title: Activation of stress-related signalling pathway in human cells upon SiO2 nanoparticles exposure as an early indicator of cytotoxicity.
abstract: BACKGROUND
  Nanomaterials such as SiO2 nanoparticles (SiO2NP) are finding increasing applications in the biomedical and biotechnological fields such as disease diagnostics, imaging, drug delivery, food, cosmetics and biosensors development. Thus, a mechanistic and systematic evaluation of the potential biological and toxic effects of SiO2NP becomes crucial in order to assess their complete safe applicability limits.
  
  
  RESULTS
  In this study, human monocytic leukemia cell line THP-1 and human alveolar epithelial cell line A549 were exposed to a range of amorphous SiO2NP of various sizes and concentrations (0.01, 0.1 and 0.5 mg/ml). Key biological indicators of cellular functions including cell population density, cellular morphology, membrane permeability, lysosomal mass/pH and activation of transcription factor-2 (ATF-2) were evaluated utilizing quantitative high content screening (HCS) approach and biochemical techniques. Despite the use of extremely high nanoparticle concentrations, our findings showed a low degree of cytotoxicity within the panel of SiO2NP investigated. However, at these concentrations, we observed the onset of stress-related cellular response induced by SiO2NP. Interestingly, cells exposed to alumina-coated SiO2NP showed low level, and in some cases complete absence, of stress response and this was consistent up to the highest dose of 0.5 mg/ml.
  
  
  CONCLUSIONS
  The present study demonstrates and highlights the importance of subtle biological changes downstream of primary membrane and endocytosis-associated phenomena resulting from high dose SiO2NP exposure. Increased activation of transcription factors, such as ATF-2, was quantitatively assessed as a function of i) human cell line specific stress-response, ii) SiO2NP size and iii) concentration. Despite the low level of cytotoxicity detected for the amorphous SiO2NP investigated, these findings prompt an in-depth focus for future SiO2NP-cell/tissue investigations based on the combined analysis of more subtle signalling pathways associated with accumulation mechanisms, which is essential for establishing the bio-safety of existing and new nanomaterials.
authors.affiliation: Department of clinical medicine, Institute of Molecular Medicine, Trinity College Dublin, Dublin 8, Ireland. bashmohamed@gmail.com
authors.forename: Bashir Mustafa
authors.initials: BM
authors.lastname: Mohamed
authors.forename: Navin Kumar
authors.initials: NK
authors.lastname: Verma
authors.forename: Adriele
authors.initials: A
authors.lastname: Prina-Mello
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Williams
authors.forename: Anthony M
authors.initials: AM
authors.lastname: Davies
authors.forename: Gabor
authors.initials: G
authors.lastname: Bakos
authors.forename: Laragh
authors.initials: L
authors.lastname: Tormey
authors.forename: Connla
authors.initials: C
authors.lastname: Edwards
authors.forename: John
authors.initials: J
authors.lastname: Hanrahan
authors.forename: Anna
authors.initials: A
authors.lastname: Salvati
authors.forename: Iseult
authors.initials: I
authors.lastname: Lynch
authors.forename: Kenneth
authors.initials: K
authors.lastname: Dawson
authors.forename: Dermot
authors.initials: D
authors.lastname: Kelleher
authors.forename: Yuri
authors.initials: Y
authors.lastname: Volkov
mesh_terms: D051698:Activating Transcription Factor 2 / Q000378:metabolism; D000537:Aluminum Oxide / Q000009:adverse effects; D002460:Cell Line; D002463:Cell Membrane Permeability / Q000187:drug effects; D006801:Humans; D008247:Lysosomes / Q000187:drug effects; D053758:Nanoparticles / Q000009:adverse effects*; D015398:Signal Transduction / Q000187:drug effects*; D012822:Silicon Dioxide / Q000009:adverse effects*; D013312:Stress, Physiological
chemical_list: C497105:ATF2 protein, human; D051698:Activating Transcription Factor 2; D012822:Silicon Dioxide; D000537:Aluminum Oxide