To Örebro University

Per- and polyfluoroalkyl substances (PFAS) are a family of persistent chemicals that continue to be released pervasively into the environment, leading to widespread human exposure. Emerging epidemiological evidence shows adverse effects on liver lipids; however, past toxicological studies have been limited by a focus on peroxisome proliferator activated receptor α (PPARα) driven effects on triglycerides in rodent systems. Here, we use a more agonostic approach incorporating lipidomics and transcriptomics to test the hypothesis that activation of human PPARα by PFOA, disrupts liver lipid homeostasis, broadly, similar to that seen in human liver diseases. Female and male mice expressing human PPAR α or that were PPARα null were fed a What We Eat In America diet and exposed to PFOA via drinking water for 6 weeks. Serum PFOA concentrations averaged 48 ± 9 μg/mL. PFOA changed the expression of ~2000 hepatic genes with expression of a larger number of genes in hPPARα versus PPARα null mice. In this occupational level PFOA exposure scenario, less than 60 % of transcriptional changes induced by PFOA depended on PPARα expression. CAR was another major molecular initiating event, with other transcription factors pathways more likely to be modulated downstream of hPPARα activation. In hPPARα mice of both sexes, PFOA increased total liver lipids. In addition to triacylglycerides, lipid classes strongly altered by PFOA exposure predominantly belong to phosphatidylcholine and sphingolipid classes. PFOA significantly decreased sphingomyelin abundance and increased ceramide abundance regardless of genotype, which coincided with an increase in expression of SMase, the enzyme that converts sphingomyelin to ceramide. These results highlight the ability of PFOA to modulate liver lipids beyond triacylglycerides in both an hPPARα-dependent and -independent manner.