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Evidence for the involvement of xenobiotic-responsive nuclear receptors in transcriptional effects upon perfluoroalkyl acid exposure in diverse species
NHEERL, ORD, US EPA, Research Triangle Park, NC, United States; NHEERL Toxicogenomics Core, US EPA, Research Triangle Park, NC, United States.
NHEERL, ORD, US EPA, Research Triangle Park, NC, United States; NHEERL Toxicogenomics Core, US EPA, Research Triangle Park, NC, United States.
Discovery Toxicology, Bristol-Myers Squibb Company, Princeton, NJ, United States.
Safety Research Team, National Institute of Animal Health, Kannondai 3-1-5, Tsukuba, Ibaraki, Japan; Department of Biology and Chemistry, City University of Hong Kong, Tat Chee Avenue, Kowloon, Hong Kong SAR, Hong Kong.ORCID iD: 0000-0001-6800-5658
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2009 (English)In: Reproductive Toxicology, ISSN 0890-6238, E-ISSN 1873-1708, Vol. 27, no 3-4, 266-277 p.Article in journal (Refereed) Published
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Text
Abstract [en]

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 (PPARα). Recent studies indicate that along with PPARα 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 PPARα (WY-14,643 (WY)). As expected, PFOA and PFOS elicited transcript profile signatures that included many known PPARα 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 PPARα, CAR, and PXR orthologs were not activated. Our results indicate that PFAAs under these experimental conditions activate PPARα, 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.

Place, publisher, year, edition, pages
Elsevier, 2009. Vol. 27, no 3-4, 266-277 p.
Keyword [en]
Liver cancer; Perfluorinated alkyl acids; Perfluorooctane sulfonate; Perfluorooctanoic acid; Peroxisome proliferators
National Category
Environmental Sciences
Research subject
Enviromental Science
Identifiers
URN: urn:nbn:se:oru:diva-49992DOI: 10.1016/j.reprotox.2008.12.011ISI: 000266050100007PubMedID: 19162173Scopus ID: 2-s2.0-64949157824OAI: oai:DiVA.org:oru-49992DiVA: diva2:950411
Conference
Workshop on Perfluorooctanoic Acid Toxicokinetics and Mechanisms of Toxicity, Res Triangle Pk, NC, 2007
Available from: 2016-07-29 Created: 2016-04-28 Last updated: 2016-08-03Bibliographically approved

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Yeung, Leo W. Y.Lam, Paul K. S.
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