4,4′-Methylene Diphenyl Diisocyanate Exposure Downregulates Endogenous Hsa-miR-206-3p Through Induction of hsa_circ_0008726 in Macrophages

Details

• Personal Author:
  Hettick JM ; Law, Brandon F. ; Lin C
• 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 revealed that MDI exposure downregulates endogenous microRNA(miR)-206-3p, activating miR-206-3p-regulated signaling, including PPP3CA/calcineurin/NFAT signaling activation in MØs, to increase chemokine production and promote chemotaxis activities of immune cells. Competitive endogenous RNA (ceRNA) species including circular RNAs (circRNAs) and long non-coding RNAs (lncRNAs) have been shown to regulate the levels of endogenous miRs through miR responding elements (MRE) binding to endogenous miRs in different cell types. The circRNA species are highly stable, circular structure RNA species that play important roles in many different biological processes and their expression can be regulated via exposures to outside stimuli; however, whether MDI-exposure can influence the expression of endogenous circRNA species is unknown. Several endogenous circRNAs have been reported to regulate endogenous hsa-miR-206-3p levels through potential ceRNA mechanisms. We hypothesize that MDI-exposure induces endogenous circRNA(s) to regulate hsa-miR-206-3p in MØs. Methods: We determined the expression of candidate hsa-miR-206-3p binding cricRNAs including hsa_circ_0000199, hsa_circ_0001264, hsa_circ_0001982, hsa_circ_0004662, hsa_circ_0007428, hsa_circ_0008726, hsa_circ_0056618, hsa_circ_0057558, hsa_circ_0058141, and hsa_circ_0072088 from MDI-glutathione (GSH) conjugate-treated differentiated THP-1 macrophages using RT-qPCR. Results: In vitro MDI-GSH exposures result in the upregulation of endogenous hsa_circ_0008726 and its host gene transcript DNAJB6; whereas other circRNA(s) examined were neither detected nor changed in MDI-GSH exposed MØs. RNA-induced silencing complex-immunoprecipitation (RISC-IP) experiments indicated that hsa-miR-206-3p can bind to hsa_circ_0008726 in MØs. The expression of endogenous hsa-miR-206-3p was either up- or down-regulated by transfection of either hsa_circ_0008726 siRNAs or overexpression plasmids of hsa_circ_0008726 in MØs, respectively. Conclusions: These results suggest MDI-exposure may downregulate endogenous hsa-miR-206-3p through induction of hsa_circ_0008726/DNAJB6 thus contributing to the upregulation of hsa-miR-206-3p-mediated regulations in MØs. [Description provided by NIOSH]
• Subjects:
  Asthma, Occupational Blood Macrophages Occupational Health Safety Toxicology
• Keywords:
  4,4-Methylene Diphenyl Diisocyanate Molecular Signaling Occupational Asthma
• ISSN:
  1096-6080
• Document Type:
  Text
• Genre:
  Abstract or Summary
• 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
• Volume:
  198
• NIOSHTIC Number:
  nn:20069318
• Citation:
  Toxicologist 2024 Mar; 198(S1):139
• CAS Registry Number:
  Diphenylmethane diisocyanate (CAS RN 101-68-8)
• Federal Fiscal Year:
  2024
• NORA Priority Area:
  Manufacturing
• Peer Reviewed:
  False
• Source Full Name:
  The Toxicologist. Society of Toxicology 63rd Annual Meeting & ToxExpo, March 10-14, 2024, Salt Lake City, Utah
• Collection(s):
  National Institute for Occupational Safety and Health
• Main Document Checksum:
  urn:sha-512:16a5c812e7c580f152c572f8ace5b1becb96f1d34e79c25abceff8484bcc5de1a7117001c344a9b34f749c0dce1be650363a6f2788c1c975eefd76914c3a81e8
• Download URL:
  https://stacks.cdc.gov/view/cdc/207818/cdc_207818_DS1.pdf
• File Type:
  [PDF - 539.03 KB ]