Genotoxicity of synthetic amorphous silica nanoparticles in rats following short‐term exposure. Part 1: Oral route

Synthetic amorphous silica (SAS) in its nanosized form is now used in food applications although the potential risks for human health have not been evaluated. In this study, genotoxicity and oxidative DNA damage of two pyrogenic (NM‐202 and 203) and two precipitated (NM‐200 and ‐201) nanosized SAS were investigated in vivo in rats following oral exposure. Male Sprague Dawley rats were exposed to 5, 10, or 20 mg/kg b.w./day for three days by gavage. DNA strand breaks and oxidative DNA damage were investigated in seven tissues (blood, bone marrow from femur, liver, spleen, kidney, duodenum, and colon) with the alkaline and the (Fpg)‐modified comet assays, respectively. Concomitantly, chromosomal damage was investigated in bone marrow and in colon with the micronucleus assay. Additionally, malondialdehyde (MDA), a lipid peroxidation marker, was measured in plasma. When required, a histopathological examination was also conducted. The results showed neither obvious DNA strand breaks nor oxidative damage with the comet assay, irrespective of the dose and the organ investigated. Similarly, no increases in chromosome damage in bone marrow or lipid peroxidation in plasma were detected. However, although the response was not dose‐dependent, a weak increase in the percentage of micronucleated cells was observed in the colon of rats treated with the two pyrogenic SAS at the lowest dose (5 mg/kg b.w./day). Additional data are required to confirm this result, considering in particular, the role of agglomeration/aggregation of SAS NMs in their uptake by intestinal cells. Environ. Mol. Mutagen. 56:218–227, 2015. © 2014 Wiley Periodicals, Inc.

[1]  R. Gurny,et al.  Interaction of biodegradable nanoparticles with intestinal cells: the effect of surface hydrophilicity. , 2010, International journal of pharmaceutics.

[2]  V. Hornung,et al.  Activation of the inflammasome by amorphous silica and TiO2 nanoparticles in murine dendritic cells , 2011, Nanotoxicology.

[3]  P. Allavena,et al.  Cancer-related inflammation , 2008, Nature.

[4]  T. Dragani,et al.  Libri Ricevuti: IARC Monographs on the Evaluation of Carcinogenic Risks to Humans , 1992 .

[5]  S. Słomkowski,et al.  Effect of surface modification of silica nanoparticles on toxicity and cellular uptake by human peripheral blood lymphocytes in vitro , 2012, Nanotoxicology.

[6]  N. Hondow,et al.  Mechanism of cellular uptake of genotoxic silica nanoparticles , 2012, Particle and Fibre Toxicology.

[7]  V. Fessard,et al.  Cytotoxic and genotoxic effects of cylindrospermopsin in mice treated by gavage or intraperitoneal injection , 2012, Environmental toxicology.

[8]  Shang Gao,et al.  In vivo biodistribution and synergistic toxicity of silica nanoparticles and cadmium chloride in mice. , 2013, Journal of hazardous materials.

[9]  H. Bouwmeester,et al.  Presence and risks of nanosilica in food products , 2011, Nanotoxicology.

[10]  M. Kirsch‐Volders,et al.  Exploring the aneugenic and clastogenic potential in the nanosize range: A549 human lung carcinoma cells and amorphous monodisperse silica nanoparticles as models , 2010, Nanotoxicology.

[11]  Catrin Albrecht,et al.  Cellular responses to nanoparticles: Target structures and mechanisms , 2007 .

[12]  Dominique Lison,et al.  The nanosilica hazard: another variable entity , 2010, Particle and Fibre Toxicology.

[13]  T. Xia,et al.  Toxic Potential of Materials at the Nanolevel , 2006, Science.

[14]  H. Bouwmeester,et al.  Knowledge gaps in risk assessment of nanosilica in food: evaluation of the dissolution and toxicity of different forms of silica , 2013, Nanotoxicology.

[15]  M. Fenech The in vitro micronucleus technique. , 2000, Mutation research.

[16]  G. Oberdörster,et al.  Nanotoxicology: An Emerging Discipline Evolving from Studies of Ultrafine Particles , 2005, Environmental health perspectives.

[17]  V. Fessard,et al.  Genotoxicity of synthetic amorphous silica nanoparticles in rats following short‐term exposure, part 2: Intratracheal instillation and intravenous injection , 2015, Environmental and molecular mutagenesis.

[18]  Yasuo Tsutsumi,et al.  Silica nanoparticles as hepatotoxicants. , 2009, European journal of pharmaceutics and biopharmaceutics : official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V.

[19]  P. Artursson,et al.  Transport of nanoparticles across an in vitro model of the human intestinal follicle associated epithelium. , 2005, European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences.

[20]  Douglas Gilliland,et al.  Amorphous silica nanoparticles do not induce cytotoxicity, cell transformation or genotoxicity in Balb/3T3 mouse fibroblasts. , 2012, Mutation research.

[21]  Wim H de Jong,et al.  Genotoxicity evaluation of amorphous silica nanoparticles of different sizes using the micronucleus and the plasmid lacZ gene mutation assay , 2011, Nanotoxicology.

[22]  U. Vogel,et al.  Distribution of silver in rats following 28 days of repeated oral exposure to silver nanoparticles or silver acetate , 2011, Particle and Fibre Toxicology.

[23]  E. Fröhlich,et al.  Models for oral uptake of nanoparticles in consumer products , 2012, Toxicology.

[24]  S. K. Sundaram,et al.  Adsorbed proteins influence the biological activity and molecular targeting of nanomaterials. , 2007, Toxicological sciences : an official journal of the Society of Toxicology.

[25]  Manuela Semmler-Behnke,et al.  Size and surface charge of gold nanoparticles determine absorption across intestinal barriers and accumulation in secondary target organs after oral administration , 2011, Nanotoxicology.

[26]  Yves-Jacques Schneider,et al.  Nanoparticles as potential oral delivery systems of proteins and vaccines: a mechanistic approach. , 2006, Journal of controlled release : official journal of the Controlled Release Society.

[27]  A. Collins,et al.  The comet assay for DNA damage and repair , 2004, Molecular biotechnology.

[28]  Xiao-Dong Zhou,et al.  In vitro toxicity of silica nanoparticles in human lung cancer cells. , 2006, Toxicology and applied pharmacology.

[29]  A. Nemmar,et al.  Amorphous silica nanoparticles impair vascular homeostasis and induce systemic inflammation , 2014, International journal of nanomedicine.

[30]  Julia Xiaojun Zhao,et al.  Toxicity of luminescent silica nanoparticles to living cells. , 2007, Chemical research in toxicology.

[31]  I. M. Neiman,et al.  [Inflammation and cancer]. , 1974, Patologicheskaia fiziologiia i eksperimental'naia terapiia.

[32]  Eun-Jung Park,et al.  Oxidative stress and pro-inflammatory responses induced by silica nanoparticles in vivo and in vitro. , 2009, Toxicology letters.

[33]  Iqbal Ahmad,et al.  Nanotoxicity of pure silica mediated through oxidant generation rather than glutathione depletion in human lung epithelial cells. , 2010, Toxicology.

[34]  J. Richmond The 3Rs - Past, Present and Future , 2000 .

[35]  I. Jang,et al.  Effect of micro/nano silica particle feeding for mice. , 2008, Journal of nanoscience and nanotechnology.

[36]  Kenneth A. Dawson,et al.  Nanoparticle size and surface properties determine the protein corona with possible implications for biological impacts , 2008, Proceedings of the National Academy of Sciences.

[37]  Kyunghee Choi,et al.  A Single Instillation of Amorphous Silica Nanoparticles Induced Inflammatory Responses and Tissue Damage until Day 28 after Exposure , 2011 .

[38]  Mina Choi,et al.  The impact of size on tissue distribution and elimination by single intravenous injection of silica nanoparticles. , 2009, Toxicology letters.

[39]  M. Kirsch‐Volders,et al.  The in vivo gut micronucleus test detects clastogens and aneugens given by gavage. , 2001, Mutagenesis.

[40]  Stefan Pfuhler,et al.  Silica nanoparticles administered at the maximum tolerated dose induce genotoxic effects through an inflammatory reaction while gold nanoparticles do not. , 2012, Mutation research.

[41]  Linlin Li,et al.  The absorption, distribution, excretion and toxicity of mesoporous silica nanoparticles in mice following different exposure routes. , 2013, Biomaterials.

[42]  Kenneth A. Dawson,et al.  Effects of the presence or absence of a protein corona on silica nanoparticle uptake and impact on cells. , 2012, ACS nano.

[43]  V. Paget,et al.  Toxicity and genotoxicity of nano-SiO2 on human epithelial intestinal HT-29 cell line. , 2012, The Annals of occupational hygiene.

[44]  Maria João Silva,et al.  Genotoxicity evaluation of nanosized titanium dioxide, synthetic amorphous silica and multi-walled carbon nanotubes in human lymphocytes. , 2014, Toxicology in vitro : an international journal published in association with BIBRA.

[45]  M A Kastenbaum,et al.  Tables for determining the statistical significance of mutation frequencies. , 1970, Mutation research.

[46]  G W Halbert,et al.  The Uptake and Translocation of Latex Nanospheres and Microspheres after Oral Administration to Rats , 1989, The Journal of pharmacy and pharmacology.

[47]  R. Tice,et al.  Single cell gel/comet assay: Guidelines for in vitro and in vivo genetic toxicology testing , 2000, Environmental and molecular mutagenesis.

[48]  Feng Gao,et al.  Oxidative stress contributes to silica nanoparticle-induced cytotoxicity in human embryonic kidney cells. , 2009, Toxicology in vitro : an international journal published in association with BIBRA.

[49]  V. Castranova,et al.  Pulmonary response to intratracheal instillation of ultrafine versus fine titanium dioxide: role of particle surface area , 2008, Particle and Fibre Toxicology.

[50]  Mauro Ferrari,et al.  Sustained small interfering RNA delivery by mesoporous silicon particles. , 2010, Cancer research.

[51]  Agnes G. Oomen,et al.  Presence of nano-sized silica during in vitro digestion of foods containing silica as a food additive. , 2012, ACS nano.

[52]  S. Pfuhler,et al.  The in vivo comet assay: use and status in genotoxicity testing. , 2005, Mutagenesis.

[53]  S. Ganapathy,et al.  Toxicity of zinc oxide nanoparticles through oral route , 2012, Toxicology and industrial health.

[54]  Robert Langer,et al.  The biocompatibility of mesoporous silicates. , 2008, Biomaterials.

[55]  D. Marko,et al.  In vitro toxicity of amorphous silica nanoparticles in human colon carcinoma cells , 2012, Nanotoxicology.

[56]  Frank A Witzmann,et al.  Nanoparticle toxicity by the gastrointestinal route: evidence and knowledge gaps. , 2013, International journal of biomedical nanoscience and nanotechnology.

[57]  Dong Chen,et al.  The shape effect of mesoporous silica nanoparticles on biodistribution, clearance, and biocompatibility in vivo. , 2011, ACS nano.

[58]  V. Préat,et al.  Mechanism of transport of saquinavir-loaded nanostructured lipid carriers across the intestinal barrier. , 2013, Journal of controlled release : official journal of the Controlled Release Society.

[59]  H. Bouwmeester,et al.  Sub-chronic toxicity study in rats orally exposed to nanostructured silica , 2014, Particle and Fibre Toxicology.

[60]  A. Florence,et al.  Nanoparticle Uptake by the Rat Gastrointestinal Mucosa: Quantitation and Particle Size Dependency , 1990, The Journal of pharmacy and pharmacology.

[61]  Iseult Lynch,et al.  Reproducible comet assay of amorphous silica nanoparticles detects no genotoxicity. , 2008, Nano letters.

[62]  Si-Shen Feng,et al.  Effects of particle size and surface coating on cellular uptake of polymeric nanoparticles for oral delivery of anticancer drugs. , 2005, Biomaterials.

[63]  A. Pandey,et al.  Induction of oxidative stress, DNA damage and apoptosis in mouse liver after sub-acute oral exposure to zinc oxide nanoparticles. , 2012, Mutation research.

[64]  Z. Chai,et al.  Acute toxicity and biodistribution of different sized titanium dioxide particles in mice after oral administration. , 2007, Toxicology letters.

[65]  Robert H Schiestl,et al.  Titanium dioxide nanoparticles induce DNA damage and genetic instability in vivo in mice. , 2009, Cancer research.