Evaluation of polycyclic aromatic hydrocarbons in the activation of early growth response-1 and peroxisome proliferator activated receptors.
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.
Kim
Jeong-Ho
JH
Department of Pathobiology, University of Tennessee, Knoxville, Tennessee 37996, USA.
Yamaguchi
Kiyoshi
K
Lee
Seong-Ho
SH
Tithof
Patricia K
PK
Sayler
Gary S
GS
Yoon
Joo-Heon
JH
Baek
Seung Joon
SJ
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*
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