Transcriptional profiling of bulk liver tissue from male and female PPARa knockout mice and mice expressing a human PPARa transgene following treatment with PFOA or vehicle drinking water in conjunction with an American diet

Per- and polyfluoroalkyl substances (PFAS) are a family of persistent chemicals that have been released pervasively in the environment leading to widespread human exposure. Emerging epidemiological evidence shows adverse effects on liver lipids, however the extent of this impact and the mechanisms through which PFAS disrupt hepatic lipid homeostasis in humans are not well understood. Here, we examine the effects of perfluorooctanoic acid (PFOA) on liver lipid profiles and probe transcriptional mechanisms contributing to liver lipid dysregulation in mice expressing human peroxisome proliferator activated receptor a (PPARa) in comparison to PPARa null mice. Male and female mice 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. Across male and female hPPARa mice, PFOA increased liver total lipids and total triacylglycerides, which was stronger in males than females and largely dependent on hPPARa. Additional lipid class 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. PFOA changed the expression of ~2,000 hepatic genes with a larger impact in hPPARa versus PPARa null mice. In this human-relevant PFOA exposure scenario, less than 60% of transcriptional changes induced by PFOA depended on PPARa expression. CAR appears to be another major molecular initiating event, with other transcription factors pathways more likely to be modulated downstream, including PPARg, pregnane X receptor, estrogen receptor a, farnesoid X receptor, and pregnane X receptor. These results highlight the ability of PFOA to modulate liver lipids beyond triacylglycerides and the need to further refine our understanding of the molecular initiating and downstream transcriptional regulators in PFAS-induced mechanisms of action.