You are here:
GENE EXPRESSION PROFILING IN WILD-TYPE AND PPARa-NULL MICE EXPOSED TO PERFLUOROOCTANE SULFONATE REVEALS PPARa-INDEPENDENT EFFECTS
Citation:
ROSEN, M. B., J. E. SCHMID, C. CORTON, R. ZEHR, B. D. ABBOTT, K. P. Das, AND C. LAU. GENE EXPRESSION PROFILING IN WILD-TYPE AND PPARa-NULL MICE EXPOSED TO PERFLUOROOCTANE SULFONATE REVEALS PPARa-INDEPENDENT EFFECTS. PPAR research. Hindawi Publishing Corporation, New York, NY, pii(1):794391, (2010).
Impact/Purpose:
This manuscript addresses the mechanism of action of PFOS, a high profile persistant organic pollutant. While PFOS is an agonist of PPARa, it's mode of action is likely to go beyond activation of this nuclear receptor. PFOS may also modestly activate other nuclear receptors. The hypothesis that PFOA may have non-PPARa related effects is supported by the observation that neonatal toxicity is observed in PPARu-null mice. The data are actively being sought by OPPTS.
Description:
Perfluorooctane sulfonate (PFOS) is a perfluoroalky1 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(PPARa) and exhibits hepatocarcinogenic potential in rodents. PFOS is also a developmental toxicant in rodents where, unlike PFOA, it's mode of action is independent of PPARa. Wild-type (WT) and PPARa-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 micro arrays. In WT mice, PFOS induced changes that were characteristic of PPARa transactivation including regulation of genes associated with lipid metabolism, peroxisome biogenesis, proteasome activation, and inflammation. PPARa-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 PPARy and/or PPARWo. 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 Cyp7aJ, a gene which is under the control of various transcription regulators. Hence, in addition to its ability to modestly activate PPARa, PFOS induces a variety of PPARa-independent effects as well.
