Potential threat of environmental toxin palytoxin to cerebral nerves: A mechanism study in vitro and in vivo

Palytoxin (PTX), a toxin naturally synthesized by marine organisms like Palythoa, Ostreopsis and Trichodesmium spp. in tropical and temperate seas, bioaccumulates in fish and crustaceans, thereby exposing humans through the food chain. Although growing evidence highlights PTX's lethal hepatotoxicity, nephrotoxicity, and cardiotoxicity, its neurotoxic effects and the underlying mechanisms remain elusive. In this study, we assessed the cerebral neurotoxicity of PTX by using HT22 neuronal cells and a chronic mouse model, conducting a comprehensive analysis of phenotypic alterations and gene expression changes. Phenotypic analysis revealed significant damage to mitochondria, endoplasmic reticulum, and axons and disruptions in energy metabolism in PTX-treated neuronal cells and mouse brains. Transcriptome sequencing and real-time quantitative reverse transcription polymerase chain reaction indicated that key genes in the JNK/p38 MAPK signaling, mitochondrial stress, and endoplasmic reticulum stress pathways were significantly altered. Furthermore, pretreatment with JNK and p38 inhibitors significantly restored mitochondrial membrane potential, ATP content, and cell viability, while reducing the expression of pro-apoptotic genes in HT22 cells. These findings confirm that JNK/p38 MAPK signaling pathways activation, leading to mitochondrial stress, is a major contributor to PTX-induced neuronal cell death at the cellular level. Chronic exposure to PTX was shown to damage mammalian cerebral nerves, carrying a potential risk for neurodegenerative diseases. Our study provides insights into the environmental and health risks associated with PTX exposure and offers a foundation for risk assessment and intervention strategies.