title: Evaluation of polycyclic aromatic hydrocarbons in the activation of early growth response-1 and peroxisome proliferator activated receptors.
abstract: Polycyclic aromatic hydrocarbons (PAHs) are ubiquitous environmental and food contaminants with known or suspected carcinogenic properties. In this study, we have evaluated whether PAHs activate the early growth response (EGR-1) gene and bind to peroxisome proliferator-activated receptor alpha (PPAR alpha) and delta (PPAR beta/delta) in cell culture systems. Luciferase reporter systems were employed and several PAHs were evaluated for their ability to activate EGR-1 and PPARs. Some PAHs enhanced EGR-1 expression and activated PPAR alpha and PPAR beta. Among them, benz(a)anthracene was found to act as a relatively potent activator of PPAR alpha and PPAR beta/delta, and to significantly enhance EGR-1 transcription. These in vitro assays were confirmed by Western blot analysis, using cell lysates of tissue samples from mouse trapped at a highly contaminated Superfund site in the Chattanooga Creek floodplain in Chattanooga, Tennessee. We have found that a PPAR target gene, glycogen synthase kinase-3beta (GSK-3beta), was down-regulated and EGR-1 was up-regulated in the mouse samples of Chattanooga Creek. In addition, select PAHs repressed GSK-3beta and induced CYP4A in FaO rat hepatoma cells. In conclusion, PAHs activate PPAR alpha and PPAR beta/delta, and up-regulate EGR-1 expression in vitro as well as in vivo. These data may provide a diversity of PAH activity in several biological pathways.
authors.affiliation: Department of Pathobiology, University of Tennessee, Knoxville, Tennessee 37996, USA.
authors.forename: Jeong-Ho
authors.initials: JH
authors.lastname: Kim
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Yamaguchi
authors.forename: Seong-Ho
authors.initials: SH
authors.lastname: Lee
authors.forename: Patricia K
authors.initials: PK
authors.lastname: Tithof
authors.forename: Gary S
authors.initials: GS
authors.lastname: Sayler
authors.forename: Joo-Heon
authors.initials: JH
authors.lastname: Yoon
authors.forename: Seung Joon
authors.initials: SJ
authors.lastname: Baek
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D051766:Early Growth Response Protein 1; D004785:Environmental Pollutants / Q000633:toxicity*; D015870:Gene Expression / Q000187:drug effects*; D017930:Genes, Reporter / Q000235:genetics; D006801:Humans; D017874:Immediate-Early Proteins / Q000235:genetics / Q000378:metabolism*; D008156:Luciferases / Q000235:genetics; D051379:Mice; D047492:Peroxisome Proliferator-Activated Receptors / Q000378:metabolism*; D011084:Polycyclic Aromatic Hydrocarbons / Q000633:toxicity*; D051381:Rats; D013329:Structure-Activity Relationship; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*
chemical_list: D004268:DNA-Binding Proteins; C497325:EGR1 protein, human; D051766:Early Growth Response Protein 1; D004785:Environmental Pollutants; D017874:Immediate-Early Proteins; D047492:Peroxisome Proliferator-Activated Receptors; D011084:Polycyclic Aromatic Hydrocarbons; D014157:Transcription Factors; D008156:Luciferases