Connecting glutathione with immune responses to occupational methylene diphenyl diisocyanate exposure

Details

• Personal Author:
  Liu J ; Redlich CA ; Wisnewski AV
• Description:
  Methylene diphenyl diisocyanate (MDI) is among the leading chemical causes of occupational asthma world-wide, however, the mechanisms of disease pathogenesis remain unclear. This study tests the hypothesis that glutathione (GSH) reacts with MDI to form quasi-stable conjugates, capable of mediating the formation of MDI-conjugated "self" protein antigens, which may participate in pathogenic inflammatory responses. To test this hypothesis, an occupationally relevant dose of MDI (0.1%w/v) was reacted with varying concentrations of GSH (10µM-10mM), and the reaction products were characterized with regard to mass/structure, and ability to carbamoylate human albumin, a major carrier protein for MDI in vivo. LC-MS/MS analysis of GSH-MDI reaction products identified products possessing the exact mass of previously described S-linked bis(GSH)-MDI and its partial hydrolysis product, as well as novel cyclized GSH-MDI structures. Upon co-incubation of GSH-MDI reaction products with human albumin, MDI was rapidly transferred to specific lysines of albumin, and the protein's native conformation/charge was altered, based on electrophoretic mobility. Three types of modification were observed, intra-molecular MDI cross-linking, addition of partially hydrolyzed MDI, and addition of "MDI-GSH", where MDI's 2nd NCO had reacted with GSH's "N-terminus". Importantly, human albumin carbamoylated by GSH-MDI was specifically recognized by serum IgG from MDI exposed workers, with binding dependent upon the starting GSH concentration, pH, and NaCl levels. Together, the data define a non-enzymatic, thiol-mediated transcarbamoylating mechanism by which GSH may promote immune responses to MDI exposure, and identify specific factors that might further modulate this process. [Description provided by NIOSH]
• Subjects:
  Aerosols Albumins Animals Hypersensitivity Inhalation Exposure Laboratories Occupational Health Safety Solvents
• Keywords:
  Albumin Aliphatic Allergens Author Keywords: Hexamethylene Diisocyanate (HDI) Carbamoylation Exposure-levels Glutathione (GSH) In-vivo-studies In-vivo-study Inhalants Laboratory-animals Models Pathogenesis Serological-techniques Serology Vapor Vapors

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• ISSN:
  0009-2797
• Document Type:
  Text
• Funding:
  Grant ; Cooperative Agreement
• Genre:
  Journal Article
• Place as Subject:
  Connecticut ; OSHA Region 1
• CIO:
  National Institute for Occupational Safety and Health (NIOSH)
• Topic:
  Workplace Safety & Health
• Location:
  North America
• Pages in Document:
  38-45
• Volume:
  205
• Issue:
  1
• NIOSHTIC Number:
  nn:20043359
• Citation:
  Chem-Biol Interact 2013 Sep; 205(1):38-45
• Contact Point Address:
  Adam V. Wisnewski, Yale University School of Medicine, 300 Cedar Street, TAC-S4157, P.O. Box 208057, New Haven, CT 06520-8057
• Email:
  adam.wisnewski@yale.edu
• CAS Registry Number:
  Diphenylmethane diisocyanate (CAS RN 101-68-8) ; Glutathione (CAS RN 70-18-8)
• Federal Fiscal Year:
  2013
• NORA Priority Area:
  Construction
• Performing Organization:
  Yale University, New Haven, Connecticut
• Peer Reviewed:
  True
• Start Date:
  20130901
• Source Full Name:
  Chemico-Biological Interactions
• End Date:
  20160831
• Collection(s):
  National Institute for Occupational Safety and Health
• Main Document Checksum:
  urn:sha-512:3bed49f29810e388b2cde6329db3dc048bf9334a20f11caf20bb9a792f27cd335b0538ec6d5d0fac92c9d93e64c76b044524445a47ff95252c92d003650bd50d
• Download URL:
  https://stacks.cdc.gov/view/cdc/195277/cdc_195277_DS1.pdf
• File Type:
  [PDF - 977.16 KB ]