In vitro cytotoxicity of six per- and polyfluoroalkyl substances (PFAS) in human immune cell lines

Per- and Polyfluoroalkyl substances (PFAS) are a group of persistent long-lived chemicals with global environmental contamination. The published literature is rife with confusing and sometimes contradictory effects of PFAS on animal and cell models, as well as epidemiological studies. Cytotoxicity studies are often used as an early indicator to guide safety requirements, regulation, and further studies and thus can be useful to understand important toxicity differences by various PFAS. Recent studies have found that PFAS are not equivalently toxic on all cell types, and that not all cell types exhibit the same sensitivity to individual PFAS. However, immune cells have not been well studied. As immune cells are important for regulating responses to environmental toxins, infection, and cancer, we sought to discover the sensitivity of these cells to various PFAS, including legacy and replacement compounds. We assessed a range of concentrations and found that immune cells are generally more robust when exposed to PFAS, and that Jurkat T-cells were more sensitive than THP-1 monocytes. As monocytes are critical for coordinating inflammatory responses to external threats with cell death cascades, we further investigated these cells. We discovered that THP-1 cells do not undergo organized or programmed death, such as apoptosis or pyroptosis, and instead PFAS exposure results in a more necrotic/lytic and unorganized death, likely contributing to potential inflammatory effects downstream.