Secondhand Smoke-Prevalent Polycyclic Aromatic Hydrocarbon Binary Mixture-Induced Specific Mitogenic and Pro-inflammatory Cell Signaling Events in Lung Epithelial Cells.
Low molecular weight polycyclic aromatic hydrocarbons (LMW PAHs; < 206.3 g/mol) are prevalent and ubiquitous environmental contaminants, presenting a human health concern, and have not been as thoroughly studied as the high MW PAHs. LMW PAHs exert their pulmonary effects, in part, through P38-dependent and -independent mechanisms involving cell-cell communication and the production of pro-inflammatory mediators known to contribute to lung disease. Specifically, we determined the effects of two representative LMW PAHs, 1-methylanthracene (1-MeA) and fluoranthene (Flthn), individually and as a binary PAH mixture on the dysregulation of gap junctional intercellular communication (GJIC) and connexin 43 (Cx43), activation of mitogen activated protein kinases (MAPK), and induction of inflammatory mediators in a mouse non-tumorigenic alveolar type II cell line (C10). Both 1-MeA, Flthn, and the binary PAH mixture of 1-MeA and Flthn dysregulated GJIC in a dose and time-dependent manner, reduced Cx43 protein, and activated the following MAPKs: P38, ERK1/2, and JNK. Inhibition of P38 MAPK prevented PAH-induced dysregulation of GJIC, whereas inhibiting ERK and JNK did not prevent these PAHs from dysregulating GJIC indicating a P38-dependent mechanism. A toxicogenomic approach revealed significant P38-dependent and -independent pathways involved in inflammation, steroid synthesis, metabolism, and oxidative responses. Genes in these pathways were significantly altered by the binary PAH mixture when compared with 1-MeA and Flthn alone suggesting interactive effects. Exposure to the binary PAH mixture induced the production and release of cytokines and metalloproteinases from the C10 cells. Our findings with a binary mixture of PAHs suggest that combinations of LMW PAHs may elicit synergistic or additive inflammatory responses which warrant further investigation and confirmation.
Department of Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA.
Ross S
RS
Osgood
Department of Pediatrics and Human Development, Michigan State University, East Lansing, Michigan, USA.
Brad L
BL
Upham
Biostatistics & Computational Biology Branch, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina, USA.
Pierre R
PR
Bushel
Department of Environmental and Occupational Health, University of Colorado Anschutz Medical Center, Aurora, Colorado, USA.
Kalpana
K
Velmurugan
Department of Environmental and Occupational Health, University of Colorado Anschutz Medical Center, Aurora, Colorado, USA.
Ka-Na
KN
Xiong
Department of Environmental and Occupational Health, University of Colorado Anschutz Medical Center, Aurora, Colorado, USA.
Alison K
AK
Bauer
D000818:Animals; D002450:Cell Communication / Q000187:drug effects; D002460:Cell Line; D018031:Connexin 43 / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism; D017629:Gap Junctions / Q000187:drug effects; D007249:Inflammation / Q000378:metabolism*; D008168:Lung / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D008934:Mitogens / Q000378:metabolism*; D011084:Polycyclic Aromatic Hydrocarbons / Q000633:toxicity*; D015398:Signal Transduction / Q000187:drug effects*; D014028:Tobacco Smoke Pollution; D059467:Transcriptome
D018031:Connexin 43; C500216:GJA1 protein, human; D008934:Mitogens; D011084:Polycyclic Aromatic Hydrocarbons; D014028:Tobacco Smoke Pollution; D020928:Mitogen-Activated Protein Kinases
P38 MAP kinase; gap junctional intercellular communication; lung alveolar type II cells; polycyclic aromatic hydrocarbons; toxicogenomic