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Immunotoxicity of perfluorooctanoic acid and perfluorooctane sulfonate and the role of peroxisome proliferator-activated receptor alpha
Citation:
DEWITT, J., A. Shnyra, M. Z. Badr, S. E. Loveless, D. Hoban, S. R. Frame, R. Cunard, S. E. Anderson, B. J. Meade, M. M. Peden-Adams, R. W. LUEBKE, AND M. I. Luster. Immunotoxicity of perfluorooctanoic acid and perfluorooctane sulfonate and the role of peroxisome proliferator-activated receptor alpha. CRITICAL REVIEWS IN TOXICOLOGY. CRC Press LLC, Boca Raton, FL, 39(1):76-94, (2009).
Impact/Purpose:
Peroxisome proliferators, including perfluorooctanoic acid (PFOA), are environmentally widespread and persistent and multiple toxicities have been reported in experimental animals and humans. These compounds trigger biological activity via activation of the alpha isotype of peroxisome proliferator activated receptors (PPARs), ligand-activated transcription factors that regulate gene expression. Activation of PPARα modulates lipid and glucose homeostasis, cell proliferation and differentiation, and inflammation. In experimental animals, exposure to PPARα ligands modifies various components of the immune system. Reported immune system effects have included altered inflammatory responses, production of cytokines, and other proteins, reduced lymphoid organ weights, and suppressed antibody synthesis. Although some immune system effects are likely the result of PPARα-mediated changes in gene expression, mounting experimental animal evidence suggests others are PPARα-independent.
Description:
Peroxisome proliferators, including perfluorooctanoic acid (PFOA), are environmentally widespread and persistent and multiple toxicities have been reported in experimental animals and humans. These compounds trigger biological activity via activation of the alpha isotype of peroxisome proliferator activated receptors (PPARs), ligand-activated transcription factors that regulate gene expression. Activation of PPARα modulates lipid and glucose homeostasis, cell proliferation and differentiation, and inflammation. In experimental animals, exposure to PPARα ligands modifies various components of the immune system. Reported immune system effects have included altered inflammatory responses, production of cytokines, and other proteins, reduced lymphoid organ weights, and suppressed antibody synthesis. Although some immune system effects are likely the result of PPARα-mediated changes in gene expression, mounting experimental animal evidence suggests others are PPARα-independent. Work in PPARα knock-out models demonstrate that hepatic peroxisome proliferation, reduced lymphoid organ weights, and suppressed antibody synthesis are PPARα-independent. Human PPARα expression is significantly less than that of rodents. However, the apparent PPARα-independence of PFOA immunotoxicity in rodents indicates that future research must explore the mechanisms of action of these compounds, including PPARα-dependent and -independent pathways of immunotoxicity. This multi-authored review contains a brief description of current and recently published work exploring PPARα ligands of therapeutic and environmental interest.
