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Due to unique physicochemical, mechanical, and electrical properties naonparticles hold great hope for cancer imaging, cancer targeting and drug delivery.
Commercial interests and potential development of mass production leads to an active worldwide ongoing research for assessment of the potential hazards of nanomaterials to biological moieties and humans.
Elusive reports on genotoxicity of nanoparticles often appear in the literature and a lack of synergy among various issues while explaining involved mechanisms is observed. The mechanisms incriminated in DNA damage depends on nanomaterials type, size, purity, dispertion as well as functionalization or coating, endocitosis and cellular internalization,
This paper reviews the most recent in vitro studies regarding the toxicity of nanomaterials at the molecular level, genotoxicity and induced oxidative stress with an emphasis on the type of nanomaterial and the mechanisms incriminated in DNA damage.
Based on our review we suggest that care should be taken for several issues such as tuning the cytotoxicity to nanomaterials by functionalizing with different surface groups in order to obtain chemical modification and subsequent improvement in DNA alteration , more complete and quantified characterization of nanoparticles, improvement in chromatographic and mass spectrometric analysis of damage DNA strands and new determination methods of apoptosis.
The promising future of nanotechnology is based on an increasing number of applications of nano-sized materials. Distinctive physical and chemical properties make nanoparticles(NPs) a not yet entirely explored treasure. However, studies have demonstrated that the same physical and chemical properties that represent the fundament of nanotechnological applications make particles capable to induce adverse effects at different biological levels (macro-organism, tissue, cell or under-cell dimension structures, including DNA). Since the possible genotoxicity of NPs represents a serious, potentially long-time danger for humans that will need deeper and more extensive research, present study will attempt to review most of the already published evidences regarding this issue taking into account the physical and chemical particularities of the most intensively studied NPs.
The aggression induced by nanoparticles induces further inflammatory pathways activation. Both acute and chronic dynamic evolution patterns following inflammation initiation have been reported. NPs. exposure and induced alteration can either stimulate rapid differing mechanisms with consequential healing, or result in a long-term chronic stage. Recognition of each type of reaction can be made based on the specific alterations of each phase. While acute phase effects is marked by tissue infiltration with segmented leucocytes (especially polymorphonuclear) as well as extravasations of erythrocytes and increased extracellular space volume, chronic inflammation is well characterized by increased macrophages and lymphocytes number, sometimes accompanied by presence of plasma cells. Also, the continuous and insufficient healing effort that is specific for chronic inflammation can be diagnosed by simultaneous increase in vascularity and proliferation of fibroblasts, resulting in granulation tissue formation. . The result of the interaction between the NP and the above described mechanisms can be either accurate healing, including mimics of the original local tissue architecture, or scar formation. However, reaction to NP contact should be understood as a dynamic process, involving one or several of the above described mechanisms depending on the type of NP, concentration, exposure approach (type, rhythm and continuity of administration).
Along with the potential to activate both humoral and cellular immunity, NPs have been recently reported to elicit genotoxicity potential through interference with transcriptional processes within cells as well as activation of various molecular changes and consequent nucleus injurious effects.. The interference with transcriptional processes induced by all types mutations: point mutation, duplication, deletion, insertion or rearrangements of nucleotide/s can induce different intensity of results, from silent mutations to major effects, depending on the type of alteration. If the process involves a key protein within important processes for the organism, it can favor disease appearance .Several mechanisms have been proposed to be the cause of DNA damage after NPs exposure. Among them, inflammation and reactive oxygen species (ROS) formation with subsequent DNA oxidative injury leading to DNA composition alterations represents the most proeminent mechanisms. Deletions or insertions, oxidized bases and base pair mutations represent some of the already known effects of oxidative stress  The mechanism of oxidative stress induced by nanoparticles is not well understood. There is evidence that free radicals can be induced at the surface of nanoparticles such as single-wall carbon nanotube (SWCNT), semiconductor quantum dots, TiO2, environmental particles (e.g. PM-10), asbestos, and a range of man-made fibers . Among ROS, the hydroxyl radical (•OH) represents the most potent oxygen specie to known affect DNA structure. The most studied element connected with the mechanisms, the 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG) has been demonstrated to induce replication G:C to T:A transversion mutations. .
Effects of DNA alterations (induced by NPs or by other agents) are very much dependant on reparatory mechanisms. It has been stated that about 30 000 to 300 000 mistakes appear during every cell division. Since most of these errors are constantly cancelled by proofreading as well as post replication mismatch repair mechanisms, the final mutation frequency is about 1 mutation per genome per cell division . However should the DNA repair competence of the cell be insufficient, the frequency of mutation frequency increases. As a result, early senescence, apoptosis or cancer can appear. One very good example is the intensely studied relationships is the link between hereditary mutations within the DNA reparatory elements BRCA1 and 2, and breast/ovarian cancer..
Carbon nanotubes (CNTs) and C60 fullerenes.
The abundance in literature data regarding both in vitro and in vivo effects of Carbon Nanotubes (CNTs) makes the material as one of the most studied types of nanoscale materials. There is an overall agreement on the existence of toxicity connected to physicochemical properties. However, data on possible genotoxic effects is still limited. Since this type of NPs is particularly stable and could activate continuous inflammatory processes after their tissue deposition, genotoxocity should represent a very important goal for future research. Safety of CNTs has received an important attention because of their rod shape (very similar with asbestos), as well as iron residues.. One if the most clear demonstration of CNT toxic effects is brought by a recent in vivo study in which multi-wall carbon nanotubes are reported to initiate mesothelioma formation in p53+/- mice following single intraperitoneal injection .
By contrast, C60 is a spherical molecule composed exclusively of carbon atoms for which several derivatives have been reported  . The properties of C60 are distinct from CNTs, thus eliciting ROS scavenging effects, direct biomolecular interaction as well as stimulating effects for radicals formation.
Both types of nanomaterials were tested regarding the potential of stimulating the production of ROS. The mechanism of the ROS formation by NPs is still not completely elucidated. It has been stated that NPs are able to stimulate ROS production through Fenton reactions catalized by iron content. An alternative pathway would be the deposition of NPs within the cells by phagocytosis, followed by increased ROS production in macrophages and leucocytes. For C60, it has been suggested that ROS formation and lipid peroxidation involves electron transfer between C60 and other types of molecules.  Recent studies reported increased ROS production and subsequent DNA damage, including 8-oxo-7,8-dihydro-2'-deoxyguanosine after exposure to NPs.  .
A study focused on fullerenes (C60), carbon black (CB) as well as ceramic fibers reported G:C base pairs (52/76, 68%) mutations to be predominant for al NPs types. Among them, 13 G:C base pairs were located in the G or C runs. The study reported no significant differences among the three particle-induced distributions of mutation hot spots (base pairs 143, 189, 320, 406 and 418, respectively). Those results can lead to the possibility of performing DNA damage sites mapping after NPs exposure. Also, G:C to C:G transversion, otherwise a rare event in both spontaneous and chemically-induced mutations in vivo, was identified by the study as the most prominent mutation type induced by all particles, regardless of their type. Since these mutations were commonly increased regardless of the type and constituents of particles, the report suggested the existence of similar mutation-inducing mechanisms for all types of particles.. However, it still needs to be considered that within the in vitro assays, UV radiation, hydrogen peroxide and peroxy radicals frequently induce oxidative stress damage and G:C to C:G transversions..
8-oxo-dG in considered as the most typical oxidative damage lesion which can pair with dA and leads G to T transversions . However, it was stated that it cannot be considered as responsible for G to C transversion since dG is not incorporated opposite 8-oxodG . The existence of several other guanine products following oxidative lesions has been reported, including imidazolone (Iz), oxazolone (Oz), spiroiminodihydantoin (Sp) and guanidinohydantoin (Gh) . Recent genetic mechanisms discoveries suggest that three of the above described molecules: Oz, Sp and Gh can represent the key molecules for G to C transversion by means of translesion synthesis systems . Their presence has also been demonstrated in bacterial cells and rat liver  . All these discoveries lead to the idea of Oz, Sp and Gh formation involvement in NP-induced G:C to C:G transversions.
Gold nanoparticles (AuNPs)
AuNPs represent the most stable metal nanoparticles. Fascinating behaviours have been reported for individual particles, multiform assembles reported within materials science research. Multiple optical, electronic as well as magnetic properties (quantum size effect) make the nanoparticles unique They present an important application potential for catalysis and biology. Also, they have been considered as having a key role in nanotechnology development.
A number of studies has been dedicated to toxicity of AuNPs. The nanomaterial has been proven to be a proficient oxidative  and nitrozative ;  stress inductor. However, similar with other types of nanoscale materials, results on genotoxicity is still in its early age.
One interesting study reports the results of an extensive cytotoxic and genotoxic evaluation. Glycolipid-conjugated gold and silver nanoparticles were tested by the authors. The in vitro evaluation, performed on HepG2 cells, revealed the presence of DNA damages induced by both types of NPs when elevated concentrations were used. However, the study reported lower intensity of genotoxic effects for gold than for silver nanoparticles induced by comparable concentrations of materials .
The observations on the affinity between gold-nanoparticles and DNA structures has led to several ideas that intend to transform genotoxicity-inducing properties into useful biomedical applications. The utilized techniques included: cross-linking, non-cross-linking hybridization, array technologies (DNA chips), etc. The future achievements coming from this research have a high potential to allow a rapid DNA screening of DNA alterations connected with human pathology .
Silver nanoparticles (AgNPs)
Like gold nanoparticle, silver nanoparticles reveal important properties  that make them a good candidate for a wide range of applications, from medicine, material sciences to physics and chemistry . Within medical field Ag-NPs are known to have as antimicrobial effects  and are extensively used in treating all types of infections, including: wounds, burns and catheter induced pathology..
In vivo studies showed that exposure to silver nanoparticles could result in inflammation, oxidative stress, myocardial infarction and thrombosis. The in vivo toxicity of silver nitrate has already been demonstrated both on human dermal fibroblasts  and on aquatic species . They form tissue deposits resulting in metal poisoning and eventually cell death..
However, it is only recently that the mechanisms underlying Ag NPs toxicity started to reveal themselves. The upregulation of oxidative stress response genes (superoxide dismutase 2, glutathione reductase 1 etc) in mouse brain following Ag-np exposure has been reported by some studies.. One recent paper focused on heavy metal toxicity reported metallothioneins upregulation associated with silver mediated toxicity . Metallothioneins(MT) are known to be key biomarkers in toxicity induced by metal particles. They promote metal detoxification and oppose to free radical attacks. 
Reports on Ag-NPs toxicity have identified the mitochondria  to be the main target of silver nanoparticles, as also certified by transmission electron microscopic (TEM) analysis. Two distinct pathways have been incriminated for AgNPs-induced cell damage. First, the similarity between the small and narrow size of AgNPs and that of proteins promotes strong interactions with proteins causing changes in structure and loss of function. The second potentialy toxic pathway is activated by the silver ions from the surface of the AgNPs. Imballance of calcium homeostasis also plays a major role in Ag-NPs effects. High rate of calcium influx and efflux in mitochondria can generate distruction of mitochondrial membrane, which is a consequence of cytoskeletal injury .It all results in increased ROS generation as well as inhibition of ATP synthesis. Reduced ATP content of the cells has also been demonstrated using fibroblast (IMR-90) and human glioblastoma cells (U251), along with elevated ROS generation level. The two alterations were dose-dependent, and so was the DNA induced damage, measured using single cell gel electrophoresis (SCGE) and cytokinesis blocked micronucleus assays (CBMN). . Administration of Ag-NPs also activated the production of micronuclei (MN) [36.], a well-known indicator of chromosome damage. Furthermore, Ca2+ overload in mitochondria could activate cytochrome C, endonuclease G and other apoptogenic factors release to the cytosol and could initiate apoptosis . However, since it was observed that the elevation in Ca2+ ions concentratin is specific for the first 48 hours after exposure, it is possible for the later stages of incubation period to be characterized by delayed induction of apoptosis. . The evidences drove to the idea of similitude between NPs-induces DNA damange pathways and carcinogenesis mechanisms activated by irradiation.
The proposed mechanism of Ag-np toxicity based on the experimental data obtained in the present study. AshaRani et al. BMC Cell Biology 2009 10:65 doi:10.1186/1471-2121-10-65.
Quartz and mineral dust particles
Although less abundant literature has been focused on quarts genotoxic effects than other types of nanoparticles, similar mechanisms have been incriminated.
Quartz is manufactured of the most common form of silica: silica dioxide (SiO2) . Present in high quantities in most forms of rocks, sands, and soils, it can exist in both amorphous (glass) and crystalline (quartz) forms. Under significant inflammation condition in rats, quartz has been reported to induce gene mutations in hypoxanthine-guanine phosphoribosyltransferase (HPRT) in alveolar epithelial cells. Differences in effects have been reported for quartz particles. While they were unable to cause increased HPRT mutations in rat lung epithelial cells in vitro, lavage cells from quartz-exposed rats clearly demonstrated such alterations. .
Metal oxide particles
Among all types of nanoparticles, titan oxide (TiO2) particles have been extensively produced for several decades. The first TiO2 particles, with dimensions over 100 nm, were considered as being poorly soluble and have therefore been thought as biologically inert in both humans and animals. The material has been used in pigment, sunscreens, and cosmetic creams fabrication .
However, latest report suggested that nano-sized TiO2 are able to activate inflammatory pathways in airways of rats and mice, induce fibrosis or tumor genesis in rat lungs, and can cause DNA damage in human lymphoblastoid cells, Chinese hamster ovary (CHO) cells and/or Syrian hamster embryo fibroblasts .Some report suggested that increased ROS production to be one very important mechanism induced by TiO2. A significant post-exposure decrease in the level of glutathione was found in rat lung alveolar macrophage. .
Even though various studies have suggested that the toxicity of TiO2 nanoparticles is higher than the larger, micron-size counterparts, the mechanisms underlying the genotoxicity of nano-sized TiO2 is still not completely elucidated. . TiO2 nanoparticles exposure of human bronchial epithelial cells has been demonstrated to induce increased levels of hydrogen peroxide (H2O2) and nitric oxide (NO) and to consequently generate oxidative DNA damage as well as micronuclei formation. . . In vivo studies, carried out on gpt transgenic mouse. revealed the superiority of TiO2 at nano-scale to elevate the mutant yield at specific loci, as compared to the genetically inert TiO2 at micro-scale. These results were in concordance with several other in vivo and in vitro reports that suggested that the diameter of inhaled or instilled particles constitutes an important factor to modulate the toxicity response .
Cobalt nanoparticles(CoNPs) and other nanoparticles
Either used as Co oxide, as a biopolymer or as an organometal compound, Co represents one of the most interesting chemical elements to be proposed for nanoscale biomedical applications. . Environmental studies have long proposed Co as the possible aetiological factor of the critical forms of lung disease within occupationally exposed workers. The same studies have also raised questions regarding long-term danger induced by exposure to some matrix-based compounds (matrix of Co(5-20%) and Ni (0-5%)) with tungsten carbide (80-95%) (WC) content.. De Boeck et al.  reported in vivo genotoxic effects after WC-Co particles exposure. Combined WC-Co mixture was reported to generate higher genotoxic effects than Co or WC alone.. Results are consistent with several other in vitro and in vivo studies on Co2+ genotoxicity, suggested to be the result of oxidative stress as well as inhibition of DNA repair mechanisms.  ,
Considering all evidences on Co toxicity, the possible cytotoxic and genotoxic effects of CoNPs represent a matter of concern..
Some authors have addressed the question of the possible genotoxicity of CoNP as compared to that of Co2+. By testing the effects of both types of materials on human fibroblasts at the equivalent volumetric dose, the study observed that NP induced increased DNA damage as compared to micron-sized particles and higher levels of aneuploidy and cytotoxicity. . Also, it has been proven, for both Co2+ and CoNPs that low concentrations do not induce toxic effects. By contrast, elevated concentrations activate unwanted mechanisms
However, in the lack of sufficient data CoNPs, genotoxicity mechanisms are thought to follow the same pathogenetic mechanisms as Co2+ . The genotoxic activity of Co is ROS mediated, as suggested by most studies, . Some authors have shown that the oxidative potential of Co2+ could be intercepted by means of chelator agents usage. They modulate the ability to produce ROS in H2O2-treated cells. Also, the addition of antioxidants in culture media diminished the free radical- induced apoptotic process.. The capacity of Co2+ to induce DNA damage could also be due to the impairment of the reparatory enzyme proteins in binding DNA.. It has been proven that the genotoxic effects of Co2 are very much influenced by the presence of Ser/Cys or Cys/Cys polymorphism of the repairatory gene hOGG1. Effects were significantly different when compared to controls (normal Ser/Ser genotype). ,
Besides ROS generation, several authors suggested that magnetic NP preferentially alter oxidative phosphorylation process after localizing at the mitochondrial level, .