HFPO-TA exposure triggers hepatomegaly and lipid peroxidation via Nrf2/keap1 antioxidant dysregulation and ferroptosis activation in the liver.

Abstract

As an alternative to perfluorooctanoic acid (PFOA), Hexafluoropropylene oxide trimer acid (HFPO-TA), is currently utilized across various industries and national life, and now, has been detected in all surroundings. Due to its widespread environmental presence and potential biological toxicity, it may adversely affect human health. Studies have shown that HFPO-TA exposure exhibits hepatotoxicity, however, the underlying mechanisms remain unclear. This study investigated the mechanisms of HFPO-TA induced hepatic oxidative stress and lipid peroxidation leading to hepatotoxicity and ferroptosis through in vivo and in vitro experiments. In the in vivo experiments, mice were exposed to 0.02, 0.1 and 0.5 mg/kg/d of HFPO-TA for 14 days, which induced hepatic oxidative stress, mitochondrial morphological changes and lipid peroxidation, leading to hepatocyte ferroptosis. In vitro experiments with AML12 cells demonstrated that HFPO-TA exposure resulted in the accumulation of reactive oxygen species (ROS), a decrease in mitochondrial membrane potential, and subsequent lipid peroxidation and cell membrane damage, ultimately causing ferroptosis. In conclusion, both in vivo and in vitro experiments provide preliminary evidence implicating the p62/Keap1/Nrf2 pathway in HFPO-TA-induced oxidative stress, increases the accumulation of lipid peroxidation products, and leads to the injury of liver tissue and AML12 cells. This study provides new insights into the hepatotoxic effects of HFPO-TA.