How PFAS Impact Liver Cell Function and Health

Per- and polyfluoroalkyl substances (PFAS) are synthetic chemicals widely present in the environment and associated with adverse health effects, notably liver disease and cancer. Despite their widespread presence, the biological mechanisms through which PFAS cause liver damage remain to be fully understood. Recent research from the Keck School of Medicine of USC has provided valuable insights by examining the effects of different PFAS compounds on human liver cells at the cellular and molecular levels.

The study utilized advanced 3D liver models called spheroids, which are composed of cells derived from human donors, including both males and females. These spheroids closely mimic the structure and function of actual liver tissue, offering a detailed platform to observe biochemical and cellular responses to PFAS exposure. Researchers exposed these models to four common PFAS chemicals—perfluorooctanoic acid (PFOA), perfluorohexanesulfonic acid (PFHxS), perfluorooctanesulfonic acid (PFOS), and perfluorononanoic acid (PFNA)—each at high levels typically found in human blood.

Analysis after seven days revealed that all four chemicals disrupted key liver cell functions. Specifically, they interfered with immune response pathways and communication between cells. Notably, PFOA and PFHxS increased fat accumulation within liver cells, with PFOA promoting fat production and PFHxS causing retention, potentially contributing to fatty liver disease. PFOS and PFNA induced cancer-related cellular changes, with PFNA displaying a stronger effect, especially activating pathways linked to inflammation, oxidative stress, and DNA repair. Importantly, the response to PFAS exposure varied between liver cells from males and females, revealing sex-specific differences in susceptibility.

To understand the mechanisms driving these effects, the scientists employed single-cell RNA sequencing and fat accumulation measurements. They discovered that each PFAS affected cellular signaling and immune processes differently, with some chemicals causing more pronounced effects. For instance, PFNA had a significant impact on cellular pathways associated with cancer development, with over 61% of the exposed cells showing gene expression changes linked to cancer pathways.

These findings highlight the complex ways in which PFAS compounds can damage the liver and progress to serious health conditions. They also emphasize the importance of reducing individual exposure, advocating for measures such as drinking filtered water and avoiding non-stick cookware. Furthermore, this research sets the stage for developing targeted treatments, including drugs that regulate fat metabolism in the liver, which could potentially counteract PFAS-induced damage.

The comprehensive study underscores the urgent need for regulatory measures to limit PFAS exposure and protect liver health worldwide. As the team continues to analyze combined effects of multiple PFAS chemicals, these insights are expected to further inform public health policies and clinical interventions aimed at mitigating the long-term impacts of these persistent chemicals.