title: Evidence for the involvement of xenobiotic-responsive nuclear receptors in transcriptional effects upon perfluoroalkyl acid exposure in diverse species.
abstract: Humans and ecological species have been found to have detectable body burdens of a number of perfluorinated alkyl acids (PFAA) including perfluorooctanoic acid (PFOA) and perfluorooctane sulfonate (PFOS). In mouse and rat liver these compounds elicit transcriptional and phenotypic effects similar to peroxisome proliferator chemicals (PPC) that work through the nuclear receptor peroxisome proliferator-activated receptor alpha (PPAR alpha). Recent studies indicate that along with PPAR alpha other nuclear receptors are required for transcriptional changes in the mouse liver after PFOA exposure including the constitutive activated receptor (CAR) and pregnane X receptor (PXR) that regulate xenobiotic metabolizing enzymes (XME). To determine the potential role of CAR/PXR in mediating effects of PFAAs in rat liver, we performed a meta-analysis of transcript profiles from published studies in which rats were exposed to PFOA or PFOS. We compared the profiles to those produced by exposure to prototypical activators of CAR, (phenobarbital (PB)), PXR (pregnenolone 16 alpha-carbonitrile (PCN)), or PPAR alpha (WY-14,643 (WY)). As expected, PFOA and PFOS elicited transcript profile signatures that included many known PPAR alpha target genes. Numerous XME genes were also altered by PFOA and PFOS but not WY. These genes exhibited expression changes shared with PB or PCN. Reexamination of the transcript profiles from the livers of chicken or fish exposed to PFAAs indicated that PPAR alpha, CAR, and PXR orthologs were not activated. Our results indicate that PFAAs under these experimental conditions activate PPAR alpha, CAR, and PXR in rats but not chicken and fish. Lastly, we discuss evidence that human populations with greater CAR expression have lower body burdens of PFAAs.
authors.affiliation: NHEERL/ORD, US EPA, Research Triangle Park, NC 27711, United States; NHEERL Toxicogenomics Core, US EPA, Research Triangle Park, NC 27711, United States.
authors.forename: Hongzu
authors.initials: H
authors.lastname: Ren
authors.affiliation: NHEERL/ORD, US EPA, Research Triangle Park, NC 27711, United States; NHEERL Toxicogenomics Core, US EPA, Research Triangle Park, NC 27711, United States.
authors.forename: Beena
authors.initials: B
authors.lastname: Vallanat
authors.affiliation: Discovery Toxicology, Bristol-Myers Squibb Company, Princeton, NJ 08543, United States.
authors.forename: David M
authors.initials: DM
authors.lastname: Nelson
authors.affiliation: Safety Research Team, National Institute of Animal Health, Kannondai 3-1-5, Tsukuba, Ibaraki 305-0856, Japan; Department of Biology and Chemistry, City University of Hong Kong, Tat Chee Avenue, Kowloon, Hong Kong SAR, PR China.
authors.forename: Leo W Y
authors.initials: LWY
authors.lastname: Yeung
authors.affiliation: Safety Research Team, National Institute of Animal Health, Kannondai 3-1-5, Tsukuba, Ibaraki 305-0856, Japan.
authors.forename: Keerthi S
authors.initials: KS
authors.lastname: Guruge
authors.affiliation: Department of Biology and Chemistry, City University of Hong Kong, Tat Chee Avenue, Kowloon, Hong Kong SAR, PR China.
authors.forename: Paul K S
authors.initials: PKS
authors.lastname: Lam
authors.affiliation: Discovery Toxicology, Bristol-Myers Squibb Company, Princeton, NJ 08543, United States.
authors.forename: Lois D
authors.initials: LD
authors.lastname: Lehman-McKeeman
authors.affiliation: NHEERL/ORD, US EPA, Research Triangle Park, NC 27711, United States; NHEERL Toxicogenomics Core, US EPA, Research Triangle Park, NC 27711, United States. Electronic address: corton.chris@epa.gov.
authors.forename: J Christopher
authors.initials: JC
authors.lastname: Corton
mesh_terms: D017738:Alkanesulfonic Acids / Q000633:toxicity*; D000818:Animals; D002210:Caprylates / Q000633:toxicity*; D000090702:Constitutive Androstane Receptor; D005466:Fluorocarbons / Q000633:toxicity*; D020869:Gene Expression Profiling; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D015201:Meta-Analysis as Topic; D051379:Mice; D000077297:Pregnane X Receptor; D051381:Rats; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics / Q000378:metabolism*; D011987:Receptors, Steroid / Q000235:genetics / Q000378:metabolism*; D013045:Species Specificity; D014158:Transcription, Genetic / Q000187:drug effects; D015262:Xenobiotics / Q000378:metabolism*
chemical_list: D017738:Alkanesulfonic Acids; D002210:Caprylates; D000090702:Constitutive Androstane Receptor; D005466:Fluorocarbons; D000077297:Pregnane X Receptor; D018160:Receptors, Cytoplasmic and Nuclear; D011987:Receptors, Steroid; D015262:Xenobiotics; C023036:perfluorooctanoic acid; C076994:perfluorooctane sulfonic acid