ToxSci Advance Access published online on October 22, 2009
Toxicological Sciences, doi:10.1093/toxsci/kfp251
Published by Oxford University Press 2009.
Characterization of Peroxisome Proliferator-Activated Receptor 
(PPAR) – Independent Effects of PPAR Activators in the Rodent Liver: Di-(2-ethylhexyl) phthalate Also Activates the Constitutive Activated Receptor
1 NHEERL Toxicogenomics Core, US EPA, Research Triangle Park, NC 27711 2 Department of Pharmacology, Toxicology, and Therapeutics, University of Kansas Medical Center, 3901 Rainbow Blvd, Kansas City, Kansas 66160 3 Toxicology Assessment Division, US-EPA, Research Triangle Park, NC 27711 4 Integrated Systems Toxicology Division, US-EPA, Research Triangle Park, NC 27711
5 Corresponding author: Chris Corton, Integrated Systems Toxicology Division, National Health and Environmental Effects Research Lab, US Environmental Protection Agency, 109 T.W. Alexander Dr., MD-B143-06, Research Triangle Park, NC 27711, corton.chris{at}epa.gov, 919-541-0092 (office), 919-541-0694 (fax), 919-801-0887 (cell)
Email addresses of authors: Hongzu Ren: ren.hongzu{at}epa.gov, Lauren Aleksunes: aleksunes{at}eohsi.rutgers.edu, Carmen Wood: wood.carmen{at}epa.gov, Beena Vallanat: vallanat.beena{at}epa.gov, Michael George: george.michael{at}epa.gov, Curtis Klaassen: CKLAASSE{at}kumc.edu, J. Christopher Corton: corton.chris{at}epa.gov
Received September 11, 2009; revision received October 8, 2009; accepted October 9, 2009
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Abstract |
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Peroxisome proliferator chemicals (PPC) are thought to mediate their effects in rodents on hepatocyte growth and liver cancer through the nuclear receptor peroxisome proliferator-activated receptor alpha (PPAR
). Recent studies indicate that the plasticizer di-2-ethylhexyl phthalate (DEHP) increased the incidence of liver tumors in PPAR-null mice. We hypothesized that some PPC, including DEHP, induce transcriptional changes independent of PPAR but dependent on other nuclear receptors, including the constitutive activated receptor (CAR) that mediates phenobarbital (PB) effects on hepatocyte growth and liver tumor induction. To determine the potential role of CAR in mediating effects of PPC, a meta-analysis was performed on transcript profiles from published studies in which rats and mice were exposed to PPC and compared the profiles to those produced by exposure to PB. Valproic acid, clofibrate and DEHP in rat liver and DEHP in mouse liver induced genes including Cyp2b family members that are known to be regulated by CAR. Examination of transcript changes by Affymetrix ST 1.0 arrays and RT-PCR in the livers of DEHP-treated wild-type, PPAR-null and CAR-null mice demonstrated that 1) most (
94%) of the transcriptional changes induced by DEHP were PPAR-dependent, 2) many PPAR-independent genes overlapped with those regulated by PB, 3) induction of genes Cyp2b10, Cyp3a11 and metallothionine-1 by DEHP was CAR-dependent but PPAR-independent and 4) induction of a number of genes (Cyp8b1, Gstm4, Gstm7) was independent of both CAR and PPAR. Our results indicate that exposure to PPAR activators including DEHP activate multiple nuclear receptors in the rodent liver.
Key Words: peroxisome proliferator-activated receptor ; transcript profiling; liver cancer; di-(2-ethylhexyl) phthalate; constitutive activated receptor; pregnane X receptor.