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Characterization of Peroxisome Proliferator-Activated Receptor a (PPARa) -Independent Effects of PPARa Activators in the Rodent Liver: Di-(2-ethylhexyl) phthalate Also Activates the Constitutive Activated Receptor
Citation:
Ren, H., L. M. Aleksunes, C. R. Wood, B. Vallant, M. H. George, C. D. Klassen, AND C. CORTON. Characterization of Peroxisome Proliferator-Activated Receptor a (PPARa) -Independent Effects of PPARa Activators in the Rodent Liver: Di-(2-ethylhexyl) phthalate Also Activates the Constitutive Activated Receptor. Presented at Society of Toxicology 49th Annual meeting, Salt Lake City, UT, March 07 - 11, 2010.
Impact/Purpose:
To determine the potential role of CAR in mediating the effects of PPC, a meta-analysis was performed in which the transcript profiles from published studies using PPC-exposed rats and mice were compared to those produced by exposure to PB.
Description:
Peroxisome proliferator chemicals (PPC) are thought to mediate their effects in rodents on hepatocyte growth and liver cancer through the nuclear receptor peroxisome proliferatoractivated receptor alpha (PPARa). Recent studies indicate that one such PPC, the plasticizer di2- ethyihexyl phthalate (DEHP), increases the incidence ofliver tumors in PPARa-null mice. We hypothesized that some PPC, including DEHP, induce transcriptional changes that are independent ofPPARabut dependent on other nuclear receptors, including the constitutive activated receptor (CAR). CAR is known to mediate the effects ofphenobarbital (PB) on hepatocyte growth and liver tumor induction. To determine the potential role ofCAR in mediating the effects ofPPC, a meta-analysis was performed in which the transcript profiles from published studies using PPC-exposed rats and mice were compared to those produced by exposure to PB. Valproic acid, clofibrate and DEHP in rat liver and DEHP in mouse liver induced genes known to be regulated by CAR, including Cyp2b family members. Further examination oftranscript changes using Affymetrix Mouse Gene 1.0 ST arrays and RT-PCR in the livers ofDEHP-treated wild-type, PPARa-null and CAR-null mice demonstrated that 1) most (-94%) ofthe transcriptional changes induced by DEHP were PPARa-dependent, 2) many PPARa-independent genes overlapped with those regulated by PB, 3) induction ofCyp2blO, Cyp3all and metallothionine-l by DEHP was CAR-dependeht but PPARa-independent and 4) induction ofa number ofgenes (Cyp8bl, Gstm4, Gstm7) was independent ofboth CAR and PPARa Our results indicate that exposure to activators ofPPARa, including DEHP, could activate multiple nuclear receptors in the rodent liver and that DEHP likely induces liver tumors in PPAko-null mice through CAR. (This abstract does not necessarily reflect US EPA policy).