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Characterization of peroxisome proliferator-activiated receptor alpha (PPARalpha)-independent effects of PPARalpha activators in the rodent liver: Di(2-ethylehexyl) phthalate activates the constitutive activated receptor
Citation:
Hongzu, R., L. M. Aleksunes, C. R. WOOD, B. VALLANAT, M. George, M. Klaassen, AND C. CORTON. Characterization of peroxisome proliferator-activiated receptor alpha (PPARalpha)-independent effects of PPARalpha activators in the rodent liver: Di(2-ethylehexyl) phthalate activates the constitutive activated receptor. TOXICOLOGICAL SCIENCES. Society of Toxicology, RESTON, VA, 113(1):45-59, (2010).
Impact/Purpose:
This work was initiated in response to earlier findings that DEHP causes liver tumors in mice which lack a functional PPARalpha. These findings Iwere interpreted by NCEA to indicate that DEHP causes liver cancer in Iwild-type mice and rats through a PPARalpha-independent mechanism. We show in this study that DEHP most likely causes liver cancer in wild-tYPe mice through PPARalpha and in PPARalpha-null mice through CAR. These findings indicate that even though liver tumors are produced in null mice that they do not necessarily indicate independence of the receptor in wild-type mice. These findings are significant for mode of action work for peroxisome proliferators in general and DEHP in particular. They also show that transcript profiling in null mice is a powerful approach to uncovering mode of action of chemicals.
Description:
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 (PPARalpha). Recent studies indicate that the plasticizer di-2-ethylhexyl phthalate (DEHP) increased the incidence of liver tumors in PPARalpha-null mice. We hypothesized that some PPC, including DEHP, induce transcriptional changes independent of PPARalpha 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, PPARalpha-null and CAR-null mice demonstrated that 1) most ( approximately 94%) of the transcriptional changes induced by DEHP were PPARalpha-dependent, 2) many PPARalpha-independent genes overlapped with those regulated by PB, 3) induction of genes Cyp2b10, Cyp3a11 and metallothionine-1 by DEHP was CAR-dependent but PPARalpha-independent and 4) induction of a number of genes (Cyp8b1, Gstm4, Gstm7) was independent of both CAR and PPARalpha. Our results indicate that exposure to PPARalpha activators including DEHP activate multiple nuclear receptors in the rodent liver.
