Journal Article
Perfluoroalkyl sulfonates cause alkyl chain length-dependent hepatic steatosis and hypolipidemia mainly by impairing lipoprotein production in APOE*3-Leiden CETP mice
Bijland, S; Rensen, PCN; Pieterman, EJ; Maas, ACE; van Der Hoorn, JW; van Erk, MJ; Havekes, LM; Willems van Dijk, K; Chang, SC; Ehresman, DJ; Butenhoff, JL; Princen, HMG
Toxicological Sciences
ISSN: 1096-6080
EISSN: 1096-0929
uses data from
3927382 TSCA 8(e) substantial risk notice: Sulfonate-based and carboxylic-based
fluorochemicals, docket 8EHQ-0598-373 - Results from a mechanistic investigation of the effect of PFBS, PFHS, and PFOS on lipid and lipoprotein metabolism in transgenic mice
Perfluorobutane sulfonate (PFBS), perfluorohexane sulfonate (PFHxS), and perfluorooctane sulfonate (PFOS) are stable perfluoroalkyl sulfonate (PFAS) surfactants, and PFHxS and PFOS are frequently detected in human biomonitoring studies. Some epidemiological studies have shown modest positive correlations of serum PFOS with non-high-density lipoprotein (HDL)-cholesterol (C). This study investigated the mechanism underlying the effect of PFAS surfactants on lipoprotein metabolism. APOE*3-Leiden.CETP mice were fed a Western-type diet with PFBS, PFHxS, or PFOS (30, 6, and 3 mg/kg/day, respectively) for 4-6 weeks. Whereas PFBS modestly reduced only plasma triglycerides (TG), PFHxS and PFOS markedly reduced TG, non-HDL-C, and HDL-C. The decrease in very low-density lipoprotein (VLDL) was caused by enhanced lipoprotein lipase-mediated VLDL-TG clearance and by decreased production of VLDL-TG and VLDL-apolipoprotein B. Reduced HDL production, related to decreased apolipoprotein AI synthesis, resulted in decreased HDL. PFHxS and PFOS increased liver weight and hepatic TG content. Hepatic gene expression profiling data indicated that these effects were the combined result of peroxisome proliferator-activated receptor alpha and pregnane X receptor activation. In conclusion, the potency of PFAS to affect lipoprotein metabolism increased with increasing alkyl chain length. PFHxS and PFOS reduce plasma TG and total cholesterol mainly by impairing lipoprotein production, implying that the reported positive correlations of serum PFOS and non-HDL-C are associative rather than causal.
cholesterol; lipoprotein; perfluorooctane sulfonate; PPAR alpha; PXR; triglyceride
