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HERO ID
697411
Reference Type
Journal Article
Title
Characterization of peroxisome proliferator-activated receptor alpha--independent effects of PPARalpha activators in the rodent liver: di-(2-ethylhexyl) phthalate also activates the constitutive-activated receptor
Author(s)
Ren, H; Aleksunes, L; Wood, C; Vallanat, B; George, M; Klaassen, C; Corton, J
Year
2010
Is Peer Reviewed?
1
Journal
Toxicological Sciences
ISSN:
1096-6080
EISSN:
1096-0929
Book Title
Toxicol Sci.
Volume
113
Issue
1
Page Numbers
45-59
Language
English
PMID
19850644
DOI
10.1093/toxsci/kfp251
Web of Science Id
WOS:000272935700005
URL
https://www.scopus.com/inward/record.uri?eid=2-s2.0-75249083175&doi=10.1093%2ftoxsci%2fkfp251&partnerID=40&md5=ef426d258ecb93f081c8b884e5d001a8
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Abstract
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 (PPAR) alpha. 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 reverse transcription-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, and Gstm7) was independent of both CAR and PPARalpha. Our results indicate that exposure to PPARalpha activators including DEHP leads to activation of multiple nuclear receptors in the rodent liver.
Keywords
peroxisome proliferator-activated receptor alpha; transcript profiling; liver cancer; di-(2-ethylhexyl) phthalate; constitutive-activated receptor; pregnane X receptor
Tags
•
Phthalates – Targeted Search for Epidemiological Studies
Excluded
Source - August 2017 Update (Private)
WOS - Forward Search Results
•
Trichloroacetic acid (TCA) (Final, 2011)
PFAS
•
Additional PFAS (formerly XAgency)
•
PFAS 150
Literature Search August 2019
Web of Science
Perfluorooctanoic acid
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