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PPAR Research
Volume 2010 (2010), Article ID 794739, 23 pages
http://dx.doi.org/10.1155/2010/794739
Research Article

Gene Expression Profiling in Wild-Type and PPAR 𝛼 -Null Mice Exposed to Perfluorooctane Sulfonate Reveals PPAR 𝛼 -Independent Effects

1Integrated Systems Toxicology Division, Office of Research and Development, National Health and Environmental Effects Research Laboratory, U.S. Environmental Protection Agency, MD 72, Research Triangle Park, NC 27711, USA
2Biostatistics and Bioinformatics Team, Office of Research and Development, National Health and Environmental Effects Research Laboratory, U.S. Environmental Protection Agency, MD 72, Research Triangle Park, NC 27711, USA
3Analytical Chemistry Team, Office of Research and Development, National Health and Environmental Effects Research Laboratory, U.S. Environmental Protection Agency, MD 72, Research Triangle Park, NC 27711, USA
4Toxicology Assessment Division, Office of Research and Development, National Health and Environmental Effects Research Laboratory, U.S. Environmental Protection Agency, MD 72, Research Triangle Park, NC 27711, USA

Received 27 April 2010; Accepted 13 July 2010

Academic Editor: Michael Cunningham

Copyright © 2010 Mitchell B. Rosen et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Perfluorooctane sulfonate (PFOS) is a perfluoroalkyl acid (PFAA) and a persistent environmental contaminant found in the tissues of humans and wildlife. Although blood levels of PFOS have begun to decline, health concerns remain because of the long half-life of PFOS in humans. Like other PFAAs, such as, perfluorooctanoic acid (PFOA), PFOS is an activator of peroxisome proliferator-activated receptor-alpha (PPAR 𝛼 ) and exhibits hepatocarcinogenic potential in rodents. PFOS is also a developmental toxicant in rodents where, unlike PFOA, its mode of action is independent of PPAR 𝛼 . Wild-type (WT) and PPAR 𝛼 -null (Null) mice were dosed with 0, 3, or 10 mg/kg/day PFOS for 7 days. Animals were euthanized, livers weighed, and liver samples collected for histology and preparation of total RNA. Gene profiling was conducted using Affymetrix 430_2 microarrays. In WT mice, PFOS induced changes that were characteristic of PPAR 𝛼 transactivation including regulation of genes associated with lipid metabolism, peroxisome biogenesis, proteasome activation, and inflammation. PPAR 𝛼 -independent changes were indicated in both WT and Null mice by altered expression of genes related to lipid metabolism, inflammation, and xenobiotic metabolism. Such results are similar to studies done with PFOA and are consistent with modest activation of the constitutive androstane receptor (CAR), and possibly PPAR 𝛾 and/or PPAR 𝛽 / 𝛿 . Unique treatment-related effects were also found in Null mice including altered expression of genes associated with ribosome biogenesis, oxidative phosphorylation, and cholesterol biosynthesis. Of interest was up-regulation of Cyp7a1, a gene which is under the control of various transcription regulators. Hence, in addition to its ability to modestly activate PPAR 𝛼 , PFOS induces a variety of PPAR 𝛼 -independent effects as well.