. (2011) performed physicochemical characterization of NiO and metallic nickel particle for their ion bioavailability and toxicological properties in human lung epithelial cells (H460). Their results showed that NiO nanoparticles induced stabilization and nuclear translocation of the HIF-1␣ transcription factor followed by up regulation of its target gene, N-myc downstream regulated gene 1/Cap 43 (NDRG1 (cap 43)). In another study on NiO and metallic nickel nanoparticles, cytotoxicity to H460 cells was seen to occur concomitantly with activation of an apoptotic response as determined by dose and time-dependent cleavage of caspases and PARP (Pietruska et al., 2011). These studies have shown that nickel-based nanoparticles, especially NiO, may elicit genotoxicity by the activation of genes such as HO-1, SP-D, HIF-1␣, and up regulation of N-myc’s downstream regulated genes.
3.1.2.
In vivo studies
Morimoto et al. (2010b) examined the induction of 21 cytokines including inflammation, fibrosis and allergy caused by well dispersed NiO nanoparticles in lung disorders. They intratracheally instilled rats with 0.2 g of NiO nanoparticles dispersed in distilled water which had a mass median diameter in water of 26 nm. Their results showed that the expression of macrophage inflammatory protein-1␣ was continually increased in lung tissue and broncho-alveolar lavage fluid (BALF). In addition, interleukin-1␣ (IL-1␣) and interleukin1I (L-1) were increased in lung tissue. BALF analysis showed a transient increase of monocyte chemotactin protein-1. They concluded that overall agglomerates of NiO nanoparticles caused persistent inflammatory effects. These effects were due to the increase in cytokine expression and persistent increase in CC chemokine. Two independent studies obtained almost similar results in studies conducted on the toxicity of NiO nanoparticle and agglomerates following intratracheal instillation in male Wistar rats (Morimoto et al., 2011a; Nishi et al., 2009). In both studies, through quantitative measurement of protein by ELISA, cytokine- induced neutrophil chemo attractant (CINC)-2␣ was elevated (3 days to 6 months). However the latter study also found that CINC1 was increased from 3 days to 3 months, and CINC-3 was increased at 3 days but decreased later on. They also observed that the lung tissue had infiltrates of neutrophils and alveolar macrophages. A persistent increase in the BALF cell count, with a significant increase in neutrophil count and alveolar macrophage count was observed in both studies. In both studies rats were exposed to NiO nanoparticles (26 nm, 3.3 mg/kg), and were dissected at 3 days, 1 week, 1, 3 and 6 months. However, in a study that used whole body inhalation system, NiO nanoparticles did not induce the gene expression of matrix metalloproteinase-2 (MMP-2) and tissue inhibitor matrix proteinase-2 (TIMP-2) mRNA in rat lungs (Morimoto et al., 2011b). MMP-2 and TIMP-2 regulate the degradation of collagen. The synthesis and degradation of collagen is thought to regulate the deposition of extracellular matrix (ECM), which is involved in inflammation and fibrosis.
647
These in vivo studies show that most genes activated by NiO nanoparticles are involved in the regulation of inflammation signal related pathways. A substance is considered genotoxic if it deleteriously affects the genome of a cell either by direct or indirect damage to the cellular DNA including effects on the cellular pathways that monitor and protect genome integrity (Donaldson and Poland, 2012). In reality the induction of genotoxic effects can be due either to direct or indirect primary genotoxicity, secondary genotoxicity or a mixture of all as the production of reactive species within a cell. In situations where a particle or substance directly interacts with the genomic DNA and causes damage, the effect is called direct primary genotoxicity, which is independent of inflammation (Schins and Knaapen, 2007). Indirect primary genotoxicity in contrast occurs when intracellular antioxidants are depleted and therefore results in an imbalance between cellular steady-state oxidants. Secondary genotoxicity does not involve the direct interaction of a particle with the target cell in which genotoxicity occurs but instead drives genotoxicity through its interaction with other cells causing the production of an environment conducive to the accumulation of genetic damage and proliferation. This is typically caused by the induction of chronic inflammation leading to persistent oxidative stress caused by the presence of inflammatory cells such as macrophages and polymorphonuclear leukocytes as well as the secretion of various pro-survival and proliferation signaling factors. Therefore, inflammation effects induced by NiO nanoparticles in the animal lung may play an important role in triggering genotoxicity.
3.2.
Carcinogenicity of nickel-based nanoparticles
3.2.1.
Experimental studies
So far there is no data on in vivo studies available regarding of tumors or cancers induced by nickel-based nanoparticle. Gillespie et al. (2010) used occupationally relevant dose ranges of nickel hydroxide and the C57BL/6 mice as their animal models. Their study showed that nickel hydroxide nanoparticles are capable of inducing inflammatory effects in the lungs in both short and long term exposure periods. The two studies mentioned previously also concluded that nanoparticle agglomerates of nickel oxide induced persistent inflammatory response, and suggested that CINC was involved in lung injury by NiO nanoparticles (Morimoto et al., 2011a; Nishi et al., 2009). Another study showed that nickel hydroxide nanoparticles appeared to have stronger inflammogenic potential then other compounds in mice that were exposed by the whole body inhalation system (Kang et al., 2011). A study compared well characterized nanoparticles of cesium oxide, titanium oxide, silica oxide, nickel oxide, zinc oxide, copper oxide nanoparticles and amine modified polystyrene beads for their inflammation potencies in the lungs of rats (Cho et al., 2010). They used two time points (24 h and 4 weeks) to evaluate the acute and chronic effects of these particles. Acutely, their results showed that patterns of the lung showed neutrophil and eosinophil infiltrates. Chronically, the NiO nanoparticles caused neutrophilic, neutrophilic/lymphocytic, eosinophilic/fibrotic/granulomatous and fibrotic granulomatous inflammation. In normal physiological conditions these factors are important protective defenses against tissue injury
648
e n v i r o n m e n t a l t o x i c o l o g y a n d p h a r m a c o l o g y 3 4 ( 2 0 1 2 ) 644–650
or infections. However, they are also capable of promoting DNA damage such as chromosomal fragmentation, DNA point mutations, DNA repair inhibition and induce formation of methylation patterns that may lead to altered gene expression profiles and the formation of DNA adducts (Singh et al., 2009; Ding et al., 2000; Kaur et al., 2009). In addition, recent research evidence shows that inflammatory microenvironment in and around tumors is an indispensable participant in the neoplastic process (Wang and Cho, 2010). A recent review by Munoz and Costa (Munoz and Costa, 2012) showed that particle uptake is a critical step in determining carcinogenicity for nickel based fine particles. They stated that uptake was greatly influenced by the surface charge of the particle. There is a need for research regarding surface charge, the level of uptake and the rate of cell transformation by nickel based nanoparticles. Evidence indicates that inflammation is a predisposing factor to cancer, therefore from the studies cited, it can be seen that nickel-based nanoparticles are capable of causing inflammation in both in vivo and in vitro studies. Inflammation is especially of relevance in cases of long term exposure. This is because in short term exposure the genetic damage may be reversible, while in long term exposure, the persistence of inflammation leaves the cell venerable to DNA aberrations that can consequently lead to mutagenesis. Therefore, well designed chronic animal experiments are necessary for detecting the carcinogenicity of nickel-based nanoparticle compounds.
3.2.2.
Epidemiological studies
Currently there is no exclusive epidemiological data regarding nickel-based nanoparticle compounds, apart from those available on nickel fine particles. In summary, the genotoxic effects induced by metallic nickel nanoparticles in vitro may occur through activation of genes related with promotion and demotion of apoptosis. In this case, both promotion and demotion of apoptosis can lead to mutagenesis. The activation of monocyte phenotypes may also play a role in the genotoxicity induced by metallic nickel nanoparticles. In the in vivo studies, metallic nickel nanoparticle were shown to be capable of inducing cancer (rhabdomyosarcoma) in an animal model, but for now, whether they can also cause cancers in humans is unclear. As for nickel-based nanoparticles, specifically NiO nanoparticles, they cause genotoxicity by altering the activities of transcription factors such as HO-1, SP-D and HIF-1␣, and up regulation of N-myc’s downstream genes. The in vivo studies implicated genes that are involved in the regulation of inflammation such as CINC-2␣, CINC-3, IL-1␣, and IL-1, which may play an important role in nickel-based nanoparticle-induced genotoxicity. However, further studies are needed to prove this, since others have shown that the expression of genes such as MMP-2 and TIMP-2 that are involved in inflammation were not induced. Although there was no direct evidence to show carcinogenic effects of nickel-based nanoparticles in both animal and human studies, however, most of the studies showed that inflammatory reactions play an important role in the neoplastic process, especially in cases of chronic inflammation. Epidemiological data for both metallic nickel and nickel-based nanoparticles is lacking. This may also be due
to the fact that nanoscience is fairly new. As the application of nickel nanoparticles are gaining a lot of momentum, studies regarding its in vitro and in vivo effects and epidemiological investigations should be encouraged.
Conflicts of interest statement The authors declare that they have no conflicts of interest.
Acknowledgements The excellent assistance of Linda Bowman in the preparation of this article is greatly appreciated. This work was partly supported by National Nature Science Foundation of China (Grant No.81273111), The Foundations of Innovative Research Team of The Educational Commission of Zhejiang Province (T200907), The Nature Science Foundation of Ningbo City (Grant No. 2012A610185), The Ningbo Scientific Project (SZX11073), The Scientific Innovation Team of Ningbo (2009B21002) and K.C. Wong Magna Fund in Ningbo University.
references
Anon., 2005. Implications of Nanotechnology for Environmental Health Research. National Academy of Sciences, Washington, DC. Bagley, R.G., Rouleau, C., St. Martin, T., Boutin, P., Weber, W., Ruzek, M., Honma, N., Nacht, M., Shankara, S., Kataoka, S., Ishida, I., Roberts, B.L., Teicher, B.A., 2008. Human endothelial precursor cells express tumor endothelial marker 1/endosialin/CD248. Mol. Cancer Ther. 7, 2536. Bajpai, R., Waseem, M., Kaw, J.L., 1994. Pulmonary response to cadmium and nickel coated fly ash. J. Environ. Pathol. Toxicol. Oncol. 13 (4), 251–257. Ban, I., Drofenik, S.J., Makovec, M.D., 2011. Synthesis of copper–nickel nanoparticles prepared by mechanical milling for use in magnetic hyperthermia. J. Magn. Magn. Mater. 323 (17), 2254–2258. Buffle, J., 2006. The key role of environmental colloids/nanoparticles for the sustainability of life. Environ. Chem. 3, 3. Buzae, C., Pacheco Blandino, I.I., Robbie, K., 2007. Nanomaterials and nanoparticles: sources and toxicity. Biointerphases 2 (4), MR17–MR172. Cameron, K.S., Buchner, V., Tchounwou, P.B., 2011. Exploring the molecular mechanisms of nickel-induced genotoxicity and carcinogenicity: a literature review. Rev. Environ. Health 26 (2), 81–92. Cho, W.S., Duffin, R., Poland, C.A., Howie, S.E., MacNee, W., Bradley, M., Megson, I.L., Donaldson, K., 2010. Metal oxide nanoparticles induce unique inflammatory footprints in the lung: important implications for nanoparticle testing. Environ. Health Perspect. 118 (12), 1699–1706. Chou, K.S., Chang, S.C., Huang, K.C., 2007. Study on the characteristics of nanosized nickel particles using sodium borohydride to promote conversion. Azo J. Mater. Online 3. Costa, M., Yan, Y., Zhao, D., Sainikow, K., 2003. Molecular mechanisms of nickel carcinogenesis: gene silencing by nickel delivery to the nucleus and gene activation/inactivation by nickel-induced cell signaling. J. Environ. Monit. 5 (2), 222–223. Ding, M., Shi, X., Castranova, V., Vallyathan, V., 2000. Predisposing factors in occupational lung cancer: inorganic minerals and chromium. J. Environ. Pathol. Toxicol. Oncol. 19 (1–2), 129–138.
e n v i r o n m e n t a l t o x i c o l o g y a n d p h a r m a c o l o g y 3 4 ( 2 0 1 2 ) 644–650
Donaldson, K., Poland, C., 2012. Inhaled nanoparticles and lung cancer – what we can learn from conventional particle toxicology. Swiss Med. Wkly. 142. Gillespie, P.A., Kang, G.S., Elder, A., Gelein, R., Chen, L., Moreira, A.L., Koberstein, J., Wong, K.M.T., Gordon, T., Chen, I.T., 2010. Pulmonary response after exposure to inhaled nickel hydroxide nanoparticles: short and long-term studies in mice. Nanotoxicology 4 (1), 106–119. Goodman, J.E., Prueitt, R.L., Thakali, S., Oller, A.R., 2011. The nickel ion bioavailability model of the carcinogenic potential of nickel-containing substances in the lung. Crit. Rev. Toxicol. 41 (2), 142–174. Grimsrud, T.K., Berge, S.R., Resmann, F., Norseth, T., Andersen, A., 2000. Assessment of historical exposures in a nickel refinery in Norway. Scand. J. Work, Environ. Health 26 (4), 338–345. Hansen, T., Clermont, G., Alves, A., Eloy, R., Brochhausen, C., Boutrand, J.P., Gatti, A.M., Kirkpatrick, C.J., 2006. Biological tolerance of different materials in bulk and nanoparticulate form in a rat model: sarcoma development by nanoparticles. J. R. Soc. Interface 3, 767–775. Horie, M., Fukui, H., Nishio, K., Endoh, S., Kato, H., Fujita, K., Miyauchi, A., Shichiri, M., Ishida, N., Kinugasa, S., Morimoto, Y., Niki, E., Yoshida, Y., Iwahashi, H., 2011. Evaluation of acute oxidative stress induced by NiO nanoparticles in vivo and in vitro. J. Occup. Health 53 (2), 64–74. Iannitti, T., Capone, S., Gatti, A., Capitani, F., Cetta, F., Palmieri, B., 2010. Intracellular heavy metal nanoparticle storage: progressive accumulation within lymph nodes with transformation from chronic inflammation to malignancy. Int. J. Nanomed. 5, 955–960. Johnson, N., Shelton, B.J., Hopenhayn, C., et al., 2011. Concentrations of arsenic, chromium, and nickel in toenail samples from Appalachian Kentucky residents. J. Environ. Pathol. Toxicol. Oncol. 30 (3), 213–223. Kang, G.S., Gillespie, P.A., Gunnison, A., Rengifo, H., Koberstein, J., Chen, L.C., 2011. Comparative pulmonary toxicity of inhaled nickel nanoparticles; role of deposited dose and solubility. Inhal. Toxicol. 23 (2), 95–103. Kasprzak, J.S., Sunderman Jr., F.W., Salnikow, K., 2003. Nickel carcinogenesis. Mutat. Res. 533, 67–97. Kaur, G., Lone, I.A., Athar, M., Alam, M.S., 2009. Guilandina bonduc L. possesses antioxidant activity and precludes ferric nitrilotriacetate (Fe-NTA) induced renal toxicity and tumor promotion response. J. Environ. Pathol. Toxicol. Oncol. 28 (2), 163–175. Kornick, R., Zug, K.A., 2008. Nickel. Dermatitis 19, 3–8. Kyono, H., Kusaka, Y., Homma, K., Kubota, H., Endo-Ichikawa, Y., 1992. Reversible lung lesions in rats due to short-term exposure to ultrafine cobalt particles. Ind. Health 30 (3–4), 103–118. Liberda, E.N., Cuevas, A.K., Gillespie, P.A., Grunic, G., Qu, Q., Chen, L.C., 2010. Exposure to inhaled nickel nanoparticles causes a reduction in number and function of bone marrow endothelial progenitor cells. Inhal. Toxicol. 22, 95–99. Magaye, R., Zhao, J., Bowman, L., Ding, M., 2012. Genotoxicity and carcinogenicity of cobalt, nickel and copper-based nanoparticles. J. Exp. Ther. Med. 4 (4), 551–561. Maynard, A.D., Kuempel, E.D., 2005. Airborne nanostructured particles and occupational health. J. Nanopart. Res. 7, 587–614. Morimoto, Y., Kobayashi, N., Shinohara, N., Myojo, T., Tanaka, I., Nakanishi, J., 2010a. Hazard assessments of manufactured nanomaterials. J. Occup. Health 52 (6), 325–334. Morimoto, Y., Ogami, A., Todoroki, M., Yamamoto, M., Murakami, M., Hirohashi, M., Oyabu, T., Myojo, T., Nishi, K., Kadoya, C., Yamasaki, S., Nagatomo, H., Fujita, K., Endoh, S., Uchida, K., Yamamoto, K., Kobayashi, N., Nakanishi, J., Tanaka, I., 2010b. Expression of inflammation-related cytokines following
649
intratracheal instillation of nickel oxide nanoparticles. Nanotoxicology 4 (2), 161–176. Morimoto, Y., Hirohashi, M., Ogami, A., Oyabu, T., Myojo, T., Hashiba, M., Mizuquchi, Y., Kambara, T., Lee, B.W., Kuroda, E., Tanaka, I., 2011a. Pulmonary toxicity following an intratracheal instillation of nickel oxide nanoparticle agglomerates. J. Occup. Health 53 (4), 293–295. Morimoto, Y., Oyabu, T., Ogami, A., et al., 2011b. Investigation of gene expression of MMP-2 and TIMP-2 mRNA in rat lung in inhaled nickel oxide and titanium dioxide nanoparticles. Ind. Health 49 (3), 344–352. Munoz, A., Costa, M., 2012. Elucidating the mechanisms of nickel compound uptake: a review of particulate and nano-nickel endocytosis and toxicity. Toxicol. Appl. Pharmacol. 260 (1), 1–16. Nagata, S., 2000. Apoptotic DNA fragmentation. Exp. Cell Res. 256 (1), 12–18. Nishi, K., Morimoto, Y., Ogami, A., Murakami, M., Myojo, T., Oyabu, T., Kadoya, C., Yamamoto, M., Todoroki, M., Hirohashi, M., Yamasaki, S., Fujita, K., Endo, S., Uchida, K., Yamamoto, K., Nakanishi, J., Tanaka, I., 2009. Expression of cytokine-induced neutrophil chemoattractant in rat lungs by intratracheal instillation of nickel oxide nanoparticles. Inhal. Toxicol. 21 (12), 1030–1039. Oberdorster, G., 2001. Pulmonary effects of inhaled ultrafine particles. Int. Arch. Occup. Environ. Health 74 (1), 1–8. Oberdorster, G., Ferin, J., Lehnert, B.E., 1994. Correlation between particle size, in vivo particle persistence, and lung injury. Environ. Health Perspect. 102 (Suppl. 5), 173–179. Oller, A.R., 2002. Respiratory carcinogenicity assessment of soluble nickel compounds. Environ. Health Perspect. 110 (5), 444–841. Park, S., Lee, Y.K., Jung, M., Kim, K.H., Chung, N., 2007. Cellular toxicity of various inhalable nanoparticles on human alveolar epithelial cells. Inhal. Toxicol. 9, 59–65. Phillip, J.I., Green, F.Y., Davis, J.C.A., Murray, J., 2010. Pulmonary and systemic toxicity following exposure to nickel nanoparticles. Am. J. Ind. Med. 53, 763–767. Pietruska, J.R., Liu, X., Smith, A., McNeil, K., Weston, P., Zhitkovich, A., Hurt, R., Kane, A.B., 2011. Bioavailability, intracellular mobilization of nickel, and HIF-1␣ activation in human lung epithelial cells exposed to metallic nickel and nickel oxide nanoparticles. Toxicol. Sci., http://dx.doi.org/10.1093/toxsci/kfr206. Salnikow, K., Costa, M., 2000. Epigenetic mechanisms of nickel carcinogenesis. J. Environ. Pathol. Toxicol. Oncol. 19 (3), 307–318. Salnikow, K., Zhitkovich, A., 2008. Genetic and epigenetic mechanisms in metal carcinogenesis and cocarcinogenesis: nickel, arsenic, and chromium. Chem. Res. Toxicol. 21 (1), 28–44. Salnikow, K., An, W.G., Melillo, G., Blagosklonny, M.V., Costa, M., 1999. Nickel-induced transformation shifts the balance between HIF-1 and p53 transcription factors. Carcinogenesis 20 (9), 1819–1823. Salnikow, K., Blagosklonny, M.V., Ryan, H., Johnson, R., Costa, M., 2000. Carcinogenic nickel induces genes involved with hypoxic stress. Cancer Res. 60 (1), 38–41. Salnikow, K., Davidson, T., Costa, M., 2002. The role of hypoxia-inducible signaling pathway in nickel carcinogenesis. Environ. Health Perspect. 110 (Suppl. 5), 831–834. Salnikow, K., Davidson, T., Zhang, Q., Chen, L.C., Su, W., Costa, M., 2003. The involvement of hypoxia-inducible transcription factor-1-dependent pathway in nickel carcinogenesis. Cancer Res. 63 (13), 3524–3530. Schins, R.P., Knaapen, A.M., 2007. Genotoxicity of poorly soluble particles. Inhal. Toxicol. 19 (Suppl. 1), 189–198.
650
e n v i r o n m e n t a l t o x i c o l o g y a n d p h a r m a c o l o g y 3 4 ( 2 0 1 2 ) 644–650
Seilkop, S.K., Oller, A.R., 2003. Respiratory cancer risks associated with low-level nickel exposure: an integrated assessment based on animal, epidemiological, and mechanistic data. Regul. Toxicol. Pharm. 37 (2), 173–190. Singh, N.M.B., Jenkins, G.S.J., Griffiths, S.M., Williams, P.M., Maffeis, T.G.G., Wright, C.J., Doak, S.H., 2009. NanoGenotoxicology: the DNA damaging potential of engineered nanomaterials. Biomaterials 30, 3891–3894. Swidwinska-Gajewska, A.M., 2007. Nanoparticles (part 1) – the product of modern technology and new hazards in the work environment. Med. Pr. 58 (3), 243–251. Tang, X., Li, C., Wu, W., 2010. Research progress on carcinogenicity of nickel and its compounds. Chin. J. Ind. Med. 4. Tepper, O.M., Capla, J.M., Galiano, R.D., Ceradini, D.J., Callaghan, M.J., Kleinman, M.E., Gurtner, G.C., 2005. Adult vasculogenesis occurs through in situ recruitment, proliferation and tubulization of circulating bone marrow-derived cells. Blood 105 (3), 1068–1077. Wang, H., Cho, C.H., 2010. Effect of NF-kappaB signaling on apoptosis in chronic inflammation-associated carcinogenesis. Curr. Cancer Drug Targets 10 (6), 593–599.
Zhang, Q., Kusaka, Y., Zhu, X., et al., 2003. Comparative toxicity of standard nickel and ultrafine nickel in lung after intratracheal instillation. J. Occup. Health 45 (1), 23–30. Zhang, X.D., Zhao, J., Bowman, L., Shi, X., Castranova, V., Ding, M., 2010. Tungsten carbide-cobalt particles activate Nrf2 and its downstream target genes in JB6 cells possibly by ROS generation. J. Environ. Pathol. Toxicol. Oncol. 29 (1), 31–40. Zhao, J., Shi, X., Castranova, V., Ding, M., 2009a. Occupational toxicology of nickel and nickel compounds. J. Environ. Pathol. Toxicol. Oncol. 28 (3), 177–208. Zhao, J., Bowman, L., Zhang, X., Shi, X., Jiang, B., Castranova, V., Ding, M., 2009b. Metallic nickel nano- and fine particles induce JB6 cell apoptosis through a caspase-8/AIF mediated cytochrome c- independent. J. Nanobiotechnology 7, 2–14. Zhu, F.Q., Chern, G.W., Tchernyshyov, O., Zhu, X.C., Zhu, J.G., Chien, C.L., 2006. Magnetic bistability and controllable reversal of asymmetric ferromagnetic nanorings. Phys. Rev. Lett. 96 (2).
Available online at www.sciencedirect.com
journal homepage: www.elsevier.com/locate/etap
Mini-review
Recent progress in studies of metallic nickel and nickel-based nanoparticles’ genotoxicity and carcinogenicity Ruth Magaye, Jinshun Zhao ∗ Department of Preventive Medicine of the Medical School, Zhejiang Provincial Key Laboratory of Pathological and Physiological Technology, Ningbo University, Ningbo, Zhejiang 315211, PR China
a r t i c l e
i n f o
a b s t r a c t
Article history:
Recently, nanoparticles have been the focus of many research and innovation. Metallic nickel
Received 28 April 2012
and nickel-based nanoparticles are among those being exploited. Nickel fine particles are
Received in revised form
known to be genotoxic and carcinogenic. It has been discovered that many properties of
9 August 2012
nano sized elements and materials are not present in their bulk states. The nano size of
Accepted 24 August 2012
these particles renders them the ability to be easily transported into biological systems, thus
Available online 6 September 2012
raising the question of their effects on the susceptible system. Therefore scientific research
Keywords:
the current knowledge on the genotoxicity and carcinogenicity potential of metallic nickel
Genotoxicity
and nickel-based nanoparticles implicated in in vitro and in vivo mammalian studies.
on the effects of nickel nanoparticles is important. This mini-review intends to summarize
Carcinogenicity
© 2012 Elsevier B.V. All rights reserved.
Nickel Nanoparticles
Contents 1. 2.
3.
∗
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Metallic nickel nanoparticles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1. Genotoxicity of metallic nickel nanoparticles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1.1. In vitro studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1.2. In vivo studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2. Carcinogenicity of metallic nickel nanoparticles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2.1. Experimental studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2.2. Epidemiological studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Nickel-based nanoparticles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1. Genotoxicity of nickel-based nanoparticles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1.1. In vitro studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Corresponding author. E-mail address: [email protected] (J. Zhao). 1382-6689/$ – see front matter © 2012 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.etap.2012.08.012
645 645 645 645 646 646 646 646 646 646 646
e n v i r o n m e n t a l t o x i c o l o g y a n d p h a r m a c o l o g y 3 4 ( 2 0 1 2 ) 644–650
3.1.2. In vivo studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Carcinogenicity of nickel-based nanoparticles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2.1. Experimental studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2.2. Epidemiological studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conflicts of interest statement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2.
1.
Introduction
In the new millennium, nanotechnology has broadened the horizon for innovators, producers and consumers in nearly all sectors, by enabling the engineering of functional systems at the molecular level. Nanoparticles are the raw materials used in nanotechnology, which have at least one of their dimensions in the range of 1–100 nm (Morimoto et al., 2010a). However, they do occur in our natural environments (Swidwinska-Gajewska, 2007) and also as the by-products of industrial processes (Swidwinska-Gajewska, 2007; Buffle, 2006; Anon., 2005). Although human beings and the environment have been able to tolerate, avoid or adapt to the naturally occurring nanoparticles, what is of relevance now is the intentional production of nanoparticles (Magaye et al., 2012). Nickel nanoparticles are new products. Some of the unique characteristics of nickel nanoparticles include a high level of surface energy, high magnetism, low melting point, high surface area, and low burning point. These characteristics are only present at the nanoscale level and have thus led to its heightened experimentation and use in industry (Zhang et al., 2003; Kyono et al., 1992). For example, researchers have explored the potential for nickel nanoparticles in the form of nanorings as memory cells (Zhu et al., 2006). Alloys of copper and nickel at the nanometer scale are being investigated for use in controlled magnetic hyperthermia applications (Ban et al., 2011), and metallic nickel nanoparticles are also showing potential for use as electrode materials in multilayer ceramic capacitors (MLCC) (Chou et al., 2007). However, concerns have been expressed that these same properties of nickel-based nanoparticles may present unique bioactivity and challenges to human health (Maynard and Kuempel, 2005), since the size of the particles in combination with the properties attained at this scale make nanoparticles unpredictable. The key factor in nanoparticle toxicity is their minute sizes, apart from the chemical composition, shape, particle aging and surface charge. Being smaller than cellular organelles and cells, it allows them to penetrate basic biological structures, which may in-turn disrupt their normal function (Buzae et al., 2007). In addition to this, the physical and chemical properties of a nanoparticle cannot be simply predicted from the properties of a fine particle with the same chemical composition. This is supported by studies which have shown that nanoparticles are more toxic than their fine particles (Oberdorster, 2001; Oberdorster et al., 1994; Zhang et al., 2010). There is evidence of adverse effects such as skin allergies, lung fibrosis and lung cancer following exposure to nickel fine particles (Kasprzak et al., 2003; Zhao et al., 2009a; Bajpai et al., 1994). Many experimental and epidemiological studies as well as reviews have also shown metallic nickel and nickel compounds in their fine state to be carcinogenic (Tang
645
647 647 647 648 648 648 648
et al., 2010; Oller, 2002; Seilkop and Oller, 2003; Grimsrud et al., 2000; Goodman et al., 2011; Costa et al., 2003; Salnikow and Zhitkovich, 2008; Salnikow and Costa, 2000; Johnson et al., 2011). Based on these evidences, the IARC classed nickel compounds as group 1: carcinogenic to humans. While, metallic nickel is classed as group 2B: possibly carcinogenic to humans. Nickel was also voted as allergen of the year by the American Contact Dermatitis Society in 2008 following an article by Kornick and Zug (2008). Recently, among the studies evaluating the potential for genotoxicity and carcinogenicity of metal-based nanoparticles, nickel based nanoparticles have also emerged. Similar to the bulk nickel and nickel compounds, inhalation is also the major route of exposure for nickel and nickel-based nanoparticles. Due to their very small size, they may also be ingested or absorbed through the gastrointestinal tract or skin. This paper will focus mainly on current knowledge concerning the potential for genotoxicity and carcinogenicity of nickel-based (metallic nickel and nickel compounds) nanoparticles implicated in in vitro and in vivo mammalian studies.
2.
Metallic nickel nanoparticles
Here we have defined metallic nickel nanoparticles as those that are used as the primary raw material without combining them with other metals, compounds or elements. Such as that which is mentioned above (Chou et al., 2007). The term nickel nanoparticle as used in this review, also refers to metallic nickel nanoparticle.
2.1.
Genotoxicity of metallic nickel nanoparticles
Many studies have examined the genotoxicity of nickel and it’s compounds by using different toxicological test systems in the past 30 years (Zhao et al., 2009a). The common test systems that are used for genotoxicity studies include comet assay, micronucleus test, Ames test, and mammalian cell mutagenicity assays. However, there have been few studies that have utilized these same systems to demonstrate genotoxicity of metallic nickel nanoparticles. Most studies have concentrated on cytotoxicity rather than genotoxicity.
2.1.1.
In vitro studies
Flow cytometry and DNA fragmentation studies showed that A549 cells exposed to nickel nanoparticles (100 nm) had greater apoptotic damage than silica and titanium oxide fine particles (Park et al., 2007). The increase in DNA fragmentation was about 20–24%. They suggested that these effects were attributable to reactive oxygen species (ROS) generation. DNA fragmentation is a key feature of apoptosis, where DNA is cleaved into internucleosomal fragments of 180 bp
646
e n v i r o n m e n t a l t o x i c o l o g y a n d p h a r m a c o l o g y 3 4 ( 2 0 1 2 ) 644–650
(Nagata, 2000). Nickel’s ability to bind with amino acids, peptides and proteins facilitates the production of ROS (Cameron et al., 2011). Another study using western blot analysis of pro-apoptotic factors such as fas (CD95), fas-associated protein with death domain (FADD), caspase-8, death receptor 3 (DR3) and BID demonstrated that metallic nickel nanoparticles (92 nm) induced higher apoptotic damage in mouse epithelial (JB6) cells (Zhao et al., 2009b). They observed that metallic nickel nanoparticles caused higher cytotoxicity and apoptotic induction than fine particles (3 m) after 24 h exposure of JB6 cells to 0.1–20 g/m2 of metallic nickel fine or nanoparticles. Taken together, cell apoptosis induced by nickel nanoparticles seems to be a common finding, which has been demonstrated to be related to genotoxicity. DNA damage can occur as a result of metal-induced generation of oxygen radicals.
2.1.2.
In vivo studies
So far there is no data on in vivo studies available regarding genotoxicity of metallic nickel nanoparticles.
2.2.
et al., 2005), it can be implied that the HIF-1␣ pathway may have been activated in their study. However, this can only be confirmed with further studies that incorporate these two molecular processes. Zhao et al. (2009b) used the activation of Bcl-2 and the antiapoptotic factor Akt as endpoints in their study on metallic nickel nano and fine particle. They concluded that activation of Bcl-2 and Akt may play an important role in preventing the release of cytochrome c from the mitochondria into the cytoplasm. Over activation of Bcl-2 and Akt can give rise to the development of cancers. In addition, cytochrome c is a functional apoptosis-initiating protein for cancer cells. Another study demonstrated that nickel nanoparticles also caused approximately the same amount of morphological damage in cultured cells as zinc, silver and aluminum-based nanoparticles (Park et al., 2007). In summary, metallic nickel nanoparticles are capable of inducing cancers as shown by only one animal study. Most other in vitro experimental evidence lies in the activation or up-regulation of cell signal pathways which are related to carcinogenicity.
Carcinogenicity of metallic nickel nanoparticles 2.2.2.
The mechanisms of metal-induced carcinogenesis are not well understood. Enhanced oxidative stress, inflammatory response and abnormal apoptosis are non-genetic factors that are elicited by nanoparticles in cells that may predispose to carcinogenicity. Many studies involving metallic nickel nanoparticles have demonstrated the induction of one or all of these non-genetic factors.
2.2.1.
Experimental studies
In an animal study (Hansen et al., 2006), the development of rhabdomyosarcomas in rats that were intramuscularly implanted with metallic nickel nanoparticles at the vertebral column were observed. Their result showed that both nickel nano and fine particles caused the formation of rhabdomyosarcomas. Pietruska et al. (2011) reported that metallic nickel nanoparticles, in contrast to fine particles, activated a toxicity pathway characteristic of carcinogenic nickel compounds (Salnikow et al., 1999, 2000, 2002, 2003) in human lung epithelial cells (H460). They showed that nickel nanoparticles caused a rapid and prolonged activation of the hypoxia inducible factor-1alpha (HIF-1␣) pathway, which was stronger than that induced by soluble nickel (II) in human lung epithelial cells. They concluded that moderate cytotoxicity and sustained activation of the HIF-1␣ pathway by metallic nickel nanoparticles could promote cell transformation and tumor progression, by tricking the cell to think that hypoxic conditions exist. The normal function of the HIF-1␣ pathway is to help trigger genes that support a cell during hypoxia and is also known to encourage tumor cell growth. In an inhalation study that utilized C57BL/6 mice to quantify bone marrow (BM) resident endothelial progenitor cells (EPCs) using flow cytometry, EPCs were found to be functionally impaired and the numbers were reduced in the bone marrow (Liberda et al., 2010). They suggested that this may lead to progression of atherosclerosis. Since hypoxic conditions encourage the proliferation of EPCs and the organization of cell clusters (Bagley et al., 2008; Tepper
Epidemiological studies
Even though evidence exists of systemic and pulmonary pathology in a human after accidental exposure to nickel nanoparticles (Phillip et al., 2010), most epidemiological studies concerning carcinogenicity of metallic nickel were done on metallic nickel fine particles. In a case study reported by Iannitti et al. (2010), nickel nanoparticles including other heavy metals were indicated as the causative agents in Hodgkin’s lymphoma. This case study showed the presence of heavy metal nanoparticles in cells, and their involvement in the onset of Hodgkin’s disease. However, as noted by Oberdorster et al. (1994), the epidemiological studies on the carcinogenicity of metallic nickel is in itself limited by; inadequate exposure information, low exposures, short follow-up periods and low number of cases. Even though there is a lack of epidemiological data, the cases cited above do show possible evidence of nickel nanoparticle involvement in the initiation of carcinogenic processes. Thus, further well designed epidemiological studies are needed to confirm the involvement of nickel nanoparticles in carcinogenicity related to occupational exposures.
3.
Nickel-based nanoparticles
Among the studies on nickel nanoparticles, most have used nickel-based nanoparticles. This is due to the fact that nickel nanoparticle compounds are widely used in industry than metallic nickel nanoparticles. Here we define nickel-based nanoparticles as nickel nanoparticles that have been combined with other compounds, metals or elements.
3.1.
Genotoxicity of nickel-based nanoparticles
3.1.1.
In vitro studies
Nickel oxide (NiO) nanoparticle (20 nm) was shown to increase the gene expression of Hemeoxygenase-1 (HO-1) and surfactant protein-D (SP-D) in A549 cells (Horie et al., 2011). This
e n v i r o n m e n t a l t o x i c o l o g y a n d p h a r m a c o l o g y 3 4 ( 2 0 1 2 ) 644–650
study highlighted that an increase in gene expression of stress responsive enzymes such as HO-1 and SP-D and translocations of the transcription factor HIF-1␣ are effects of NiO nanoparticles. Pietruska et al. (2011) performed physicochemical characterization of NiO and metallic nickel particle for their ion bioavailability and toxicological properties in human lung epithelial cells (H460). Their results showed that NiO nanoparticles induced stabilization and nuclear translocation of the HIF-1␣ transcription factor followed by up regulation of its target gene, N-myc downstream regulated gene 1/Cap 43 (NDRG1 (cap 43)). In another study on NiO and metallic nickel nanoparticles, cytotoxicity to H460 cells was seen to occur concomitantly with activation of an apoptotic response as determined by dose and time-dependent cleavage of caspases and PARP (Pietruska et al., 2011). These studies have shown that nickel-based nanoparticles, especially NiO, may elicit genotoxicity by the activation of genes such as HO-1, SP-D, HIF-1␣, and up regulation of N-myc’s downstream regulated genes.
3.1.2.
In vivo studies
Morimoto et al. (2010b) examined the induction of 21 cytokines including inflammation, fibrosis and allergy caused by well dispersed NiO nanoparticles in lung disorders. They intratracheally instilled rats with 0.2 g of NiO nanoparticles dispersed in distilled water which had a mass median diameter in water of 26 nm. Their results showed that the expression of macrophage inflammatory protein-1␣ was continually increased in lung tissue and broncho-alveolar lavage fluid (BALF). In addition, interleukin-1␣ (IL-1␣) and interleukin1I (L-1) were increased in lung tissue. BALF analysis showed a transient increase of monocyte chemotactin protein-1. They concluded that overall agglomerates of NiO nanoparticles caused persistent inflammatory effects. These effects were due to the increase in cytokine expression and persistent increase in CC chemokine. Two independent studies obtained almost similar results in studies conducted on the toxicity of NiO nanoparticle and agglomerates following intratracheal instillation in male Wistar rats (Morimoto et al., 2011a; Nishi et al., 2009). In both studies, through quantitative measurement of protein by ELISA, cytokine- induced neutrophil chemo attractant (CINC)-2␣ was elevated (3 days to 6 months). However the latter study also found that CINC1 was increased from 3 days to 3 months, and CINC-3 was increased at 3 days but decreased later on. They also observed that the lung tissue had infiltrates of neutrophils and alveolar macrophages. A persistent increase in the BALF cell count, with a significant increase in neutrophil count and alveolar macrophage count was observed in both studies. In both studies rats were exposed to NiO nanoparticles (26 nm, 3.3 mg/kg), and were dissected at 3 days, 1 week, 1, 3 and 6 months. However, in a study that used whole body inhalation system, NiO nanoparticles did not induce the gene expression of matrix metalloproteinase-2 (MMP-2) and tissue inhibitor matrix proteinase-2 (TIMP-2) mRNA in rat lungs (Morimoto et al., 2011b). MMP-2 and TIMP-2 regulate the degradation of collagen. The synthesis and degradation of collagen is thought to regulate the deposition of extracellular matrix (ECM), which is involved in inflammation and fibrosis.
647
These in vivo studies show that most genes activated by NiO nanoparticles are involved in the regulation of inflammation signal related pathways. A substance is considered genotoxic if it deleteriously affects the genome of a cell either by direct or indirect damage to the cellular DNA including effects on the cellular pathways that monitor and protect genome integrity (Donaldson and Poland, 2012). In reality the induction of genotoxic effects can be due either to direct or indirect primary genotoxicity, secondary genotoxicity or a mixture of all as the production of reactive species within a cell. In situations where a particle or substance directly interacts with the genomic DNA and causes damage, the effect is called direct primary genotoxicity, which is independent of inflammation (Schins and Knaapen, 2007). Indirect primary genotoxicity in contrast occurs when intracellular antioxidants are depleted and therefore results in an imbalance between cellular steady-state oxidants. Secondary genotoxicity does not involve the direct interaction of a particle with the target cell in which genotoxicity occurs but instead drives genotoxicity through its interaction with other cells causing the production of an environment conducive to the accumulation of genetic damage and proliferation. This is typically caused by the induction of chronic inflammation leading to persistent oxidative stress caused by the presence of inflammatory cells such as macrophages and polymorphonuclear leukocytes as well as the secretion of various pro-survival and proliferation signaling factors. Therefore, inflammation effects induced by NiO nanoparticles in the animal lung may play an important role in triggering genotoxicity.
3.2.
Carcinogenicity of nickel-based nanoparticles
3.2.1.
Experimental studies
So far there is no data on in vivo studies available regarding of tumors or cancers induced by nickel-based nanoparticle. Gillespie et al. (2010) used occupationally relevant dose ranges of nickel hydroxide and the C57BL/6 mice as their animal models. Their study showed that nickel hydroxide nanoparticles are capable of inducing inflammatory effects in the lungs in both short and long term exposure periods. The two studies mentioned previously also concluded that nanoparticle agglomerates of nickel oxide induced persistent inflammatory response, and suggested that CINC was involved in lung injury by NiO nanoparticles (Morimoto et al., 2011a; Nishi et al., 2009). Another study showed that nickel hydroxide nanoparticles appeared to have stronger inflammogenic potential then other compounds in mice that were exposed by the whole body inhalation system (Kang et al., 2011). A study compared well characterized nanoparticles of cesium oxide, titanium oxide, silica oxide, nickel oxide, zinc oxide, copper oxide nanoparticles and amine modified polystyrene beads for their inflammation potencies in the lungs of rats (Cho et al., 2010). They used two time points (24 h and 4 weeks) to evaluate the acute and chronic effects of these particles. Acutely, their results showed that patterns of the lung showed neutrophil and eosinophil infiltrates. Chronically, the NiO nanoparticles caused neutrophilic, neutrophilic/lymphocytic, eosinophilic/fibrotic/granulomatous and fibrotic granulomatous inflammation. In normal physiological conditions these factors are important protective defenses against tissue injury
648
e n v i r o n m e n t a l t o x i c o l o g y a n d p h a r m a c o l o g y 3 4 ( 2 0 1 2 ) 644–650
or infections. However, they are also capable of promoting DNA damage such as chromosomal fragmentation, DNA point mutations, DNA repair inhibition and induce formation of methylation patterns that may lead to altered gene expression profiles and the formation of DNA adducts (Singh et al., 2009; Ding et al., 2000; Kaur et al., 2009). In addition, recent research evidence shows that inflammatory microenvironment in and around tumors is an indispensable participant in the neoplastic process (Wang and Cho, 2010). A recent review by Munoz and Costa (Munoz and Costa, 2012) showed that particle uptake is a critical step in determining carcinogenicity for nickel based fine particles. They stated that uptake was greatly influenced by the surface charge of the particle. There is a need for research regarding surface charge, the level of uptake and the rate of cell transformation by nickel based nanoparticles. Evidence indicates that inflammation is a predisposing factor to cancer, therefore from the studies cited, it can be seen that nickel-based nanoparticles are capable of causing inflammation in both in vivo and in vitro studies. Inflammation is especially of relevance in cases of long term exposure. This is because in short term exposure the genetic damage may be reversible, while in long term exposure, the persistence of inflammation leaves the cell venerable to DNA aberrations that can consequently lead to mutagenesis. Therefore, well designed chronic animal experiments are necessary for detecting the carcinogenicity of nickel-based nanoparticle compounds.
3.2.2.
Epidemiological studies
Currently there is no exclusive epidemiological data regarding nickel-based nanoparticle compounds, apart from those available on nickel fine particles. In summary, the genotoxic effects induced by metallic nickel nanoparticles in vitro may occur through activation of genes related with promotion and demotion of apoptosis. In this case, both promotion and demotion of apoptosis can lead to mutagenesis. The activation of monocyte phenotypes may also play a role in the genotoxicity induced by metallic nickel nanoparticles. In the in vivo studies, metallic nickel nanoparticle were shown to be capable of inducing cancer (rhabdomyosarcoma) in an animal model, but for now, whether they can also cause cancers in humans is unclear. As for nickel-based nanoparticles, specifically NiO nanoparticles, they cause genotoxicity by altering the activities of transcription factors such as HO-1, SP-D and HIF-1␣, and up regulation of N-myc’s downstream genes. The in vivo studies implicated genes that are involved in the regulation of inflammation such as CINC-2␣, CINC-3, IL-1␣, and IL-1, which may play an important role in nickel-based nanoparticle-induced genotoxicity. However, further studies are needed to prove this, since others have shown that the expression of genes such as MMP-2 and TIMP-2 that are involved in inflammation were not induced. Although there was no direct evidence to show carcinogenic effects of nickel-based nanoparticles in both animal and human studies, however, most of the studies showed that inflammatory reactions play an important role in the neoplastic process, especially in cases of chronic inflammation. Epidemiological data for both metallic nickel and nickel-based nanoparticles is lacking. This may also be due
to the fact that nanoscience is fairly new. As the application of nickel nanoparticles are gaining a lot of momentum, studies regarding its in vitro and in vivo effects and epidemiological investigations should be encouraged.
Conflicts of interest statement The authors declare that they have no conflicts of interest.
Acknowledgements The excellent assistance of Linda Bowman in the preparation of this article is greatly appreciated. This work was partly supported by National Nature Science Foundation of China (Grant No.81273111), The Foundations of Innovative Research Team of The Educational Commission of Zhejiang Province (T200907), The Nature Science Foundation of Ningbo City (Grant No. 2012A610185), The Ningbo Scientific Project (SZX11073), The Scientific Innovation Team of Ningbo (2009B21002) and K.C. Wong Magna Fund in Ningbo University.
references
Anon., 2005. Implications of Nanotechnology for Environmental Health Research. National Academy of Sciences, Washington, DC. Bagley, R.G., Rouleau, C., St. Martin, T., Boutin, P., Weber, W., Ruzek, M., Honma, N., Nacht, M., Shankara, S., Kataoka, S., Ishida, I., Roberts, B.L., Teicher, B.A., 2008. Human endothelial precursor cells express tumor endothelial marker 1/endosialin/CD248. Mol. Cancer Ther. 7, 2536. Bajpai, R., Waseem, M., Kaw, J.L., 1994. Pulmonary response to cadmium and nickel coated fly ash. J. Environ. Pathol. Toxicol. Oncol. 13 (4), 251–257. Ban, I., Drofenik, S.J., Makovec, M.D., 2011. Synthesis of copper–nickel nanoparticles prepared by mechanical milling for use in magnetic hyperthermia. J. Magn. Magn. Mater. 323 (17), 2254–2258. Buffle, J., 2006. The key role of environmental colloids/nanoparticles for the sustainability of life. Environ. Chem. 3, 3. Buzae, C., Pacheco Blandino, I.I., Robbie, K., 2007. Nanomaterials and nanoparticles: sources and toxicity. Biointerphases 2 (4), MR17–MR172. Cameron, K.S., Buchner, V., Tchounwou, P.B., 2011. Exploring the molecular mechanisms of nickel-induced genotoxicity and carcinogenicity: a literature review. Rev. Environ. Health 26 (2), 81–92. Cho, W.S., Duffin, R., Poland, C.A., Howie, S.E., MacNee, W., Bradley, M., Megson, I.L., Donaldson, K., 2010. Metal oxide nanoparticles induce unique inflammatory footprints in the lung: important implications for nanoparticle testing. Environ. Health Perspect. 118 (12), 1699–1706. Chou, K.S., Chang, S.C., Huang, K.C., 2007. Study on the characteristics of nanosized nickel particles using sodium borohydride to promote conversion. Azo J. Mater. Online 3. Costa, M., Yan, Y., Zhao, D., Sainikow, K., 2003. Molecular mechanisms of nickel carcinogenesis: gene silencing by nickel delivery to the nucleus and gene activation/inactivation by nickel-induced cell signaling. J. Environ. Monit. 5 (2), 222–223. Ding, M., Shi, X., Castranova, V., Vallyathan, V., 2000. Predisposing factors in occupational lung cancer: inorganic minerals and chromium. J. Environ. Pathol. Toxicol. Oncol. 19 (1–2), 129–138.
e n v i r o n m e n t a l t o x i c o l o g y a n d p h a r m a c o l o g y 3 4 ( 2 0 1 2 ) 644–650
Donaldson, K., Poland, C., 2012. Inhaled nanoparticles and lung cancer – what we can learn from conventional particle toxicology. Swiss Med. Wkly. 142. Gillespie, P.A., Kang, G.S., Elder, A., Gelein, R., Chen, L., Moreira, A.L., Koberstein, J., Wong, K.M.T., Gordon, T., Chen, I.T., 2010. Pulmonary response after exposure to inhaled nickel hydroxide nanoparticles: short and long-term studies in mice. Nanotoxicology 4 (1), 106–119. Goodman, J.E., Prueitt, R.L., Thakali, S., Oller, A.R., 2011. The nickel ion bioavailability model of the carcinogenic potential of nickel-containing substances in the lung. Crit. Rev. Toxicol. 41 (2), 142–174. Grimsrud, T.K., Berge, S.R., Resmann, F., Norseth, T., Andersen, A., 2000. Assessment of historical exposures in a nickel refinery in Norway. Scand. J. Work, Environ. Health 26 (4), 338–345. Hansen, T., Clermont, G., Alves, A., Eloy, R., Brochhausen, C., Boutrand, J.P., Gatti, A.M., Kirkpatrick, C.J., 2006. Biological tolerance of different materials in bulk and nanoparticulate form in a rat model: sarcoma development by nanoparticles. J. R. Soc. Interface 3, 767–775. Horie, M., Fukui, H., Nishio, K., Endoh, S., Kato, H., Fujita, K., Miyauchi, A., Shichiri, M., Ishida, N., Kinugasa, S., Morimoto, Y., Niki, E., Yoshida, Y., Iwahashi, H., 2011. Evaluation of acute oxidative stress induced by NiO nanoparticles in vivo and in vitro. J. Occup. Health 53 (2), 64–74. Iannitti, T., Capone, S., Gatti, A., Capitani, F., Cetta, F., Palmieri, B., 2010. Intracellular heavy metal nanoparticle storage: progressive accumulation within lymph nodes with transformation from chronic inflammation to malignancy. Int. J. Nanomed. 5, 955–960. Johnson, N., Shelton, B.J., Hopenhayn, C., et al., 2011. Concentrations of arsenic, chromium, and nickel in toenail samples from Appalachian Kentucky residents. J. Environ. Pathol. Toxicol. Oncol. 30 (3), 213–223. Kang, G.S., Gillespie, P.A., Gunnison, A., Rengifo, H., Koberstein, J., Chen, L.C., 2011. Comparative pulmonary toxicity of inhaled nickel nanoparticles; role of deposited dose and solubility. Inhal. Toxicol. 23 (2), 95–103. Kasprzak, J.S., Sunderman Jr., F.W., Salnikow, K., 2003. Nickel carcinogenesis. Mutat. Res. 533, 67–97. Kaur, G., Lone, I.A., Athar, M., Alam, M.S., 2009. Guilandina bonduc L. possesses antioxidant activity and precludes ferric nitrilotriacetate (Fe-NTA) induced renal toxicity and tumor promotion response. J. Environ. Pathol. Toxicol. Oncol. 28 (2), 163–175. Kornick, R., Zug, K.A., 2008. Nickel. Dermatitis 19, 3–8. Kyono, H., Kusaka, Y., Homma, K., Kubota, H., Endo-Ichikawa, Y., 1992. Reversible lung lesions in rats due to short-term exposure to ultrafine cobalt particles. Ind. Health 30 (3–4), 103–118. Liberda, E.N., Cuevas, A.K., Gillespie, P.A., Grunic, G., Qu, Q., Chen, L.C., 2010. Exposure to inhaled nickel nanoparticles causes a reduction in number and function of bone marrow endothelial progenitor cells. Inhal. Toxicol. 22, 95–99. Magaye, R., Zhao, J., Bowman, L., Ding, M., 2012. Genotoxicity and carcinogenicity of cobalt, nickel and copper-based nanoparticles. J. Exp. Ther. Med. 4 (4), 551–561. Maynard, A.D., Kuempel, E.D., 2005. Airborne nanostructured particles and occupational health. J. Nanopart. Res. 7, 587–614. Morimoto, Y., Kobayashi, N., Shinohara, N., Myojo, T., Tanaka, I., Nakanishi, J., 2010a. Hazard assessments of manufactured nanomaterials. J. Occup. Health 52 (6), 325–334. Morimoto, Y., Ogami, A., Todoroki, M., Yamamoto, M., Murakami, M., Hirohashi, M., Oyabu, T., Myojo, T., Nishi, K., Kadoya, C., Yamasaki, S., Nagatomo, H., Fujita, K., Endoh, S., Uchida, K., Yamamoto, K., Kobayashi, N., Nakanishi, J., Tanaka, I., 2010b. Expression of inflammation-related cytokines following
649
intratracheal instillation of nickel oxide nanoparticles. Nanotoxicology 4 (2), 161–176. Morimoto, Y., Hirohashi, M., Ogami, A., Oyabu, T., Myojo, T., Hashiba, M., Mizuquchi, Y., Kambara, T., Lee, B.W., Kuroda, E., Tanaka, I., 2011a. Pulmonary toxicity following an intratracheal instillation of nickel oxide nanoparticle agglomerates. J. Occup. Health 53 (4), 293–295. Morimoto, Y., Oyabu, T., Ogami, A., et al., 2011b. Investigation of gene expression of MMP-2 and TIMP-2 mRNA in rat lung in inhaled nickel oxide and titanium dioxide nanoparticles. Ind. Health 49 (3), 344–352. Munoz, A., Costa, M., 2012. Elucidating the mechanisms of nickel compound uptake: a review of particulate and nano-nickel endocytosis and toxicity. Toxicol. Appl. Pharmacol. 260 (1), 1–16. Nagata, S., 2000. Apoptotic DNA fragmentation. Exp. Cell Res. 256 (1), 12–18. Nishi, K., Morimoto, Y., Ogami, A., Murakami, M., Myojo, T., Oyabu, T., Kadoya, C., Yamamoto, M., Todoroki, M., Hirohashi, M., Yamasaki, S., Fujita, K., Endo, S., Uchida, K., Yamamoto, K., Nakanishi, J., Tanaka, I., 2009. Expression of cytokine-induced neutrophil chemoattractant in rat lungs by intratracheal instillation of nickel oxide nanoparticles. Inhal. Toxicol. 21 (12), 1030–1039. Oberdorster, G., 2001. Pulmonary effects of inhaled ultrafine particles. Int. Arch. Occup. Environ. Health 74 (1), 1–8. Oberdorster, G., Ferin, J., Lehnert, B.E., 1994. Correlation between particle size, in vivo particle persistence, and lung injury. Environ. Health Perspect. 102 (Suppl. 5), 173–179. Oller, A.R., 2002. Respiratory carcinogenicity assessment of soluble nickel compounds. Environ. Health Perspect. 110 (5), 444–841. Park, S., Lee, Y.K., Jung, M., Kim, K.H., Chung, N., 2007. Cellular toxicity of various inhalable nanoparticles on human alveolar epithelial cells. Inhal. Toxicol. 9, 59–65. Phillip, J.I., Green, F.Y., Davis, J.C.A., Murray, J., 2010. Pulmonary and systemic toxicity following exposure to nickel nanoparticles. Am. J. Ind. Med. 53, 763–767. Pietruska, J.R., Liu, X., Smith, A., McNeil, K., Weston, P., Zhitkovich, A., Hurt, R., Kane, A.B., 2011. Bioavailability, intracellular mobilization of nickel, and HIF-1␣ activation in human lung epithelial cells exposed to metallic nickel and nickel oxide nanoparticles. Toxicol. Sci., http://dx.doi.org/10.1093/toxsci/kfr206. Salnikow, K., Costa, M., 2000. Epigenetic mechanisms of nickel carcinogenesis. J. Environ. Pathol. Toxicol. Oncol. 19 (3), 307–318. Salnikow, K., Zhitkovich, A., 2008. Genetic and epigenetic mechanisms in metal carcinogenesis and cocarcinogenesis: nickel, arsenic, and chromium. Chem. Res. Toxicol. 21 (1), 28–44. Salnikow, K., An, W.G., Melillo, G., Blagosklonny, M.V., Costa, M., 1999. Nickel-induced transformation shifts the balance between HIF-1 and p53 transcription factors. Carcinogenesis 20 (9), 1819–1823. Salnikow, K., Blagosklonny, M.V., Ryan, H., Johnson, R., Costa, M., 2000. Carcinogenic nickel induces genes involved with hypoxic stress. Cancer Res. 60 (1), 38–41. Salnikow, K., Davidson, T., Costa, M., 2002. The role of hypoxia-inducible signaling pathway in nickel carcinogenesis. Environ. Health Perspect. 110 (Suppl. 5), 831–834. Salnikow, K., Davidson, T., Zhang, Q., Chen, L.C., Su, W., Costa, M., 2003. The involvement of hypoxia-inducible transcription factor-1-dependent pathway in nickel carcinogenesis. Cancer Res. 63 (13), 3524–3530. Schins, R.P., Knaapen, A.M., 2007. Genotoxicity of poorly soluble particles. Inhal. Toxicol. 19 (Suppl. 1), 189–198.
650
e n v i r o n m e n t a l t o x i c o l o g y a n d p h a r m a c o l o g y 3 4 ( 2 0 1 2 ) 644–650
Seilkop, S.K., Oller, A.R., 2003. Respiratory cancer risks associated with low-level nickel exposure: an integrated assessment based on animal, epidemiological, and mechanistic data. Regul. Toxicol. Pharm. 37 (2), 173–190. Singh, N.M.B., Jenkins, G.S.J., Griffiths, S.M., Williams, P.M., Maffeis, T.G.G., Wright, C.J., Doak, S.H., 2009. NanoGenotoxicology: the DNA damaging potential of engineered nanomaterials. Biomaterials 30, 3891–3894. Swidwinska-Gajewska, A.M., 2007. Nanoparticles (part 1) – the product of modern technology and new hazards in the work environment. Med. Pr. 58 (3), 243–251. Tang, X., Li, C., Wu, W., 2010. Research progress on carcinogenicity of nickel and its compounds. Chin. J. Ind. Med. 4. Tepper, O.M., Capla, J.M., Galiano, R.D., Ceradini, D.J., Callaghan, M.J., Kleinman, M.E., Gurtner, G.C., 2005. Adult vasculogenesis occurs through in situ recruitment, proliferation and tubulization of circulating bone marrow-derived cells. Blood 105 (3), 1068–1077. Wang, H., Cho, C.H., 2010. Effect of NF-kappaB signaling on apoptosis in chronic inflammation-associated carcinogenesis. Curr. Cancer Drug Targets 10 (6), 593–599.
Zhang, Q., Kusaka, Y., Zhu, X., et al., 2003. Comparative toxicity of standard nickel and ultrafine nickel in lung after intratracheal instillation. J. Occup. Health 45 (1), 23–30. Zhang, X.D., Zhao, J., Bowman, L., Shi, X., Castranova, V., Ding, M., 2010. Tungsten carbide-cobalt particles activate Nrf2 and its downstream target genes in JB6 cells possibly by ROS generation. J. Environ. Pathol. Toxicol. Oncol. 29 (1), 31–40. Zhao, J., Shi, X., Castranova, V., Ding, M., 2009a. Occupational toxicology of nickel and nickel compounds. J. Environ. Pathol. Toxicol. Oncol. 28 (3), 177–208. Zhao, J., Bowman, L., Zhang, X., Shi, X., Jiang, B., Castranova, V., Ding, M., 2009b. Metallic nickel nano- and fine particles induce JB6 cell apoptosis through a caspase-8/AIF mediated cytochrome c- independent. J. Nanobiotechnology 7, 2–14. Zhu, F.Q., Chern, G.W., Tchernyshyov, O., Zhu, X.C., Zhu, J.G., Chien, C.L., 2006. Magnetic bistability and controllable reversal of asymmetric ferromagnetic nanorings. Phys. Rev. Lett. 96 (2).