Perfluorooctanoic acid activates multiple nuclear receptor pathways and skews expression of genes regulating cholesterol homeostasis in liver of humanized PPARα mice fed an American diet

Humans are exposed to perand polyfluoroalkyl substances (PFAS) in their drinking water, food, air, dust, and by direct use of consumer products. Increased concentrations of serum total cholesterol and low density lipoprotein cholesterol are among the endpoints best supported by epidemiology. The objectives of this study were to generate a new model for examining PFAS-induced dyslipidemia and to conduct molecular studies to better define mechanism(s) of action. We tested the hypothesis that perfluorooctanoic acid (PFOA) exposure at a human-relevant level dysregulates expression of genes controlling cholesterol homeostasis in livers of mice expressing human PPAR alpha (hPPAR alpha). Female and male hPPAR alpha and PPAR alpha null mice were fed a diet based on the What we eat in America analysis and exposed to PFOA in drinking water (8 mu M) for 6 weeks. This resulted in a serum PFOA concentration of 48 mu g/ml. PFOA increased liver mass, which was associated with histologically-evident lipid accumulation. Pooled analyses of serum lipoprotein cholesterol suggest that PFOA increased serum cholesterol, particularly in male mice. PFOA induced PPAR alpha and constitutive androstane receptor target gene expression in liver. Expression of genes in four pathways regulating cholesterol homeostasis were also measured. PFOA decreased expression of Hmgcr in a PPAR alpha-dependent manner. PFOA decreased expression of Ldlr and Cyp7a1 in a PPAR alpha-independent manner. Apob expression was not changed. Sex differences were evident. This novel study design (hPPAR alpha mice, American diet, long term exposure) generated new insight on the effects of PFOA on cholesterol regulation in the liver and the role of hPPAR alpha.