Early atherosclerotic phenotypic alterations induced by PFOS exposure: a network toxicology and zebrafish model study

Perfluorooctane sulfonate (PFOS), a typical persistent emerging environmental contaminant, is closely correlated with increased cardiovascular disease risks. Atherosclerosis serves as the core pathological basis of cardiovascular disorders, yet the explicit molecular mechanism underlying PFOS-induced pro-atherosclerotic toxicity remains unclear, limiting the assessment of its environmental cardiovascular hazards. This study integrated network toxicology prediction, in silico molecular docking and in vivo zebrafish experiments to explore the key signaling axis and pathogenic mechanism of PFOS-aggravated atherosclerosis. We screened overlapping target genes of PFOS toxicity and atherosclerosis, identified core hub genes and enriched pathways, validated PFOS-protein binding affinity via molecular docking, and verified in vivo toxic phenotypes and key gene expression changes through zebrafish exposure assays. Sixty overlapping target genes were screened, with 10 hub genes (predominantly CCL2 and CCR2) significantly enriched in cytokine-receptor interaction and chemokine signaling pathways. All core hub proteins exhibited high binding affinity with PFOS, with binding energies below − 6 kcal/mol. In vivo results confirmed that PFOS exposure triggered dose-dependent developmental toxicity, lipid metabolism disorder, excessive inflammatory infiltration, and significant upregulation of CCL2 and CCR2 in zebrafish. PFOS exposure was associated with exacerbated early atherosclerotic lesions, possibly through disrupted lipid homeostasis and activation of the CCL2/CCR2 inflammatory cascade, which may serve as an upstream driver of vascular inflammation and macrophage infiltration. This integrated computational and in vivo study characterizes key pathogenic events associated with PFOS cardiovascular toxicity, provides correlative molecular insights into the pro-atherosclerotic effects of PFOS, and identifies potential biomarker candidates for the toxicological safety evaluation of emerging per- and polyfluoroalkyl substance (PFAS) alternatives.