Citation:

Rosen, M., K. Das, J. Rooney, B. Abbott, C. Lau, AND C. Corton. PPARα-independent transcriptional targets of perfluoroalkyl acids revealed by transcript profiling. TOXICOLOGY. Elsevier Science Ltd, New York, NY, 387:95-107, (2017).

Impact/Purpose:

This paper represents the continuing efforts at ORD to support OW, OCSPP, OLEM and Regions in investigating the potential hepatotoxic effects of perfluoroalkyl acids (PFAAs). The adverse effects of PFAAs vary among chemicals based on their functional groups (carboxylate and sulfonate) and carbon chain lengths (from C4 to C14). Such variations are largely driven by the pharmacokinetic (how fast the chemicals are eliminated from the body) and pharmacodynamic (how potent the chemicals are at the target tissues) properties of the individual PFAA. Previous studies from our laboratory have described the pharmacokinetic properties and toxicity profiles of a number of these PFAAs. Our findings have supported the EPA SNURs (Docket control number OPPTS-50639D) and Consent Agreement with industry to cease production of perfluorooctane sulfonate (PFOS) and perfluorooctanoate (PFOA) in the U.S. (http://www.epa.gov/oppt/pfoa/pubs/pfas.html), Action Plan to initiate rulemaking under section 6 of the TSCA to manage long-chain perfluorinated chemicals (http://www.epa.gov/oppt/existingchemicals/pubs/actionplans/pfcs.html), as well as the health advisories for PFOA and PFOS in drinking water issued by OW in 2009 and 2016 (http://water.epa.gov/drink/standards/hascience.cfmin; https://www.epa.gov/ground-water-and-drinking-water/drinking-water-health-advisories-pfoa-and-pfos). In 2002, 3M ceased production of PFOS and related chemistries, and in 2013, DuPont announced the termination of PFOA production. Hepatotoxicity of PFAAs is a signature of PFAA effect in animal models. Correspondingly, biomonitoring and epidemiological studies in highly exposed as well as general human populations have indicated positive associations between body burdens of PFOS and PFOA and untoward metabolic effects such as increases of serum cholesterol, LDL, and uric acid as well as altered liver enzyme activities. This study characterized the potential molecular mechanisms mediating these hepatic effects, focusing on the involvement of a number of transcription factors revealed by measuring gene expression in the livers of PFAA-treated wild-type mice and mice nullizygous for one of the main targets of PFAAs, peroxisome proliferator-activated receptor alpha (PPARα). Our findings will support human health risk assessment of these chemicals by EPA and other regulatory agencies.

Description:

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 α (PPARα), although the biological effects of these compounds are likely mediated by other factors in addition to PPARα. To evaluate the effects of PFHxS and PFNA, male wild-type and Pparα-null mice were dosed by oral gavage with PFHxS (3 or 10mg/kg/day), PFNA (1 or 3mg/kg/day), or vehicle for 7days, 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 PPARα-dependent manner, approximately 11-24% of regulated genes in PFAA-treated mice were independent of PPARα. The possibility that PFAAs regulate gene expression through other molecular pathways was evaluated. Using data available through a microarray database, PFAA gene expression profiles were found to exhibit significant similarity to profiles from mouse tissues exposed to agonists of the constitutive activated receptor (CAR), estrogen receptor α (ERα), and PPARγ. Human PPARγ and ERα 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 5B (STAT5B). These results indicate that, in addition to activating PPARα as a primary target, PFAAs also have the potential to activate CAR, PPARγ, and ERα as well as suppress STAT5B.

URLs/Downloads:

Record Details: