4,4′-Methylene Diphenyl Diisocyanate-Glutathione Conjugate Exposure Downregulates Endogenous Hsa-miR-381-3p Through Induction of Circular RNA hsa_circ_0099188 in Macrophages

Details

• Personal Author:
  Lin, C. ; Law, Brandon F. ; Hettick, Justin M.
• Description:
  Background and Purpose: Exposure to 4,4'-methylene diphenyl diisocyanate (MDI), the most widely used monomeric diisocyanate, in the occupational setting may lead to the development of occupational asthma (OA). Currently, the underlying molecular mechanism(s) by which MDI induces OA have yet to be elucidated. Alveolar macrophage (MØ) dysfunction plays an important role in asthma pathogenesis. Previously, our laboratory showed that MDI exposure downregulates endogenous microRNA(miR)-206-3p/-381-3p, activating miR-206-3p/-381-3p-regulated signaling, including PPP3CA/calcineurin/NFAT and KLF4 signaling activation in MØs, to increase chemokine production and promote chemotaxis activities of immune cells. Our previous report showed that MDI exposure in the form of MDI-glutathione (GSH) conjugate may influence the expression of endogenous circular RNA (circRNA) hsa_circ_0008726 to modulate endogenous hsa-miR-206-3p and hsa-miR-206-3p-mediated downstream regulatory pathways; however, the MDI-mediated circRNA response(s) that target endogenous hsa-miR-381-3p and hsa-miR-381-3p-mediated downstream regulatory pathways is currently unknown. Several endogenous circRNAs have been reported to regulate endogenous hsa-miR-381-3p levels through potential competitive endogenous RNA (ceRNA) mechanisms. We hypothesize that MDI-GSH conjugate exposure induces endogenous circRNA(s) to regulate hsa-miR-381-3p in MØs. Methods: We determined the expression of candidate hsa-miR-381-3p binding circRNAs including hsa_circ_0021593, hsa_circ_0084003, and hsa_circ_0099188 from MDI-GSH conjugate-treated differentiated THP-1 macrophages using RT-qPCR. Results: In vitro MDI-GSH conjugate exposures result in the upregulation of endogenous hsa_circ_0099188 and its host gene transcript thyrotropin releasing hormone degrading enzyme (TRHDE); whereas other circRNA(s) examined were neither detected nor changed in MDI-GSH conjugate exposed MØs. RNA-induced silencing complex-immunoprecipitation (RISC-IP) experiments indicated that hsa-miR-381-3p binds to hsa_circ_0099188 in MØs. The expression of endogenous hsa-miR-381-3p was either up- or down-regulated by transfection of either hsa_circ_0099188 siRNAs or hsa_circ_0099188 overexpression plasmid in MØs, respectively. Conclusions: These results suggest MDI exposure may downregulate endogenous hsa-miR-381-3p through induction of hsa_circ_0099188/TRHDE thus contributing to the upregulation of hsa-miR-381-3p-mediated regulations in MØs. Description provided by NIOSH
• Subjects:
  • Asthma, Occupational
  • Macrophages
  • Occupational Health
  • Safety
• Keywords:
  • 4,4-Methylene diphenyl diisocyanate; Occupational asthma; Macrophages; Molecular signaling; Toxicology
• Source:
  Toxicologist 2025 Mar; 204(S1):470
• ISSN:
  1096-6080
• Document Type:
  Text
• Genre:
  Abstract or Summary
• Place as Subject:
  Philadelphia Region OSHA ; 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:
  2 pdf pages
• Volume:
  204
• NIOSHTIC Number:
  nn:20071586
• CAS Registry Number:
  • Diphenylmethane diisocyanate (CAS RN 101-68-8)
• Federal Fiscal Year:
  2025
• NORA Priority Area:
  Manufacturing
• Peer Reviewed:
  False
• Download URL:
  https://stacks.cdc.gov/view/cdc/259361/cdc_259361_DS1.pdf
• File Type:
  [PDF - 279.65 KB]
• Collection(s):
  National Institute for Occupational Safety and Health
• Main Document Checksum:
  urn:sha-512:8531f60a6e363a50192f0173bad330349ff4a147a4ac2a10d2ff7ddfc2137edb496b4df2a6842a274aaff4b412192b5d5002cd9030bdb3fa93d31d088b08ad82