Nano-ferric oxide induced neoplastic-like transformation in a human primary cell model: iron homeostasis disruption

Details

• Personal Author:
  Davidson DC ; Demokritou P ; Derk R ; Kornberg T ; Schwegler-Berry D ; Stueckle, Todd A. ; Wang L
• Description:
  As incorporation of engineered nanomaterials (ENMs) into new technologies rise, the potential for long-term, low dose inhalation exposures is expected with largely unknown adverse outcomes to human health. Past ENM toxicity assessment has focused on acute and relatively short term sub-chronic exposures associated with inflammation and fibrosis, with relatively little attention paid to ENM-associated tumorigenesis. The current study evaluated the use of a human primary small airway epithelial cell (pSAEC) model to serve as a Tier I neoplastic transformation screening model for proposed ENM tiered risk assessment. Low passage pSAECs were continuously exposed in vitro to 0.6 ug/cm2 of nano-sized cerium oxide (CeO2) or ferric oxide (Fe2O3) for 6 and 10 weeks. Multiwalled carbon nanotube (MWCNT Mitsui 7; 0.06 ug/cm2), with known transformation and lung cancer promotion potential, served as a positive control while saline or dispersant exposed cells served as passage controls. At each time point, exposed cells were evaluated for several cancer hallmarks to evaluate neoplastic transformation potential. At 10 weeks, Fe2O3-exposed cells displayed significant enhanced proliferation, invasion, soft agar colony formation and colony forming unit ability suggesting a neoplastic-like transformation. MWCNT-exposed cells exhibited increased colony formation ability while nCeO2 was negative in all assays except proliferation. Next, Fe2O3 and MWCNT soft agar colonies were isolated and placed in culture to evaluate persistence and longevity of the transformed phenotype. All isolated clones, along with the 10 week Fe2O3-exposed cells, maintained their transformed phenotypes, even after repeated (12-30) passages and freezing. Further studies using fluorescent imaging and protein expression analysis suggested that potential disruption to iron homeostasis gave rise to increased intracellular iron and increased ROS production which is well-known to cause oxidative damage and promote cell transformation. Sub-chronic in vitro exposures with cancer hallmark screening using human primary cell models holds promise as a Tier I screening model for ENM-associated tumorigenesis. [Description provided by NIOSH]
• Subjects:
  Carcinogens Cells, Cultured Environmental Exposure Fibrosis Immune System Lung Occupational Health Respiratory System Safety Toxicology
• Keywords:
  Cell Cultures Cell Culture Techniques Cerium Compounds Cerium Oxides Dose Response Exposure Assessment Exposure Levels Humans Immune Reaction Inhalation Iron Compounds Iron Oxides Lung Cells Models Nanotechnology Neoplastic Agents Risk Assessment Tumorigenesis

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• ISSN:
  1096-6080
• Document Type:
  Text
• Genre:
  Abstract or Summary
• Place as Subject:
  Louisiana ; Massachusetts ; OSHA Region 1 ; OSHA Region 3 ; OSHA Region 6 ; West Virginia
• CIO:
  National Institute for Occupational Safety and Health (NIOSH)
• Division:
  HELD - Health Effects Laboratory Division
• Topic:
  Workplace Safety & Health
• Location:
  North America
• Volume:
  150
• Issue:
  1
• NIOSHTIC Number:
  nn:20047714
• Citation:
  Toxicologist 2016 Mar; 150(1):419
• CAS Registry Number:
  Ceria (CAS RN 1306-38-3) ; Ferrous oxide (CAS RN 1345-25-1) ; Iron (CAS RN 7439-89-6)
• Federal Fiscal Year:
  2016
• NORA Priority Area:
  Manufacturing
• Peer Reviewed:
  False
• Source Full Name:
  The Toxicologist. Society of Toxicology 55th Annual Meeting and ToxExpo, March 13-17, 2016, New Orleans, Louisiana
• Collection(s):
  National Institute for Occupational Safety and Health
• Main Document Checksum:
  urn:sha-512:98cdf891ce0b6e4eb44bf52cee5bf52f070ef64dd33901f69574e44e8db81b4cf995450926c41c9c8941d301a406e448ffcd1ace4754894e4b907f0acead5248
• Download URL:
  https://stacks.cdc.gov/view/cdc/202713/cdc_202713_DS1.pdf
• File Type:
  [PDF - 442.00 KB ]