PPARα-independent transcriptional targets of perfluoroalkyl acids revealed by transcript profiling

Perfluoroalkyl acids (PFAAs) are ubiquitous and persistent environmental contaminants. Compounds such as perfluoroocanoic acid (PFOA), perfluorooctane sulfonate (PFOS), perfluorononanoic acid (PFNA), and perfluorohexane sulfonate (PFHxS) are readily found in the tissues of humans and wildlife. While PFOA and PFOS have been the subject of numerous studies since they were first described over a decade ago, less is known about the biological activity of PFHxS and PFNA. Most PFAAs are activators of peroxisome proliferator-activated receptor a (PPAR alpha), although the biological effects of these compounds are likely mediated by other factors in addition to PPAR alpha. To evaluate the effects of PFHxS and PFNA, male wild-type and Ppar alpha-null mice were dosed by oral gavage with PFHxS (3 or 10 mg/kg/day), PFNA (1 or 3 mg/kg/day), or vehicle for 7 days, and liver gene expression was evaluated by full-genome microarrays. Gene expression patterns were then compared to historical in-house data for PFOA and PFOS in addition to the experimental hypolipidemic agent,WY-14,643. While WY-14,643 altered most genes in a PPARa-dependent manner, approximately 11-24% of regulated genes in PFAA-treated mice were independent of PPAR alpha. The possibility that PFAAs regulate gene expression through other molecular pathways was evaluated. Using data available through a microarray database, PFAA gen& expression profiles were found to exhibit significant similarity to profiles from mouse tissues exposed to agonists of the constitutive activated receptor (CAR), estrogen receptor a (ERa), and PPAR gamma. Human PPAR gamma and ER alpha were activated by all four PFAAs in trans-activation assays from the ToxCast screening program. Predictive gene expression biomarkers showed that PFAAs activate CAR in both genotypes and cause feminization of the liver transcriptome through suppression of signal transducer and activator of transcription 5 B (STAT5B). These results indicate that, in addition to activating PPAR alpha as a primary target, PFAAs also have the potential to activate CAR, PPAR gamma, and ERa as well as suppress STAT5B.