Perfluoroalkyl Sulfonates Cause Alkyl Chain Length–Dependent Hepatic Steatosis and Hypolipidemia Mainly by Impairing Lipoprotein Production in APOE*3-Leiden CETP Mice

Abstract

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.

Associations between serum concentrations of perfluoroalkyl acids and serum lipid levels in a Chinese population

“…Membrane transport may also play an important role if cholesterol and PFAAs share common processes or are influenced by common factors. Bijland et al (2011) observed that dietary PFOS increased expression of PFOS genes involved in fatty acid uptake and transport in APOE n 3-Leiden.CETP mice. Watkins et al (2013) found that among four PFAAs (PFOA, PFNA, PFHxS, and PFOS), only PFOS was associated with LINE-1 DNA methylation, which is known to regulate gene expression and may influence serum lipids (Nelson et al, 2011).…”

“…Nuclear receptors play a key role in lipid metabolism and adipogenesis, raising the concern that PFAAs may disrupt lipid regulation (Maher et al, 2008;Fang et al, 2012). In addition, another study utilizing the APOEn3-Leiden.CETP mouse model showed that PFOS may reduce TC by impairing lipoprotein production (Bijland et al, 2011). Compared with the effects found in animals, studies in humans have reported inconsistent associations between PFAAs and serum lipids (Frisbee et al, 2010a;Nelson et al, 2010;Fisher et al, 2013).…”

Longitudinal Assessment of Lipid and Hepatic Clinical Parameters in Workers Involved With the Demolition of Perfluoroalkyl Manufacturing Facilities

“…36 Using the APOE*3-Leiden.CETP mouse model that has an attenuated clearance of apolipoprotein B-containing lipoproteins and exhibits human-like lipoprotein metabolism when fed a Western-type diet, Bijland et al 36 reported that serum PFOS concentrations (range, 85,600 to-to 124,700 ng/mL) resulted in markedly lowered plasma triglycerides and lower lipoprotein levels (VLDL and HDL). Gene expression data suggested that these effects were mediated largely by PPARα and PXR.…”

Extensive literature search and provision of summaries of studies related to the oral toxicity of perfluoroalkylated substances (PFASs), their precursors and potential replacements in experimental animals and humans. Area 1: Data on toxicokinetics (absorption, distribution, metabolism, excretion) in in vitro studies, experimental animals and humans. Area 2: Data on toxicity in experimental animals. Area 3: Data on observations in humans

“…per day to male mice (APOE*3-Leiden.E3L CETP) for 4-6 weeks, reduced triglycerides, cholesterol, non-high density lipoprotein, high density lipoproteincholesterol, plasma ApoA1, low density lipoprotein, apoB production, free fatty acids and glycerol and increased lipase activity and clearance of triolein (Bijland et al, 2011).…”

“…per day for 4-6 weeks was reported to reduce plasma triglycerides, cholesterol and increase clearance of triolein (Bijland et al, 2011).…”