PROJECT SUMMARY
The ubiquitous environmental contaminants collectively known as PFAS (Per- and polyfluoroalkyl
substances) have been dubbed “forever chemicals” due to their persistence in the environment. In humans,
they have been associated with a wide variety of illnesses, including: cancer, immunotoxicities, hepatotoxicity
hyperlipidemias, and developmental defects. Despite their toxicological threat to human health, the exact
molecular mechanisms by which they exert their effects have remained elusive. A common theme existing
between many of these disease states is the disruption of immune system homeostasis, which manifests itself
in an increased risk for cancer and other immunotoxicities. Our long-term goal is to delineate the molecular
mechanisms related to PFAS-induced innate immune system dysfunction in the liver. The objective of this
particular application is to characterize how PFAS, through modulation of key metabolic enzymes, may impact
the production of oxylipins by hepatocytes. The impact of these findings will provide mechanistic insight into
which innate immune cell mediators contribute to immunosuppression by PFAS. Our central hypothesis is that
CYP, COX, and LOX inhibition by PFAS leads to dysregulation of oxylipin synthesis, promoting immune
suppression. We will test this hypothesis through employing two specific aims. In our first aim, we will identify
the CYP, COX, and LOX oxylipin metabolic pathways inhibited by the PFAS compounds via direct enzyme
inhibition assays and a targeted lipidomics approach. This aim will define the impacts of PFAS on the
generation of liver-derived inflammatory mediators in exposed individuals. In our second aim, we will
characterize the inflammatory response to LPS in PFAS-exposed primary hepatocytes. Here, we will
characterize oxylipin metabolism and cytokine production in response to PFAS and LPS exposure to delineate
how hepatocytes respond to inflammatory signals after PFAS exposure, thus providing insight into the potential
health effects during an immunological challenge. To date, the potential effects of PFAS on hepatic immune
responses is not well understood. This proposal will further delineate the molecular mechanisms of PFAS on
oxylipin production and immunological challenge, providing a strong foundation for understanding the role of
PFAS in immune system dysregulation, which is key to developing treatments for those who have been
exposed and preventing the observed immunopathology.
