Abstract

Perfluorooctane sulfonate (PFOS), a pervasive and persistent environmental pollutant, has been epidemiologically linked to thyroid disorders, but its toxic effect in papillary thyroid carcinoma (PTC) remains unclear. This study provides the clinical evidence that PFOS accumulates at significantly higher levels in human PTC tumor tissues compared to adjacent normal tissues ( p = 0.037), highlighting tissue-specific bioaccumulation. To investigate the health impact, we modeled chronic environmental exposure using human PTC cells treated with low, environmentally relevant concentrations of PFOS (0.01,0.05 μM). Chronic exposure markedly enhanced malignant phenotypes, including proliferation, migration, and invasion. Mechanistically, PFOS activated the PI3K/AKT/mTOR signaling pathway, which subsequently drove epithelial-mesenchymal transition (EMT), as shown by upregulation of β-catenin and SNAI1, and increased expression of matrix metalloproteinases (MMP-2 and MMP-9). These pro-tumor effects were partially reversed by pharmacological inhibitor BEZ235 for PI3K/mTOR. In vivo validation using a mouse xenograft model confirmed that PFOS exposure promotes tumor growth and upregulates the same pathway and effector molecules. This study provides integrated clinical and experimental evidence that PFOS exposure at environmentally relevant concentrations promotes PTC progression by inducing PI3K/AKT/mTOR-mediated EMT and associated enzyme secretion, providing crucial experimental evidence for the toxic role of PFOS as an environmental contaminant in thyroid tumors and underscoring the urgent need for enhanced environmental health risk assessment and regulation.