In vitro characterization of the immunotoxic potential of several perfluorinated compounds (PFCs)

We have previously shown that PFOA and PFOS directly suppress cytokine secretion in immune cells, with different mechanisms of action. In particular, we have demonstrated a role for PPAR-alpha in PFOA-induced immunotoxicity, and that PFOS has an inhibitory effect on LPS-induced I-kappa B degradation. These studies investigate the immunomodulatory effects of four other PFCs, namely PFBS, PFOSA, PFDA, and fluorotelomer using in vitro assays. The release of the pro-inflammatory cytokines IL-6 and TNF-alpha was evaluated in lipolysaccharide (LPS)-stimulated human peripheral blood leukocytes ( hPBL) and in the human promyelocytic cell line THP-1, while the release of IL-10 and IFN-gamma was evaluated in phytohemagglutinin (PHA)-stimulated hPBL All PFCs suppressed LPS-induced TNF-alpha production in hPBL and THP-1 cells, while IL-6 production was suppressed by PFOSA, PFOS, PFDA and fluorotelomer. PFBS, PFOSA, PFOS, PFDA and fluorotelomer inhibited PHA-induced IL-10 release, while IFN-gamma secretion was affected by PFOSA, PFOS, PFDA and fluorotelomer. Leukocytes obtained from female donors appear to be more sensitive to the in vitro immunotoxic effects of PFCs when their responses are compared to the results obtained using leukocytes from male donors. Mechanistic investigations demonstrated that inhibition of TNF-alpha release in TIP-1 cells occurred at the transcriptional level. All PFCs, including PFOA and PFOS, decreased LPS-induced NF-kappa B activation. With the exception of PFOA, none of the PFCs tested was able to activate PPAR alpha driven transcription in transiently transfected THP-1 cells, excluding a role for PPAR alpha in the immunomodulation observed. PFBS and PFDA prevented LPS-induced I-kappa B degradation. Overall, these studies suggest that PFCs affect NF-kappa B activation, which directly suppresses cytokine secretion by immune cells. Our results indicate that PFOA is the least active of the PFCs examined followed by PFBS, PFDA, PFOS, PFOSA and fluorotelomer.