Immunotoxicity of Perfluorooctanoic Acid and Perfluorooctane Sulfonate and the Role of Peroxisome Proliferator-Activated Receptor Alpha

Abstract

Perfluorooctanoic acid (PFOA) and perfluorooctane sulfonate (PFOS) are environmentally widespread and persistent chemicals with multiple toxicities reported in experimental animals and humans. These compounds can trigger biological activity by activating the alpha isotype of peroxisome proliferator-activated receptors (PPARs), ligand-activated transcription factors that regulate gene expression; however, some biological effects may occur independently of the receptor. Activation of the peroxisome proliferator-activated receptor alpha (PPARα) modulates lipid and glucose homeostasis, cell proliferation and differentiation, and inflammation. Reported immunomodulation in experimental animals exposed to PFOA and PFOS has included altered inflammatory responses, production of cytokines and other proteins, reduced lymphoid organ weights, and altered antibody synthesis. Mounting experimental animal evidence suggests PPARα independence of some immune effects. This evidence originates primarily from studies with PPARα knockout models exposed to PFOA that demonstrate hepatic peroxisome proliferation, reduced lymphoid organ weights, and altered antibody synthesis. As human PPARα expression is significantly less than that of rodents, potential PPARα independence indicates that future research must explore mechanisms of action of these compounds, including PPARα -dependent and -independent pathways. This multiauthored review contains brief descriptions of current and recently published work exploring immunomodulation by PFOA and PFOS, as well as a short overview of other PPARα ligands of therapeutic and environmental interest.

Keywords:

• immunomodulation
• ligand-activated transcription factors
• perfluoroalkyl acids

ACKNOWLEDGEMENTS

We thank Dr. Linda Birnbaum, Dr. Dori Germolec, Dr. Erin Hines, and Dr. MaryJane Selgrade for reviewing the article and providing helpful suggestions. Partial support was provided by a University of North Carolina–U.S. Environmental Protection Agency Cooperative Training Agreement (CT829472) and a National Institute of Environmental Health Sciences interagency agreement with the National Institute of Occupational Safety and Health (927ZCTG).