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Toxicogenomic profiling of perfluorononanoic acid in wild-type and PPARa-null mice
Citation:
ROSEN, M. B., J. E. SCHMID, D. Zehr, K. DAS, H. REN, B. D. ABBOTT, C. LAU, AND C. CORTON. Toxicogenomic profiling of perfluorononanoic acid in wild-type and PPARa-null mice. Presented at Society of Toxicology 2010 Annual Meeting, Salt Lake City, UT, March 07 - 11, 2010.
Impact/Purpose:
These results lend support to an increased understanding that, in addition to their primary mode of action as activators of PPARa, PFAAs such as PFNA have the potential to activate other nuclear receptors.
Description:
Perfluorononanoic acid (PFNA) is a ubiquitous environmental contaminant and a developmental toxicant in laboratory animals. Like other perfluoroalkyl acids (PFAAs) such as perfluorooctane sulfonate (PFOA) and perfluoroalkyl acid (PFOS), PFNA is a known activator ofperoxisome proliferator-activated receptor-alpha (PPARa). In comparison to PFOA and PFOS, PFNA is a more potent activator of PPARa and displays greater acute hepatic toxicity. Male wild-type (WT) and PPARa-null (Null) mice were dosed by oral gavage with PFNA (l or 3 mg/kg/day), or vehicle for 7 days. Animals were euthanized, livers weighed, and liver samples collected for preparation of total RNA. Gene profiling was conducted on 4 mice per group using Affymetrix 430_2 GeneChips. As expected, PFNA altered the expression of genes associated with a variety ofPPARa-regulated functions in WT mice such as fatty acid/energy metabolism, inflammation, peroxisome biogenesis, and proteasome biogenesis. As observed for other PFAAs, activation ofthe constitutive androstane receptor (CAR) was indicated in both WT and Null mice. In Null mice, regulation of genes related to lipid metabolism was found as were changes related to inflammation and oxidative stress. Genes normally associated with activation ofPPARa such as Acaal, Cyp4a14, Ehhadh, Mel, and Acoxl were up-regulated in Null mice as well. Thus, in addition to activation of PPARa, these data indicate that activation of CAR and presumably other PPAR subtypes such as PPARy may be found in PFNA-exposed mice. These results lend support to an increased understanding that, in addition to their primary mode ofaction as activators of PPARa, PFAAs such as PFNA have the potential to activate other nuclear receptors. (This abstract does not necessarily reflect EPA policy.)