ATF4 participates in perfluorooctane sulfonate-induced neurotoxicity by regulating ferroptosis

Abstract

Evidence from animal and human research suggests that perfluorooctane sulfonate (PFOS), a prevalent persistent organic pollutant (POP), exerts neurotoxic effects, but the precise mechanisms remain unclear. Additionally, the function of activating transcription factor 4 (ATF4), a crucial modulator of cellular metabolism, redox balance, and survival, in PFOS-induced neurotoxicity has not been fully elucidated. In vitro metabolomics studies revealed that PFOS elevated the intracellular concentration of reactive oxygen species (ROS) and lowered the levels of reduced L-glutathione (GSH). Significant alterations in the mRNA and protein expression levels of ferroptosis-related biomarkers, including ferroptosis-related genes [NRF2, nuclear receptor coactivator 4 (NCOA4), KEAP1, xCT/SLC7A11, GPX4, and FTH1], cellular iron, and lipid peroxidation were observed. Moreover, erastin (Ers) exacerbated lipid peroxidation, which was alleviated by ferrostatin-1 (Fer-1) and N-acetyl-L-cysteine (NAC). In mice, PFOS exposure damaged the structure and function of the hippocampus, including decreasing the number of neurons and impairing spatial learning and memory capacity. Importantly, ferroptosis was also observed in vivo, concomitant with the inhibition of ATF4, which was also observed in vitro. ATF4 silencing further increased ROS levels, lipid peroxidation, and ferroptosis induced by PFOS, whereas NAC and Fer-1 abrogated the effects of ATF4 silencing. Treatment with E235, an ATF4 activator, alleviated PFOS-induced ferroptosis. In conclusion, this study revealed that ATF4-mediated ferroptosis is involved in PFOS-induced neurotoxicity, offering novel mechanistic insights into the neurotoxic effects of PFOS and potentially paving the way for new therapeutic strategies.