title: Low levels of the air pollutant 1-nitropyrene induce DNA damage, increased levels of reactive oxygen species and endoplasmic reticulum stress in human endothelial cells.
abstract: Both epidemiological and experimental studies suggest that exposure to high levels of air pollution is a risk factor associated with cardiovascular disease. Traffic emission is a major source of exposure to persistent air pollutants such as nitrated polycyclic aromatic hydrocarbons (nitro-PAHs). 1-Nitropyrene (1-NP), one of the most abundant nitro-PAHs in diesel exhausts, was selected as a model nitro-PAH for the present study. The aim of the study was to investigate the effects of 1-NP in human umbilical vein endothelial cells (HUVECs) and the metabolic pathways involved. The nitroreductase inhibitor dicoumarol and the coplanar aryl hydrocarbon receptor (AhR) ligand PCB 126 were used to modulate the metabolism of 1-NP. The results revealed that low levels (< or =10microM) of 1-NP induced DNA damage, increased levels of reactive oxygen species (ROS) and increased protein expression of the endoplasmic reticulum (ER) stress chaperone GRP78. A decrease in cell viability was only observed following exposure to a higher level of 1-NP (15microM). Inhibition of nitroreductive metabolism by dicoumarol attenuated the induction of DNA damage, intracellular ROS levels and GRP78 expression. This suggests that the effects of 1-NP on HUVEC were mediated by metabolites mainly formed at nitroreduction. Our findings suggest that the human blood vessel endothelium is a sensitive target tissue for the major nitro-PAH constituent in diesel exhaust.
authors.affiliation: Uppsala University, Department of Pharmaceutical Biosciences, BMC, Uppsala, Sweden. helen.andersson@farmbio.uu.se
authors.forename: Helén
authors.initials: H
authors.lastname: Andersson
authors.forename: Elena
authors.initials: E
authors.lastname: Piras
authors.forename: Jemal
authors.initials: J
authors.lastname: Demma
authors.forename: Björn
authors.initials: B
authors.lastname: Hellman
authors.forename: Eva
authors.initials: E
authors.lastname: Brittebo
mesh_terms: D000393:Air Pollutants / Q000633:toxicity*; D002470:Cell Survival / Q000187:drug effects; D004249:DNA Damage / Q000187:drug effects*; D001728:Dicumarol; D004305:Dose-Response Relationship, Drug; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000378:metabolism; D000091342:Endoplasmic Reticulum Chaperone BiP; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D006360:Heat-Shock Proteins / Q000235:genetics; D006801:Humans; D018832:Molecular Chaperones / Q000235:genetics; D011078:Polychlorinated Biphenyls; D011721:Pyrenes / Q000008:administration & dosage / Q000633:toxicity*; D017382:Reactive Oxygen Species / Q000378:metabolism*; D014471:Umbilical Veins / Q000187:drug effects / Q000378:metabolism; D001335:Vehicle Emissions / Q000633:toxicity
chemical_list: D000393:Air Pollutants; D000091342:Endoplasmic Reticulum Chaperone BiP; C000717247:HSPA5 protein, human; D006360:Heat-Shock Proteins; D018832:Molecular Chaperones; D011721:Pyrenes; D017382:Reactive Oxygen Species; D001335:Vehicle Emissions; D001728:Dicumarol; D011078:Polychlorinated Biphenyls; C032668:1-nitropyrene; C023035:3,4,5,3',4'-pentachlorobiphenyl