Translational Pathology: Relevance of Toxicologic Pathology to Human Health

Details

• Corporate Authors:
  Society of Toxicologic Pathology to Human Health
• Description:
  Introduction: Flavorings-related lung disease is associated with inhaling vapors of diacetyl (2,3-butanedione), an a-dicarbonyl flavoring which reacts with proteins. Cells process misfolded proteins by ubiquitination and proteosomal degradation. However, ubiquitination at lysine 63 (K63-ubiquitination) can activate signaling cascades instead of degrading proteins. We examined the hypothesis that diacetyl inhalation increases total ubiquitin and K63-ubiquitin aggregates in airway epithelium. We also examined the modifying effect of dicarbonyl/L-xylulose reductase (DCXR), which metabolizes diacetyl. Experimental design: Wildtype and DCXR knockout mice inhaled target concentrations of 0, 100, 200, or 300 ppm diacetyl for 6 hours. Methods: At 1 day post-exposure, we counted airway epithelial cells with aggregated immunoreactive total ubiquitin or K63-ubiquitin. In a follow-up experiment, olfactory bulb (OB) Tnfa and olfactory marker protein (Omp) mRNA and lung Tnfa and Scgb1a1 mRNA were measured 1 day after inhaling 200 ppm diacetyl. Results: In terminal bronchioles, cells with aggregated K63-linked ubiquitin increased in wildtype and knockout mice inhaling 200 ppm. In larger bronchioles, all tested diacetyl concentrations increased cells with aggregated total ubiquitin and K63-ubiquitin irrespective of genotype. At 200 ppm, diacetyl increased Tnfa in OB of wildtype mice and this was enhanced in knockout mice. Irrespective of genotype, Omp decreased in OB, suggesting olfactory neuron loss. In knockout but not wildtype mice, 200 ppm decreased lung Scgb1a1, suggesting club cell loss. Conclusion: Aggregated ubiquitin and K63-ubiquitin suggest biological responses to protein damage. DCXR may modify diacetyl toxicity. Impact: K63-ubiquitination in airway epithelium may be a mechanistically-based biomarker of protein damage in airway epithelium. [Description provided by NIOSH]
• Subjects:
  Biomarkers Environmental Monitoring Food Additives Genetics Hazardous Substances Laboratories Lung Lung Diseases Nervous System Occupational Health Respiratory System Respiratory Tract Diseases Safety Solvents

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• Keywords:
  Respiratory-system-disorders; Pulmonary-system-disorders; Lung-disorders; Lung-function; Lung-irritants; Food-additives; Carbonyls; Vapors; Proteins; Cellular-function; Inhalation-studies; Lung-cells; Laboratory-animals; Laboratory-testing; Exposure-assessment; Exposure-levels; Recombinant-DNA; Genes; Olfactory-disorders; Toxic-effects; Biomarkers; Neurotoxicity; Airway-resistance
• Publisher:
  Society of Toxicologic Pathology
• Document Type:
  Text
• Genre:
  Proceedings
• Place as Subject:
  OSHA Region 3 ; West Virginia
• CIO:
  National Institute for Occupational Safety and Health (NIOSH)
• Division:
  HELD - Health Effects Laboratory Division
• Topic:
  Workplace Safety & Health
• Location:
  North America
• Pages in Document:
  52 pdf pages
• NIOSHTIC Number:
  nn:20045694
• Citation:
  Society of Toxicologic Pathology 33rd Annual Symposium, June 22-26, 2014, Washington, DC. Reston, VA: Society of Toxicologic Pathology, 2014 Jun; :23
• CAS Registry Number:
  Butanedione (CAS RN 431-03-8)
• Federal Fiscal Year:
  2014
• NORA Priority Area:
  Manufacturing
• Peer Reviewed:
  False
• Source Full Name:
  Society of Toxicologic Pathology 33rd Annual Symposium, June 22-26, 2014, Washington, DC
• Collection(s):
  National Institute for Occupational Safety and Health
• Main Document Checksum:
  urn:sha-512:175371d3c3d760ed0c3a89a83689cb76a1369c175cb1372072a1516d3465ac02f78a84862cae25002662c738a9eb9d30a8791fdbd5fad3529ddeacd045715f40
• Download URL:
  https://stacks.cdc.gov/view/cdc/231525/cdc_231525_DS1.pdf
• File Type:
  [PDF - 5.94 MB ]