全氟辛烷磺酸对人骨髓间充质干细胞成神经分化的损伤作用
Effects of Perfluorooctane Sulfonate on Neuronal Differentiation of Human Bone Marrow Mesenchymal Stem Cells
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摘要: 流行病学结果显示全氟辛烷磺酸(perfluorooctane sulfonate, PFOS)暴露与儿童认知能力降低相关，动物毒理学研究表明围产期PFOS暴露造成子代认知能力下降等神经损伤。但是发育中神经系统对PFOS暴露响应更敏感的毒理学机制尚不清楚。本研究基于人骨髓间充质干细胞(human bone marrow derived mesenchymal stem cells, hBMSCs)体外神经分化模型，评估环境相关浓度PFOS暴露对不同分化阶段细胞的毒性效应。在无显著细胞毒性浓度下，分化过程中暴露于20～500 nmol·L-1 PFOS对神经元突触产生抑制效应并呈剂量依赖性，抑制率为24.2%～43.9%。细胞经诱导成神经分化后暴露于PFOS，仅在500 nmol·L-1暴露组产生了显著抑制效应，抑制率为17.7%。通过免疫荧光染色检测神经元标志物微管相关蛋白2 (microtubule-associated protein 2, MAP2)，分化过程中100 nmol·L-1和500 nmol·L-1的PFOS暴露显著抑制了MAP2的表达，抑制率分别为15.9%和18.6%，但分化后PFOS暴露未对MAP2表达产生显著影响。通过对Ca2+进行实时成像及图像捕捉，发现PFOS暴露刺激成神经分化的细胞钙瞬变，500 nmol·L-1的PFOS暴露诱导钙瞬变峰值F/F0升高至对照组的1.25倍，提示细胞成神经分化及神经元信号转导等受到干扰。研究结果发现成神经分化过程中细胞对PFOS暴露更为敏感，从细胞分化层面提示了PFOS发育神经毒性的潜在毒理机制，须进一步研究PFOS对细胞分化和细胞命运的敏感靶标，为该类新污染物的健康风险评价和管控提供依据。Abstract: Epidemiological studies have shown that perfluorooctane sulfonate (PFOS) exposure is associated with cognitive decline in children. Toxicological studies in animals showed that perinatal PFOS exposure caused cognitive decline and other neurological damage in offspring. However, the potential toxicological mechanisms underlying the sensitive response of the developmental nervous system to PFOS exposure remain unclear. Employing an in vitro neural differentiation model of human bone marrow mesenchymal stem cells (hBMSCs), the present study evaluated the toxic effects of environmentally relevant concentrations of PFOS at different stages of differentiation. In the absence of significant cytotoxicity, 20~500 nmol·L-1 PFOS exposure during differentiation inhibited neuronal synaptogenesis in a dose-dependent manner, with inhibition ranging from 24.2% to 43.9%. PFOS exposure in differentiated cells produced significant inhibitory effects only at 500 nmol·L-1, where the neurite outgrowth was repressed by 17.7%. The neuronal biomarker microtubule-associated protein 2 (MAP2) was detected by immunofluorescence staining. Exposure to PFOS at 100 nmol·L-1 and 500 nmol·L-1 during differentiation significantly inhibited the expression of MAP2, by 15.9% and 18.6%, respectively. Exposure to PFOS after differentiation had no significant effects on MAP2 expression. The real-time imaging and image capture of Ca2+ showed that PFOS stimulated the calcium transient of differentiated cells, where 500 nmol·L-1 of PFOS induced a calcium transient with peak F/F0 increasing to 1.25 folds of control, suggesting that neural differentiation and neuronal signal transduction were disturbed. The results showed that the cells during neural differentiation were more sensitive to PFOS exposure, suggesting the potential toxicological mechanism underlying the developmental neurotoxicity of PFOS based on impairment in cell differentiation. Further studies are needed to identify the sensitive targets of PFOS in cell differentiation and cell fate, to provide a basis for health risk assessment and control of this category of new pollutants.
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