Mechanistic insights into the neurotoxicity of F53B: Effects on metabolic dysregulation and apoptosis of dopaminergic neurons

F53B (6:2 chlorinated polyfluorinated ether sulfonate), a substitute for perfluorooctane sulfonate (PFOS), is widely used as a chromium mist inhibitor in the electroplating industry. However, significant concern has arisen owing to its biological toxicity. Several studies on F53B toxicity in mammals have focused on hepatotoxicity, immunotoxicity, developmental toxicity, and reproductive toxicity, while its neurotoxic effects, especially in relation to neurodegenerative diseases such as Parkinson's disease (PD), remain unclear. In this study, we investigated the neurotoxic effects of F53B on dopaminergic neurons and explored its potential risk associated with PD in a cellular model. Potential target prediction and validation experiments demonstrated that F53B induced apoptosis in dopaminergic neurons. We also discovered that F53B triggered oxidative stress and inflammatory responses, and stimulated nitric oxide (NO) generation in the PD cellular model. Subsequently, untargeted metabolomics and lipidomics approaches were integrated to explore the molecular mechanisms underlying the response of dopaminergic neurons to F53B exposure. The results suggested that F53B disrupted arginine and proline metabolism, energy metabolism, and caused lipid dysregulation, particularly promoting the hydrolysis of sphingomyelin (SM) into ceramide (Cer). Overall, this study provides evidence that F53B exposure could increase the potential risk of PD and offers novel insights into its neurotoxicity mechanisms.