Oxidative stress and pro-inflammatory responses induced by silica nanoparticles in vivo and in vitro
Introduction
Silicas (SiO2) are the most abundant compounds in the earth's crust except carbon and they can be divided into crystalline or non-crystalline (amorphous) silica. Amorphous silicas are divided into naturally occurring amorphous silicas and synthetic forms. Synthetic amorphous silicas (SAS) are intentionally manufactured and it has been known that SAS do not contain measurable levels of crystalline silica which causes adverse health effects such as silicosis (Arts et al., 2007). Based on this knowledge, SAS are used in various industrial fields and are being used as the materials for nanoparticles. Various nanoparticles made from SAS are also widely used in chemical and biomedical products such as printer toners, varnishes, cancer therapy, DNA delivery, and enzyme immobilization (Barik et al., 2008). With the rapid increase of nanoparticle applications, the concerns on the health impacts caused by amorphous silica nanoparticles are also increasing.
Regarding the toxicity of crystalline silica particles, inhalation of the crystalline form of silica has been a well-known exposure route and historically associated with the development of a severe respiratory disease, silicosis which is lung-pneumoconiosis characterized by alveolar proteinosis and diffused fibrosis (Hamilton et al., 2008, Iyer et al., 1996). Based on the evidence obtained from both animal models and epidemiological studies, the IARC (International Agency for Research on Cancer) has concluded that there are sufficient evidences that inhaled crystalline silica from occupational sources, in the form of quartz, cristobalite or tridymite is carcinogenic to humans (IARC, 1997, Cocco et al., 2007). There are many reports on the pathogenesis of silicosis induced by crystalline silica. Investigators have studied the effects of crystalline silica particles on the induction of cytokines such as IL-1β, IL-6, IL-10, TNF-α and transforming growth factor (TGF); chemokines such as monocyte chemoattractant protein-1 (MCP-1) and macrophage inflammatory protein-2(MIP-2); the reactive oxygen species (ROS), reactive nitrogen species (RNS) and nitric oxide (NO)-generated mainly through iNOS (Rimal et al., 2005, Øvrevik et al., 2006).
However, the toxicities of the amorphous synthetic silica particles, micro-sized particles, and nano-sized particles, have not been widely studied (Cho et al., 2007). Recently, data on the growth inhibition of silica nanoparticles on the green alga Pseudokirchneriella subcapitata were published (Van Hoecke et al., 2008). Silica nanoparticles also showed cytotoxicity in different types of cultured mammalian cell lines (Chang et al., 2007, Jin et al., 2007, Lin et al., 2006). As in vivo studies, the acute and subacute lung toxicities of ultrafine colloidal silica particles were assessed using mice. When cellular and biochemical parameters in bronchoalveolar lavage fluid (BALF) were assessed in the mice intratracheally instilled with ultrafine silica particles, moderate to severe pulmonary inflammation was observed (Kaewamatawong et al., 2006).
It seems that pro-inflammatory responses induced by nanoparticles have been focused as one of the toxic mechanisms. Recently, a few types of nanoparticles such as titanium dioxide and carbon black showed pro-inflammatory effects on epithelial cells in vitro (Monteiller et al., 2007). But, information on the pro-inflammatory responses induced by amorphous silica nanoparticles has not been fully released yet.
In this study, we investigated the oxidative stress and pro-inflammatory responses both in mice and in RAW 264.7 cell line to evaluate the toxicity and possible mechanisms of amorphous silica nanoparticles.
Section snippets
Maintenance of animals, cell culture and nanoparticle treatment
ICR mice were purchased from Orient-Bio Animal Company (Seongnam, Gyeonggi, Korea) and were maintained for adaptation in animal room before the study. The environmental conditions of animal room are maintained as follows; temperature, 23 ± 1 °C; relative humidity, 55 ± 5%; 12 h light/dark cycle. Silica nanoparticles was intraperitoneally treated to the mice with the dosages of 50 mg/kg, 100 mg/kg, and 250 mg/kg for the splenocytes proliferation test. For the test of macrophage activation, NO synthesis,
Activation of peritoneal macrophages in mice
Mice were treated with silica nanoparticles 50 mg/kg through intraperitoneal injection, and were sacrificed at 12 h, 24 h, 48 h, 72 h after treatments, respectively. Macrophages were harvested from the peritoneal cavity of mouse and were incubated in CO2 incubator for 3 h to observe the morphological changes. Activated macrophages, which showed the cytoplasmic spreading, were observed in the mice sacrificed at 12 h after silica nanoparticle treatment. However, cytotoxic effect was also shown in the
Discussion
Toxicological studies are rapidly increasing both in engineered nanomaterials and in naturally occurring particles (Kipen and Laskin, 2005, Kagan et al., 2005, Curtis et al., 2006, Hardman, 2006). As one of the toxic mechanisms of nanoparticles, ROS generation may be the most widely studied. Recently, ROS generation in cultured cells treated with C60 fullerenes, single-walled nanotubes (SWNTs), cerium oxide nanoparticles, and other metal particles have been reported (Hussain et al., 2005, Park
Conflict of interest statement
None.
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