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ToxSci Advance Access published online on February 16, 2005
Toxicological Sciences, doi:10.1093/toxsci/kfi118
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Toxicological Sciences © The Author [2005]. Published by Oxford University Press [on behalf of the Society of Toxicology]. All rights reserved. For Permissions, please email: journals.permissions@oupjournals.org
Received December 6, 2005
Accepted February 9, 2005

Environmental Toxicology

Evaluation of polycyclic aromatic hydrocarbons in the activation of early growth response-1 and peroxisome proliferator activated receptors

Jeong-Ho Kim 1, Kiyoshi Yamaguchi 1, Seong-Ho Lee 1, Patricia K. Tithof 1, Gary S. Sayler 2, Joo-Heon Yoon 3, and Seung Joon Baek 1*

1 Department of Pathobiology, University of Tennessee, Knoxville, TN 37996
2 Department of Microbiology, University of Tennessee, Knoxville, TN 37996
3 Department of Otorhinolaryngology, Yonsei University College of Medicine, Seoul, South Korea

* To whom correspondence should be addressed.
Seung Joon Baek, E-mail: sbaek2{at}utk.edu


  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{delta}. 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-3{beta} (GSK-3{beta}), was downregulated and EGR-1 was up-regulated in the mouse samples of Chattanooga Creek. In addition, select PAHs repressed GSK-3{beta} and induced CYP4A in FaO rat hepatoma cells. In conclusion, PAHs activate PPAR{alpha} and PPAR{beta}/{delta}, and upregulate EGR-1 expression in vitro as well as in vivo. These data may provide a diversity of PAH activity in several biological pathways.

Keywords: PAHs; PPAR{alpha}; PPAR{delta}; EGR-1; GSK-3{beta}.
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