An in vitro liver model - assessing oxidative stress and genotoxicity following exposure of hepatocytes to a panel of engineered nanomaterials

Particle and Fibre Toxicology, Jul 2012

Background Following exposure via inhalation, intratracheal instillation or ingestion some nanomaterials (NM) have been shown to translocate to the liver. Since oxidative stress has been implicated as a possible mechanism for NM toxicity this study aimed to investigate the effects of various materials (five titanium dioxide (TiO2), two zinc oxide (ZnO), two multi-walled carbon nanotubes (MWCNT) and one silver (Ag) NM) on oxidative responses of C3A cell line as a model for potential detrimental properties of nanomaterials on the liver. Results We noted a dose dependant decrease in the cellular glutathione content following exposure of the C3A cells to Ag, the ZnO and the MWCNTs. Intracellular ROS levels were also measured and shown to increase significantly following exposure of the C3A to the low toxicity NMs (MWCNT and TiO2). The antioxidant Trolox in part prevented the detrimental effect of NMs on cell viability, and decreased the NM induced IL8 production after exposure to all but the Ag particulate. Following 4 hr exposure of the C3A cells to sub-lethal levels of the NMs, the largest amount of DNA damage was induced by two of the TiO2 samples (7 nm and the positively charged 10 nm particles). Conclusions All ten NMs exhibited effects on the hepatocyte cell line that were at least in part ROS/oxidative stress mediated. These effects included mild genotoxicity and IL8 production for all NM except the Ag possibly due to its highly cytotoxic nature.

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An in vitro liver model - assessing oxidative stress and genotoxicity following exposure of hepatocytes to a panel of engineered nanomaterials

Particle and Fibre Toxicology An in vitro liver model - assessing oxidative stress and genotoxicity following exposure of hepatocytes to a panel of engineered nanomaterials Ali Kermanizadeh 0 Birgit K Gaiser 0 Gary R Hutchison 1 Vicki Stone 0 0 Heriot-Watt University, School of Life Sciences, Nanosafety Research Group , Edinburgh EH14 4AS , UK 1 Edinburgh Napier University, School of Life, Sport and Social Sciences , Sighthill Campus, Sighthill Court, Edinburgh EH11 4BN , UK Background: Following exposure via inhalation, intratracheal instillation or ingestion some nanomaterials (NM) have been shown to translocate to the liver. Since oxidative stress has been implicated as a possible mechanism for NM toxicity this study aimed to investigate the effects of various materials (five titanium dioxide (TiO2), two zinc oxide (ZnO), two multi-walled carbon nanotubes (MWCNT) and one silver (Ag) NM) on oxidative responses of C3A cell line as a model for potential detrimental properties of nanomaterials on the liver. Results: We noted a dose dependant decrease in the cellular glutathione content following exposure of the C3A cells to Ag, the ZnO and the MWCNTs. Intracellular ROS levels were also measured and shown to increase significantly following exposure of the C3A to the low toxicity NMs (MWCNT and TiO2). The antioxidant Trolox in part prevented the detrimental effect of NMs on cell viability, and decreased the NM induced IL8 production after exposure to all but the Ag particulate. Following 4 hr exposure of the C3A cells to sub-lethal levels of the NMs, the largest amount of DNA damage was induced by two of the TiO2 samples (7 nm and the positively charged 10 nm particles). Conclusions: All ten NMs exhibited effects on the hepatocyte cell line that were at least in part ROS/oxidative stress mediated. These effects included mild genotoxicity and IL8 production for all NM except the Ag possibly due to its highly cytotoxic nature. Liver; Nanomaterials; Oxidative stress; Antioxidant; Genotoxicity - Background As the field of nanotechnology develops, there are now over 1300 consumer products on the market with a claim to contain elements of nanotechnology [1]. The potential for public and occupational exposure is therefore likely to increase, and so there is an urgent necessity to consider the possibility of any detrimental health consequences with this increased exposure to nanomaterials. This is achieved in the form of a critical risk assessment conducted as part of a large consortium (FP7 project ENPRA Risk Assessment of Engineered Nanoparticle). The risk is assessed based upon the level of exposure to the manufactured NM, toxicity of the particle in question, route of exposure and the persistence in the organism of the particular material. Hence it is crucial to identify the hazards associated with NM exposure both in vitro and in vivo, consequently assembling a knowledge base of the human health effects associated with NM exposure [2]. Engineered nanomaterials are manufactured from a diverse group of substances each with an array of unique physicochemical characteristics, hence a varied range of materials need to be evaluated for a comprehensive toxicity profile allowing for a structure activity relationship to be generated. It is likely that NMs will differ in the levels of toxicity induced and the mechanism by which they exert these adverse effects. Therefore we investigated a panel of ten widely used nanomaterials (five different TiO2, two MWCNTs, two ZnO and one Ag). The lungs and the gastrointestinal tract are in constant contact with the external environment so it is not surprising to find these systems being primary exposure sites for NMs [3,4]. It is believed that NMs administered via the ingestion, inhalation or intravenous injection might eventually reach secondary tissues, one of which is the liver [5,6]. The liver is the metabolic centre of the body [6]. It has a crucial role in metabolic homeostasis, as it is responsible for the storage, synthesis, metabolism and redistribution of carbohydrates, fats and vitamins. It also produces large numbers of serum proteins and an array of enzymes and cytokines [7]. The liver receives and accumulates materials at much higher volumes compared to other organs and alongside the kidneys might be responsible for the clearance of NMs from the blood [6,8,9]. Previous studies have shown that the uptake and translocation of TiO2 NMs following intratracheal instillation has resulted in accumulation of nanomaterials within the liver [8-10]. There is an abundant body of evidence suggesting the involvement of oxidative stress in the pathogenesis of various disorders and diseases. Reactive oxygen species (ROS) and other free radicals are critical intermediates in the normal physiology and pathophysiology of the liver [5]. Oxygen species are important in the creation of oxidative stimuli required for normal physiologic homeostasis of hepatocytes, as well as playing (...truncated)


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Ali Kermanizadeh, Birgit K Gaiser, Gary R Hutchison, Vicki Stone. An in vitro liver model - assessing oxidative stress and genotoxicity following exposure of hepatocytes to a panel of engineered nanomaterials, Particle and Fibre Toxicology, 2012, pp. 28, 9, DOI: 10.1186/1743-8977-9-28