Unveiling the neurodevelopmental toxicity of PFOA and PFOS: evidence from integration of in silico and in vitro study

Perfluorooctanoic acid (PFOA) and perfluorooctane sulfonate (PFOS) are well-known neurodevelopmental toxicants, but the potential molecular mechanism needs to be further clarified. This study aimed to investigate the underlying mechanism of PFOA and PFOS-induced neurodevelopmental toxicity by integrating network toxicology, transcriptomic data from autism spectrum disorder patients and in vitro study. Network toxicology identified 42 core targets that enriched in a total of 105 significant GO entries and 142 KEGG pathways. With the disease-context comparison from the transcriptomic, 10 hub targets and 22 common KEGG pathways were identified. Cellular senescence-associated responses including cellular senescence and cell cycle were proposed as one of the potential mechanisms underlying PFOA and PFOS co-exposure-induced neurodevelopmental toxicity. Molecular docking analysis showed that PFOA and PFOS elicits potential binding capacities with hub targets, with TP53 and MAPK 13 exhibiting lower binding affinities with both PFASs, further predicting the potential role of these targets in PFASs-induced neurodevelopmental toxicity. After PFOA and PFOS co-treatment, reduced cell viability, a senescence-like phenotype characterized by cell cycle arrest and increased positive senescence β-galactosidase, upregulation of senescence-associated biomarkers including TP53, p53, p21 and IL-6 as well as the significant up-regulation of MAPK1, MAPK3, MAPK13 and MAPK14 genes were observed in human neuroblastoma SH-SY5Y cells. Thereafter, these findings suggested the multi-target and multi-pathway characteristic of PFOA and PFOS co-exposure-induced neurodevelopmental toxicity with cellular senescence-associated responses as one of the potential molecular mechanisms.