title: Nanomolar levels of PAHs in extracts from urban air induce MAPK signaling in HepG2 cells.
abstract: Polycyclic aromatic hydrocarbons (PAHs) are common environmental pollutants that occur naturally in complex mixtures. Many of the adverse health effects of PAHs including cancer are linked to the activation of intracellular stress response signaling. This study has investigated intracellular MAPK signaling in response to PAHs in extracts from urban air collected in Stockholm, Sweden and Limeira, Brazil, in comparison to BP in HepG2 cells. Nanomolar concentrations of PAHs in the extracts induced activation of MEK4 signaling with down-stream increased gene expression of several important stress response mediators. Involvement of the MEK4/JNK pathway was confirmed using siRNA and an inhibitor of JNK signaling resulting in significantly reduced MAPK signaling transactivated by the AP-1 transcription factors ATF2 and c-Jun. ATF2 was also identified as a sensitive stress responsive protein with activation observed at extract concentrations equivalent to 0.1 nM BP. We show that exposure to low levels of environmental PAH mixtures more strongly activates these signaling pathways compared to BP alone suggesting effects due to interactions. Taken together, this is the first study showing the involvement of MEK4/JNK/AP-1 pathway in regulating the intracellular stress response after exposure to nanomolar levels of PAHs in environmental mixtures.
authors.affiliation: Institute of Environmental Medicine, Karolinska Institutet, Box 210, SE-171 77 Stockholm, Sweden.
authors.forename: I W H
authors.initials: IW
authors.lastname: Jarvis
authors.affiliation: Department of Analytical Chemistry, Stockholm University, Svante Arrhenius väg 16, SE-106 91 Stockholm, Sweden.
authors.forename: C
authors.initials: C
authors.lastname: Bergvall
authors.affiliation: Faculty of Technology, State University of Campinas (UNICAMP), Limeira, São Paulo 13484-332, Brazil.
authors.forename: D A
authors.initials: DA
authors.lastname: Morales
authors.affiliation: Institute of Environmental, Chemical and Pharmaceutical Sciences, Federal University of São Paulo (UNIFESP), Diadema, São Paulo 09972-270, Brazil.
authors.forename: F
authors.initials: F
authors.lastname: Kummrow
authors.affiliation: Faculty of Technology, State University of Campinas (UNICAMP), Limeira, São Paulo 13484-332, Brazil.
authors.forename: G A
authors.initials: GA
authors.lastname: Umbuzeiro
authors.affiliation: Department of Analytical Chemistry, Stockholm University, Svante Arrhenius väg 16, SE-106 91 Stockholm, Sweden.
authors.forename: R
authors.initials: R
authors.lastname: Westerholm
authors.affiliation: Institute of Environmental Medicine, Karolinska Institutet, Box 210, SE-171 77 Stockholm, Sweden.
authors.forename: U
authors.initials: U
authors.lastname: Stenius
authors.affiliation: Institute of Environmental Medicine, Karolinska Institutet, Box 210, SE-171 77 Stockholm, Sweden. Electronic address: Kristian.Dreij@ki.se.
authors.forename: K
authors.initials: K
authors.lastname: Dreij
mesh_terms: D000388:Air / Q000032:analysis; D000393:Air Pollutants / Q000032:analysis / Q000633:toxicity*; D001564:Benzo(a)pyrene / Q000633:toxicity; D015153:Blotting, Western; D002460:Cell Line; D004785:Environmental Pollutants / Q000633:toxicity; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D007202:Indicators and Reagents; D048670:MAP Kinase Kinase 4 / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000502:physiology*; D011084:Polycyclic Aromatic Hydrocarbons / Q000032:analysis / Q000633:toxicity*; D034622:RNA Interference; D060888:Real-Time Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects*; D018808:Transcription Factor AP-1 / Q000187:drug effects / Q000235:genetics; D015533:Transcriptional Activation / Q000187:drug effects; D014504:Urban Health
chemical_list: D000393:Air Pollutants; D004785:Environmental Pollutants; D007202:Indicators and Reagents; D011084:Polycyclic Aromatic Hydrocarbons; D018808:Transcription Factor AP-1; D001564:Benzo(a)pyrene; D048049:Extracellular Signal-Regulated MAP Kinases; C102548:Mapk4 protein, rat; D020928:Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4
keywords: Air particulate matter; Benzo[a]pyrene; Complex mixtures; MAPK; PAHs