Sublethal concentrations of PFOS and PFDA differentially impact brood size and gene expression in Caenorhabditis elegans

Although banned in many countries, per- and polyfluorinated alkylated substances (PFAS) persist in the environment, where they pose significant health risks to humans and animals, yet the molecular mechanisms of toxicity remain largely unknown. Using two legacy PFAS chemicals, one data rich and one data poor, we evaluated the consequences of exposure within the Adverse Outcome Pathway (AOP) framework using the whole-body 3R model organism Caenorhabditis elegans. Early key events (KEs) were characterized through RNA-sequencing to explore changes in gene expression, relating these to the adverse outcomes of development and reproductive toxicity (DART). Sub-lethal concentrations of perfluorooctane sulfonate (PFOS) and perfluorodecanoic acid (PFDA) significantly upregulated the expression of detoxification enzymes and downregulated DART-related genes. As bioaccumulation can drive toxic potencies, the concentration of each PFAS was analytically determined. When concentration-response relationships were expressed using external concentrations, PFDA appeared significantly more potent than PFOS for each measured endpoint. However, analytical determination of internal concentrations of both PFAS in the nematodes using LC-MS/MS, showed PFOS and PFDA have more similar body burden. These data demonstrate that both PFAS substantially accumulate in C. elegans, with PFDA accumulating to a greater extent than PFOS, explaining the lower external effect concentrations of PFAS.