Objective The aim is to investigate the neurotoxicity of PFOS and its mechanism, and to provide experimental evidence for further study on the neurotoxicity of PFOS.Methods The experiment was divided into two groups, the control (0 μM) and the PFOS groups(1, 10, 50, 100, 150, 200 μM).The cell viability and time-efficiency of SH-SY5Y were determined by CCK8, the morphology and rate of apoptosis were tested by AO-EB dual fluorescent labeling and Annexin-Ⅴ FITC/PI double-staining, respectively.The effect of PFOS on oxidative stress damage in SH-SY5Y cells was detected by UV spectrophotometry and fluorescence methods.QPCR method was used to detect the effects of PFOS on has-miR-16, has-rniR-22, which could regulate BDNF mRNA translation in post-transcription level, and the mRNA expression levels of BDNF, ERK/1/2, CREB in SH-SY5Y cells.Elisa was used to detect the expression level of BDNF protein on SH-SY5Y cell supernatant.The protein expression levels such as TrkB, ERK1/2, pERK1/2, CREB, pCREB in SH-SY5Y cell were detected by Western Blot method.Results The outcomes of CCK8 test showed a drop of survival rate in a time-dose effective relationship.The apoptosis rate increased in correlating with the PFOS concentration for 48 hours after contamination indicated by both AO-EB dual fluorescent observation and Annexin-V FITC/PI dual-dyeing flow-cytometry.The results of UV and fluorescence spectrophotometry showed that PFOS induced SH-SY5Y cell superoxide dismutase (SOD) and glutathione reductase (GSH) decreased, compared with the control, the highest group of PFOS decreased GSH from 8.00±0.12 nmol/mg protein to 5.89±0.90 nmol/mg protein.While the total reactive oxygen species (ROS) and malondialdehyde (MDA) levels increased, compared with the control, the highest group of PFOS elevated MDA from 1.92±0.17 nmol/mg protein to 6.95±0.26 nmol/mg protein.QPCR and Western Blot results showed that PFOS disturbs BDNF-ERK-CREB signaling in association with increased microRNA-22 in SH-SY5Y cells, compared with the control, the BDNF protein expression levels in culture supemant of 100μM group decreased from 60±1.2 ng/mL to 29±1.5 ng/mL.Conclusions ① PFOS exposure decreased the cell viability of SH-SY5Y cells, induced SH-SY5Y cells apoptosis and produced oxidative stress damage in a dose-dependent manner.② PFOS disturbed BDNF-ERK-CREB signaling pathway in association with increased microRNA-22 in SH-SY5Y cells, and may be one of the mechanisms of the neurotoxicity of PFOS.