Adverse Outcome Pathway Assessment of Organomodified Nanoclays Pulmonary Toxicity Using In Vitro High-Content Screening: Correlations with In Vivo Effect

Details

• Personal Author:
  Coyle J ; Derk R ; Dinu CZ ; Gupta R ; Jensen J ; Kornberg TG ; Rojanasakul LW ; Stueckle, Todd A. ; Wagner A
• Description:
  Nanoclay-enabled composite technology continues to expand based on incorporation of organomodified nanoclay (ONC), montmorillonite coated with different quaternary ammonium compounds, within polymer matrices. Given the forecasts for airborne occupational exposures to occur, little is known about pulmonary health risks along the ONC life cycle. Our recent in vivo exposure study indicated that both pre- and post-incinerated ONCs caused low grade, persistent inflammation with a pro-fibrotic signaling response at day 28 post-exposure, with unknown modes of action. This study hypothesized that both pre- and post-incinerated ONC exposure elicits differential modes of action on pulmonary cells compared to uncoated nanoclay, and that relevant human in vitro models correlate with in vivo effects. To assess ONC life cycle pulmonary toxicity, differentiated human monocytes (THP-1), small airway epithelial (SAEC), and primary lung fibroblasts (LF) were evaluated using multiplex fluorescent high content screening for dose-dependent (0-20 microg/cm2) pulmonary adverse outcome pathways (AOPs). Pre-incinerated uncoated nanoclay (UC) exposure resulted in mild THP-1 macrophage Cathespin B release, LDH release, and apoptosis while ONC (>/= 2 microg/cm2) caused a robust, dose-dependent necrosis, with little evidence for Caspase 1 activation. Incinerated nanoclays (>/= 2 microg/ cm2) elicited Caspase 1 and 3 activation. UC exposure to SAECs triggered mitochondrial depolarization while CC showed no effect. UC and CC exposure instigated increased LF proliferation, collagen I, pro-collagen III, and fibronectin production, which correlated to similar elevated ECM protein expression in day 28 nanoclay-exposed mouse lung tissue. Incinerated CC (I-CC; 20 microg/cm2) showed cytotoxicity to all cells while I-UC showed little effect on cellular AOPs. In summary, incineration status and presence of organic coating influences the potential mode of action of the pulmonary response. Specifically, the ONC coating protected against a silica-induced inflammatory response, but induced macrophage plasma and phagosome membrane damage, SAEC membrane damage, and robust stimulation of in vitro/in vivo LF reticular fiber and collagen production. [Description provided by NIOSH]
• Subjects:
  Aluminum Silicates Blood Cytotoxins Enzymes Fibrosis Immune System Laboratories Lung Macrophages Minerals Occupational Health Polymers Respiratory System Safety Toxicology

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• Keywords:
  Ammonium Compounds Cellular Effects Cellular Reactions Coatings Cytotoxic Effects Cytotoxicity Dose Response Enzyme Activity Exposure Assessment Fibroblasts Immune Reaction Incineration In Vitro Study In Vivo Study Laboratory Animals Laboratory Testing Lung Cells Lung Tissue Membrane Dysfunction Models Nanoclays Nanocomposites Nanotechnology Nanotoxicology Organic Compounds Pulmonary Effects Screening Methods Silicates Toxic Effects

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• ISSN:
  1096-6080
• Document Type:
  Text
• Genre:
  Abstract or Summary
• Place as Subject:
  OSHA Region 3 ; OSHA Region 6 ; Texas ; 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:
  162
• Issue:
  1
• NIOSHTIC Number:
  nn:20051250
• Citation:
  Toxicologist 2018 Mar; 162(1):411
• CAS Registry Number:
  Ammonium (CAS RN 14798-03-9)
• Federal Fiscal Year:
  2018
• NORA Priority Area:
  Manufacturing
• Peer Reviewed:
  False
• Source Full Name:
  The Toxicologist. Society of Toxicology 57th Annual Meeting and ToxExpo, March 11-15, 2018, San Antonio, Texas
• Collection(s):
  National Institute for Occupational Safety and Health
• Main Document Checksum:
  urn:sha-512:4f045ef23de0a4067c4892d9604b03f40dca76b98e56a02e99980c8990b4c6331bcd373c0690ee98ed0447bb36cf3ae462a271d5841602d1efdf66929d63ffd1
• Download URL:
  https://stacks.cdc.gov/view/cdc/211315/cdc_211315_DS1.pdf
• File Type:
  [PDF - 840.24 KB ]