Perfluorooctanoic acid stimulated mitochondrial biogenesis and gene transcription in rats

Perfluorooctanoic acid (PFOA), used in the production of non-stick surface compounds, exhibits a worldwide distribution in the serum of humans and wildlife. In rodents PFOA transactivates PPAR alpha and PPAR gamma nuclear receptors and increases mitochondrial DNA (mtDNA) copy number, which may be critical to the altered metabolic state of affected animals. A key regulator of mitochondrial biogenesis and transcription of mitochondrial genes is the PPAR gamma coactivator-1 alpha (Pgc-1 alpha) protein. The purpose of this study was to determine if Pgc-1 alpha is implicated in the stimulation of mitochondrial biogenesis that occurs following the treatment of rats with PFOA. Livers from adult male Sprague-Dawley rats that received a 30 mg/kg daily oral dose of PFOA for 28 days were used for all experiments. Analysis of mitochondrial replication and transcription was performed by real time PCR. and proteins were detected using western blotting. PFOA treatment caused a transcriptional activation of the mitochondrial biogenesis pathway leading to a doubling of mtDNA copy number. Further, transcription of OXPHOS genes encoded by mtDNA was 3-4 times greater than that of nuclear encoded genes, suggestive of a preferential induction of mtDNA transcription. Western blot analysis revealed an increase in Pgc-1 alpha, unchanged Tfam and decreased Cox 11 and Cox IV subunit protein expression. We conclude that PFOA treatment in rats induces mitochondrial biogenesis at the transcriptional level with a preferential stimulation of mtDNA transcription and that this occurs by way of activation of the Pgc-1 alpha pathway. Implication of the Pgc-1 alpha pathway is consistent with PPAR gamma transactivation by PFOA and reveals new understanding and possibly new critical targets for assessing or averting the associated metabolic disease. (C) 2009 Elsevier Ireland Ltd. All rights reserved.