The role of lipid metabolism and peroxisome proliferator activation in mediating pro-cancer phenotypes of poly- and perfluoroalkyl substances in testicular cancer

Poly- and perfluoroalkyl substances (PFAS) are of human health concern as epidemiological studies show significant associations with testicular germ cell tumors (TGCTs). Here, the effects of perfluorooctanesulfonic acid (PFOS), lithium bis(trifluoromethylsulfonyl)imide (HQ-115), and hexafluoropropylene oxide dimer acid (GenX) on TGCT cells were investigated. Concentrations (10 nM to 1 µM) modelled PFAS doses in relevant human exposure ranges and acute and short-term timepoints (18 h and 4 days) captured proximal mechanisms of action. Metabolomic studies revealed that HQ-115 altered metabolites associated with steroid biosynthesis and lipid metabolism. Peroxisome-proliferator activation receptor (PPAR) target gene expression was altered upon HQ-115 and GenX exposure. Lastly, PFAS exposure altered the activity of PPARs, in TGCT cells, with the most prominent effects being antagonist activity toward PPARγ. These data support that PFAS may act as fatty acid mimics to modulate fatty acid metabolic and steroidogenic endocrine outcome leading to pro-cancer phenotypes in TGCTs.