PFOA Exposure Elicits Quantitative Lipidomic Changes in the Pancreas in a Mouse Model of Pancreatic Cancer

Pancreatic cancer is the fourth leading cause of cancer deaths in the US and predicted to rise to second by 2030. Several risk factors have been identified as potential contributors to pancreatic cancer development including lifestyle factors and long-term exposure to occupational and environmental carcinogens. In mice, exposure to perfluorooctanoic acid (PFOA) leads to diabetic outcomes and pancreatic cancer, while epidemiologic studies have linked PFOA exposure to type 1, type 2, and gestational diabetes, obesity, and pancreatic cancer. While multiple studies have evaluated changes in serum lipid levels in association with PFOA exposure, none to date have evaluated PFOA-associated lipid alterations in the pancreas. Using the LSL-KRas^G12D; Pdx-1-Cre (KC) mouse model of pancreatic cancer, we report upregulation of lipid species within the acylcarnitine (CAR) and ceramide (Cer) lipid groups and downregulation of lipids in the phosphatidylcholine, phosphatidylethanolamine (PE), and phosphatidylserine groups following exposure to 1 and 5 ppm PFOA for 6 months. The most upregulated lipids following PFOA exposure included individual Cer and CAR species while PE species comprised the top group of downregulated lipids. Thromboxane B2 (TXB2), a proinflammatory eicosanoid, was the most upregulated lipid in the 1 and 5 ppm KC treatment groups with a fold-change of ~12-fold and ~31-fold in the 1 and 5 ppm KC treatment groups, respectively. As these lipid alterations have been linked to mitochondrial dysfunction, obesity, and inflammation, our results suggest that PFOA-induced lipid alterations may be involved in adverse health outcomes including diabetes and pancreatic cancer.