Developmental Neurotoxicity Of Perfluorooctane Sulfonate By Prenatal Exposure

Perfluorooctane sulfonate (PFOS), which is a kind of fluorine-saturated eight-carbon compounds belonged to the degradation product of many perfluorinated compounds, has been used in a variety of commercial and industrial applications. Since 1950s, concentration of PFOS in the environment increased gradually. PFOS is believed to be an emerging persistent organic pollutant because of its worldwide distribution, extreme stability and bioaccumulative nature. Recent years studies indicated that the scope and extent of environmental contamination caused by PFOS had gone beyond our anticipation. In 2001, it was classified as a kind of persistent organic pollutants by environmental protection agency of U.S and should be strictly administered. The study of toxicity about PFOS has been become one of the hotspots of toxicology research.Scientific research have showed that PFOS can cause body weight of experimental animals lessen, liver hyperplasia, lipid metabolism and energy metabolism disorders, hormone metabolic disorders, embryonic toxicity and and potentially developmental neurotoxicity. Since PFOS can across the placental barrier and the blood brain barrier and can accumulate embryonic brain tissue, the developmental neurotoxicity has been attracted more attention. Recent studies show that prenatal and lactation exposure to PFOS exposure lead to the impairment of offspring movement function and cognitive function. Although PFOS is a potentially developmental nerve poison, its toxic effect mechanism is unclear. This study will explore that prenatal exposure to PFOS may cause offspring neurotoxicity and its mechanisms. It provides the experimental and theoretical basis for the evaluation of the potential health effects of PFOS. PartⅠ:Gene expression profiling in the hippocampus of pups by prenatal exposure to PFOSObjective:To study the changes of gene expression profile in the hippocampus of pups by prenatal exposure to PFOS. Method:Pregnant Sprague Dawley (SD) rats were administrated 0.1,0.6, and 2.0mg/kg bw/day by gavage from gestation day (GD) 2 to GD21. Control received 0.5% Tween-20 vehicle (4mg/kg bw/day). PFOS concentrations in hippocampus of offspring were observed on postnatal day (PND) 0 and PND21. Agilent expression microarray was used to evaluate the changes of gene expression profile in the hippocampus of pups by prenatal exposure to PFOS. Results:PFOS was increased in serum, hippocampus and cortex in dose-dependent manner, and gradually decreased depending on time. The concentrations of PFOS in tissue on PNDO were higher than on PND21. The differentially expressed genes were related to cell cycle, cell apoptosis, long-term potentiation, calcium ion signal pathways, synapse, neurodegenerative diseases, inflammation, etc. Conclusion:Prenatal exposure to PFOS altered the expression of genes that were related to cell cycle, cell apoptosis, long-term potentiation, calcium ion signaling pathways, synapse, and inflammation.PartⅡ:The effect of inflammation-like glial response in offspring brain induced by prenatal PFOS exposureObjective:To study the effect of inflammation-like glial response in offspring brain induced by prenatal PFOS exposure. Method:Pregnant Sprague Dawley (SD) rats were given 0.1,0.6, and 2.0mg/kg bw/day by gavage from gestation day (GD) 2 to GD21. Control received 0.5% Tween-20 vehicle (4ml/kg bw/day). Reactive astrocytes were detected by GFAP of immunohistochemical staining. QPCR was used to detect mRNA level of GFAP, S100β, IL-1β, TNF-α, CREB, AP-1and NF-κb in offspring hippocampus and cortex. The protein level of GFAP was detected by western blot. Results:In 2.0mg/kg-d PFOS group, the mRNA levels of GFAP, S100β, IL-1β,TNF-α, CREB, AP-1and NF-κb were significantly increased compared with control group either on PNDO or on PND21. Compared with control, the protein levels of GFAP were significantly increased in all treated groups either on PNDO or on PND21. Conclusion:PFOS can increase the expression of inflammatory factor and transcription factor as well as active astrocyte, and lead to the inflammation-like glial response in offspring brain.PartⅢ:The effect of prenatal exposure to PFOS on synaptic ultra-structure of pupsObjective:To study the effect of prenatal exposure to PFOS on synaptic ultra-structure of pups. Method:Pregnant Sprague Dawley (SD) rats were adminstrated 0.1, 0.6, and 2.0mg/kg bw/day by gavage from gestation day (GD) 2 to GD21. Control received 0.5% Tween-20 vehicle (4mg/kg bw/day). QPCR was used to detect mRNA level of Synl and Syp in offspring hippocampus and cortex. The protein levels of Synl and Syp were detected by western blot. The synaptic ultra-structure of hippocampus was analyzed by electron microscope. Results:In 2.0mg/kg-d PFOS group, the expression of Synl and Syp in hippocampus were significant decreased compared with control group either on PNDO or on PND21. In cortex, the expression of Synl were significant decreased in PFOS-treated group, but the expression of Syp in cortex increased. In the hippocampus of PFOS exposed offspring, synaptic vesicles became decreased, active synaptic zone became shorter, and synaptic curvature became uneven.Conclusion:PFOS can change the expression of Syp and Synl as well as impair the synaptic ultra-structure, which may play an important role in the developmental neruotoxicity of PFOS.