全氟辛烷磺酸(PFOS)对人骨髓间充质干细胞PPARs亚型及分化潜能的影响
Interference of Perfluorooctane Sulfonate (PFOS) on PPARs Subtypes and Differentiation Potential in Human Bone Marrow Mesenchymal Stem Cells
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摘要: 过氧化物酶体增殖物激活受体（peroxisome proliferators-activated receptors， PPARs）是全氟辛烷磺酸（perflurooctane sulfonate， PFOS）的首要分子靶标，但PPARs各亚型在PFOS毒性效应中可能产生不同调控作用，相关机理并不清楚。本研究采用人骨髓间充质干细胞体外分化模型，研究PFOS暴露对PPARs亚型的干扰，及其与细胞分化之间的关联。结果显示，PFOS在0.1、1和10 μmol·L-1浓度下诱导PPARα、PPARβ和PPARγ的mRNA表达水平上调，在1 μmol·L-1浓度下分别最高上调至对照组的6.31倍、6.44倍和15.4倍。与PPARγ激活一致，PFOS促进细胞成脂分化，脂质形成升高。同时，PFOS暴露抑制细胞成骨分化，钙结节形成下降，成骨分化早期标志物基因Runt相关转录因子2（runt-related transcription factor 2， Runx2）和碱性磷酸酶（alkaline phosphatase， ALP）表达下调。此外，PFOS作用下，细胞基因表达谱中差异表达基因的富集分析显示，受干扰的通路主要涉及细胞分化、骨代谢和脂质代谢相关通路。相反，PFOS暴露使骨保护素的mRNA水平升高，与PPARβ上调一致。研究结果提示，PFOS对PPARs各亚型的激活在对干细胞分化的干扰效应中可能产生不同的作用，有必要进一步研究，以深入理解全氟多氟烷基化合物的毒性机制。
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关键词:
- 全氟辛烷磺酸 /
- 干细胞 /
- 过氧化物酶体增殖物激活受体 /
- 多向分化潜能
Abstract: Peroxisome proliferators-activated receptors (PPARs) are the primary targets of perflurooctane sulfonate (PFOS). However, three subtypes of PPARs may exert diverse effects on the toxic response induced by PFOS, whereas related mechanism remains unclear. In the present study, an in vitro differentiation model of human bone marrow-derived mesenchymal stem cells (hBMSCs) was employed to evaluate the interference of PFOS exposure on PPARs subtypes and the association with abnormal cell differentiation. The results showed that PFOS induced upregulation of mRNA expression of PPARα, PPARβ, and PPARγ at concentrations of 0.1, 1 and 10 μmol·L-1, up to 6.31 folds, 6.44 folds, and 15.4 folds in the treatment group of 1 μmol·L-1 of PFOS compared to vehicle control. Being consistent with PPARγ activation, PFOS promoted adipogenic differentiation and increased lipid formation in hBMSCs. Meanwhile, PFOS exposure inhibited osteogenic differentiation, decreased calcium nodule formation, and reduced the expression of runt-related transcription factor 2 (Runx2) and alkaline phosphatase (ALP), which are the marker genes of early osteogenic differentiation. In addition, the enrichment analysis of differentially expressed genes affected by PFOS in the gene profile of hBMSCs revealed that the disturbed pathways were mainly related to cell differentiation, bone metabolism and lipid metabolism. In contrast, PFOS exposure increased the mRNA expression of osteoprotectin, consistent with the upregulation of PPARβ. The results demonstrate that the activation of PPARs subtypes by PFOS may exert different effects on stem cell differentiation. Further research is necessary to gain an insight to understand the toxicity mechanism of per-and polyfluoroalkyl compounds. -
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