title: In vitro evaluation of the immunotoxic potential of perfluorinated compounds (PFCs).
abstract: There is evidence from both epidemiology and laboratory studies that perfluorinated compounds may be immunotoxic, affecting both cell-mediated and humoral immunity. The overall goal of this study was to investigate the mechanisms underlying the immunotoxic effects of perfluorooctane sulfonate (PFOS) and perfluorooctane acid (PFOA), using in vitro assays. The release of the pro-inflammatory cytokines IL-6, IL-8, and TNF-α was evaluated in lipolysaccharide (LPS)-stimulated human peripheral blood leukocytes and in the human promyelocytic cell line THP-1, while the release of IL-4, IL-10 and IFN-γ was evaluated in phytohaemagglutinin (PHA)-stimulated peripheral blood leukocytes. PFOA and PFOS suppressed LPS-induced TNF-α production in primary human cultures and THP-1 cells, while IL-8 was suppressed only in THP-1 cells. IL-6 release was decreased only by PFOS. Both PFOA and PFOS decreased T-cell derived, PHA-induced IL-4 and IL-10 release, while IFN-γ release was affected only by PFOS. In all instances, PFOS was more potent than PFOA. Mechanistic investigations carried out in THP-1 cells demonstrated that the effect on cytokine release was pre-transcriptional, as assessed by a reduction in LPS-induced TNF-α mRNA expression. Using siRNA, a role for PPAR-α could be demonstrated for PFOA-induced immunotoxicity, while an inhibitory effect on LPS-induced I-κB degradation could explain the immunomodulatory effect of PFOS. The dissimilar role of PPAR-α in PFOA and PFOS-induced immunotoxicity was consistent with the differing effects observed on LPS-induced MMP-9 release: PFOA, as the PPAR-α agonist fenofibrate, modulated the release, while PFOS had no effect. Overall, these studies suggest that PFCs directly suppress cytokine secretion by immune cells, and that PFOA and PFOS have different mechanisms of action.
authors.affiliation: Laboratory of Toxicology, Department of Pharmacological Sciences, Università degli Studi di Milano, Via Balzaretti 9, 20133 Milano, Italy. emanuela.corsini@unimi.it
authors.forename: Emanuela
authors.initials: E
authors.lastname: Corsini
authors.forename: Anna
authors.initials: A
authors.lastname: Avogadro
authors.forename: Valentina
authors.initials: V
authors.lastname: Galbiati
authors.forename: Mario
authors.initials: M
authors.lastname: dell'Agli
authors.forename: Marina
authors.initials: M
authors.lastname: Marinovich
authors.forename: Corrado L
authors.initials: CL
authors.lastname: Galli
authors.forename: Dori R
authors.initials: DR
authors.lastname: Germolec
mesh_terms: D017738:Alkanesulfonic Acids / Q000276:immunology / Q000633:toxicity*; D002210:Caprylates / Q000276:immunology / Q000633:toxicity*; D045744:Cell Line, Tumor; D016207:Cytokines / Q000187:drug effects* / Q000378:metabolism; D005466:Fluorocarbons / Q000276:immunology / Q000633:toxicity*; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism; D007371:Interferon-gamma / Q000187:drug effects / Q000378:metabolism; D007378:Interleukins / Q000378:metabolism; D007962:Leukocytes / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D008070:Lipopolysaccharides; D020780:Matrix Metalloproteinase 9 / Q000187:drug effects / Q000378:metabolism; D047493:PPAR alpha / Q000187:drug effects / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000187:drug effects / Q000378:metabolism
chemical_list: D017738:Alkanesulfonic Acids; D002210:Caprylates; D016207:Cytokines; D005466:Fluorocarbons; D018836:Inflammation Mediators; D007378:Interleukins; D008070:Lipopolysaccharides; D047493:PPAR alpha; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma; C023036:perfluorooctanoic acid; C076994:perfluorooctane sulfonic acid; D020780:Matrix Metalloproteinase 9