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Early Mechanistic Events Induced by Low Molecular Weight Polycyclic Aromatic Hydrocarbons in Mouse Lung Epithelial Cells: A Role for Eicosanoid Signaling.


ABSTRACT: Low molecular weight polycyclic aromatic hydrocarbons (LMW PAHs; < 206.3 g/mol) are under regulated environmental contaminants (eg, secondhand smoke) that lead to gap junction dysregulation, p38 MAPK activation, and increased mRNA production of inflammatory mediators, such as cytokines and cyclooxygenase (COX2), in lung epithelial cells. However, the early mechanisms involving lipid signaling through the arachidonic acid pathway and subsequent eicosanoid production leading to these downstream events are not known. Common human exposures are to mixtures of LMW PAHs, thus C10 cells (a mouse lung epithelial cell line) were exposed to a representative binary PAH mixture, 1-methylanthracene (1-MeA) and fluoranthene (Flthn), for 30 min-24 h with and without p38 and cytosolic phospholipase A2 (cPLA2) inhibitors. Cytosolic phospholipase A2 inhibition reversed PAH-induced phospho-p38 MAPK activation and gap junction dysregulation at 30 min. A significant biphasic increase in cPLA2 protein was observed at 30 min, 2, and 4 h, as well as COX2 protein at 2 and 8 h. Untargeted metabolomics demonstrated a similar trend with significantly changing metabolites at 30 min and 4 h of exposure relative to 1 h; a "cPLA2-like" subset of metabolites within the biphasic response were predominately phospholipids. Targeted metabolomics showed several eicosanoids (eg, prostaglandin D2 (PGD2), PGE2α) were significantly increased at 4, 8, and 12 h following exposure to the binary PAH mixture and this effect was p38-dependent. Finally, PAH metabolism was not observed until after 8 h. These results indicate an early lipid signaling mechanism of LMW PAH toxicity in lung epithelial cells due to parent PAH compounds.

SUBMITTER: Siegrist KJ 

PROVIDER: S-EPMC6484882 | biostudies-literature | 2019 May

REPOSITORIES: biostudies-literature

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Early Mechanistic Events Induced by Low Molecular Weight Polycyclic Aromatic Hydrocarbons in Mouse Lung Epithelial Cells: A Role for Eicosanoid Signaling.

Siegrist Katelyn J KJ   Romo DeeDee D   Upham Brad L BL   Armstrong Michael M   Quinn Kevin K   Vanderlinden Lauren L   Osgood Ross S RS   Velmurugan Kalpana K   Elie Marc M   Manke Jonathan J   Reinhold Dominik D   Reisdorph Nichole N   Saba Laura L   Bauer Alison K AK  

Toxicological sciences : an official journal of the Society of Toxicology 20190501 1


Low molecular weight polycyclic aromatic hydrocarbons (LMW PAHs; < 206.3 g/mol) are under regulated environmental contaminants (eg, secondhand smoke) that lead to gap junction dysregulation, p38 MAPK activation, and increased mRNA production of inflammatory mediators, such as cytokines and cyclooxygenase (COX2), in lung epithelial cells. However, the early mechanisms involving lipid signaling through the arachidonic acid pathway and subsequent eicosanoid production leading to these downstream ev  ...[more]

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