Per- and polyfluoroalkyl substances induce cytotoxicity in NCI-H446 cells through modulating proliferation,...

Per- and polyfluoroalkyl substances (PFAS), a class of environmental pollutants with strong environmental persistence and bioaccumulation. However, the potential impacts and related mechanisms on small cell lung cancer (SCLC) remain unclear. This study integrated techniques including CCK8, qRT-PCR, and Flow Cytometry in NCI-H446 cells to compare the cytotoxicity of perfluorooctanoic acid (PFOA, a representative traditional PFAS) and its substitute Gen-X, and explore their associated mechanisms with cell proliferation, apoptosis, and m⁶A epigenetic regulation. Results showed both PFOA and Gen-X exerted significant toxicity on NCI-H446 cells, with Gen-X being less toxic than PFOA. Low-concentration PFOA (10 μM) significantly promoted cell proliferation, while Gen-X showed no such effect at the same concentration. At elevated exposure concentrations (100, 400 μM), both PFOA and Gen-X significantly inhibited cell proliferation and induced cell apoptosis. Additionally, they notably altered the expression of key regulators of cellular m⁶A methylation modification (e.g., WTAP, YTHDF1/3), with PFOA interfering more significantly with the m⁶A regulatory network than Gen-X. This study elucidates the distinct toxic effects of PFOA and its substitute Gen-X on SCLC cells, revealing their mechanisms through proliferation, apoptosis, and m⁶A regulation, thereby providing new insights into PFAS-related lung cancer risk and environmental health assessment.