| Autor: |
Shipley, Jonathan M., Hurst, Christopher H., Tanaka, Sue S., DeRoos, Fred L., Butenhoff, John L., Seacat, Andrew M., Waxman, David J. |
| Předmět: |
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| Zdroj: |
Toxicological Sciences; Jul2004, Vol. 80 Issue 1, p151-160, 10p, 3 Charts, 5 Graphs |
| Abstrakt: |
Peroxisome proliferator-activated receptors (PPARs) are ligand-dependent transcription factors that activate target genes involved in lipid metabolism, energy homeostasis, and cell differentiation in response to diverse compounds, including environmental chemicals. The liver-expressed receptor PPARα mediates peroxisome proliferative responses associated with rodent hepatocarcinogenesis. Previous studies have established that certain perfluorooctanesulfonamide-based chemicals (PFOSAs) alter lipid metabolism, are hepatic peroxisome proliferators, and induce hepatocellular adenoma formation in rodents, suggesting that they activate PPARα. The present study investigates this question and characterizes the activation of mouse and human PPARα by PFOSAs. Perfluorooctanesulfonate (PFOS), an end-stage metabolite common to several PFOSAs, was found to activate both mouse and human PPARα in a COS-1 cell-based luciferase reporter trans-activation assay. Half-maximal activation (EC50) occurred at 13–15 μM PFOS, with no significant difference in the responsiveness of mouse and human PPARα. Mouse and human PPARα were activated by perfluorooctanesulfonamide (FOSA) over a similar concentration range; however, cellular toxicity precluded an accurate determination of EC50 values. Studies of 2-N-ethylperfluorooctanesulfonamido ethanol were less informative due to its insolubility. These findings were verified in an FAO rat hepatoma cell line that stably expresses PPARα, where the endogenous PPARα target genes peroxisomal bifunctional enzyme and peroxisomal 3-ketoacyl-CoA thiolase were activated up to ∼10–20-fold by PFOS and FOSA. The interactions of PPARα with PFOS and FOSA, and the potential of these chemicals for activation of unique sets of downstream target genes, may help explain the diverse biological effects exhibited by PFOSAs and may aid in the evaluation of human and environmental risks associated with exposure to this important class of fluorochemicals. [ABSTRACT FROM AUTHOR] |
| Databáze: |
Complementary Index |
| Externí odkaz: |
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