title: Persistent activation of DNA damage signaling in response to complex mixtures of PAHs in air particulate matter.
abstract: Complex mixtures of polycyclic aromatic hydrocarbons (PAHs) are present in air particulate matter (PM) and have been associated with many adverse human health effects including cancer and respiratory disease. However, due to their complexity, the risk of exposure to mixtures is difficult to estimate. In the present study the effects of binary mixtures of benzo[a]pyrene (BP) and dibenzo[a,l]pyrene (DBP) and complex mixtures of PAHs in urban air PM extracts on DNA damage signaling was investigated. Applying a statistical model to the data we observed a more than additive response for binary mixtures of BP and DBP on activation of DNA damage signaling. Persistent activation of checkpoint kinase 1 (Chk1) was observed at significantly lower BP equivalent concentrations in air PM extracts than BP alone. Activation of DNA damage signaling was also more persistent in air PM fractions containing PAHs with more than four aromatic rings suggesting larger PAHs contribute a greater risk to human health. Altogether our data suggests that human health risk assessment based on additivity such as toxicity equivalency factor scales may significantly underestimate the risk of exposure to complex mixtures of PAHs. The data confirms our previous findings with PAH-contaminated soil (Niziolek-Kierecka et al., 2012) and suggests a possible role for Chk1 Ser317 phosphorylation as a biological marker for future analyses of complex mixtures of PAHs.
authors.affiliation: Institute of Environmental Medicine, Karolinska Institutet, Box 210, SE-171 77 Stockholm, Sweden. Ian.Jarvis@ki.se
authors.forename: Ian W H
authors.initials: IW
authors.lastname: Jarvis
authors.forename: Christoffer
authors.initials: C
authors.lastname: Bergvall
authors.forename: Matteo
authors.initials: M
authors.lastname: Bottai
authors.forename: Roger
authors.initials: R
authors.lastname: Westerholm
authors.forename: Ulla
authors.initials: U
authors.lastname: Stenius
authors.forename: Kristian
authors.initials: K
authors.lastname: Dreij
mesh_terms: D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics / Q000378:metabolism; D001564:Benzo(a)pyrene / Q000633:toxicity*; D001580:Benzopyrenes / Q000633:toxicity*; D015153:Blotting, Western; D002470:Cell Survival / Q000187:drug effects; D000071877:Checkpoint Kinase 1; D020552:Comet Assay; D019363:Cytochrome P-450 CYP1A1 / Q000235:genetics / Q000378:metabolism; D065633:Cytochrome P-450 CYP1B1; D004249:DNA Damage; D056945:Hep G2 Cells; D006801:Humans; D016014:Linear Models; D008099:Liver / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D052638:Particulate Matter / Q000633:toxicity*; D011494:Protein Kinases / Q000378:metabolism*; D012313:RNA / Q000737:chemistry / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D014505:Urban Population
chemical_list: D001580:Benzopyrenes; D052638:Particulate Matter; D001564:Benzo(a)pyrene; D012313:RNA; D001189:Aryl Hydrocarbon Hydroxylases; C585496:CYP1B1 protein, human; D019363:Cytochrome P-450 CYP1A1; D065633:Cytochrome P-450 CYP1B1; D011494:Protein Kinases; C000605867:CHEK1 protein, human; D000071877:Checkpoint Kinase 1; C041517:dibenzo(a,l)pyrene