Gonyautoxins induce cytotoxicity in human intestinal Caco-2 cells: Oxidative stress, apoptosis, and transcriptional responses.

Human health risks posed by paralytic shellfish toxins (PSTs) are primarily attributed to the consumption of PSTs-contaminated shellfish. However, the specific cytotoxic effects of PSTs on human intestinal epithelial cells and their underlying molecular mechanisms remain poorly characterized. In this study, we investigated the cytotoxicity and mechanisms of PSTs on human intestinal Caco-2 cells, focusing on viability, oxidative stress, apoptosis, and transcriptional responses. Results demonstrated that 72 μmol L-1 of gonyautoxin 1-4 (GTX1-4) markedly reduced cell viability and concomitantly triggered apoptosis. Dose-dependent reactive oxygen species (ROS) overproduction was observed in both 7.2 and 72 μmol L-1 exposure groups, leading to significant lipid peroxidation with malondialdehyde (MDA) levels at 48 h increased by 5.4- and 7.5-fold, respectively. This oxidative stress overwhelmed antioxidant defenses, manifesting as superoxide dismutase (SOD) /catalase (CAT) inhibition alongside glutathione peroxidase (GSH-Px) upregulation. Transcriptomic analysis identified 8742 differentially expressed genes in high-toxin groups, enriched in pathways regulating signal transduction (phosphatidylinositol 3-kinase-protein kinase B (PI3K-AKT), mitogen-activated protein kinase (MAPK), tumor necrosis factor (TNF), ras-related protein 1 (Rap1)), stress responses (DNA repair, interleukin-17 (IL-17) signaling), and disease mechanisms. Transcriptomic results suggest that PSTs may induce a cytokine storm involving 38 upregulated genes and cell cycle dysfunction in Caco-2 cells. These findings provide critical insights into the enterotoxicity of PSTs and their potential health implications, and lay the groundwork for understanding PST hazards on human health.