潘一帆,
秦会,
张疆雨,
刘薇,
大连理工大学环境学院, 工业生态与环境工程教育部重点实验室, 大连 116024
作者简介: 郑璐(1993-),女,硕士,研究方向为干细胞环境毒理学,E-mail:zhenglulu@mail.dlut.edu.cn.
通讯作者: 刘薇,liu_wei@dlut.edu.cn
基金项目: 国家重点研发计划项目(2016YFC0401108);国家自然科学基金资助项目(21777020)中图分类号: X171.5
Interference of Perfluorooctane Sulfonate (PFOS) on PPARs Subtypes and Differentiation Potential in Human Bone Marrow Mesenchymal Stem Cells
Zheng Lu,Pan Yifan,
Qin Hui,
Zhang Jiangyu,
Liu Wei,
Key Laboratory of Industrial Ecology and Environmental Engineering of Ministry of Education, School of Environmental Science and Technology, Dalian University of Technology, Dalian 116024, China
Corresponding author: Liu Wei,liu_wei@dlut.edu.cn
CLC number: X171.5
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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。
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.
Key words:PFOS/
stem cells/
peroxisome proliferator-activated receptors/
multidirectional differentiation potential.
史亚利, 蔡亚岐. 全氟和多氟化合物环境问题研究[J]. 化学进展, 2014, 26(4):665-681Shi Y L, Cai Y Q. Study of per-and polyfluoroalkyl substances related environmental problems[J]. Progress in Chemistry, 2014, 26(4):665-681(in Chinese) |
周秀鹃, 盛南, 王建设, 等. 全氟和多氟化合物替代品的研究进展[J]. 生态毒理学报, 2017, 12(3):3-12Zhou X J, Sheng N, Wang J S, et al. The current research status of several kinds of fluorinated alternatives[J]. Asian Journal of Ecotoxicology, 2017, 12(3):3-12(in Chinese) |
Olsen G W, Burris J M, Ehresman D J, et al. Half-life of serum elimination of perfluorooctanesulfonate, perfluorohexanesulfonate, and perfluorooctanoate in retired fluorochemical production workers[J]. Environmental Health Perspectives, 2007, 115(9):1298-1305 |
王玉, 张倩, 刘薇, 等. 胚胎期和哺乳期全氟辛烷磺酸(PFOS)暴露致大鼠学习记忆能力下降[J]. 生态毒理学报, 2013, 8(5):671-677Wang Y, Zhang Q, Liu W, et al. Decline of learning and memory abilities in rats induced by prenatal and lactational exposure to perfluorooctane sulfonate (PFOS)[J]. Asian Journal of Ecotoxicology, 2013, 8(5):671-677(in Chinese) |
Matilla-Santander N, Valvi D, Lopez-Espinosa M J, et al. Exposure to perfluoroalkyl substances and metabolic outcomes in pregnant women:Evidence from the Spanish INMA birth cohorts[J]. Environmental Health Perspectives, 2017, 125(11):117004 |
DeWitt J C. Conclusions and Recommendations[M]//Toxicological Effects of Perfluoroalkyl and Polyfluoroalkyl Substances. Cham:Springer International Publishing, 2015:479-482 |
Jeon M J, Kim J A, Kwon S H, et al. Activation of peroxisome proliferator-activated receptor-γ inhibits the Runx2-mediated transcription of osteocalcin in osteoblasts[J]. Journal of Biological Chemistry, 2003, 278(26):23270-23277 |
Scholtysek C, Katzenbeisser J, Fu H, et al. PPARβ/δ governs Wnt signaling and bone turnover[J]. Nature Medicine, 2013, 19(5):608-613 |
Betts K S. Growing knowledge:Using stem cells to study developmental neurotoxicity[J]. Environmental Health Perspectives, 2010, 118(10):A432-A437 |
Kumar V, Jahan S, Singh S, et al. Progress toward the development of in vitro model system for chemical-induced developmental neurotoxicity:Potential applicability of stem cells[J]. Archives of Toxicology, 2015, 89(2):265-267 |
Pan Y F, Qin H, Liu W, et al. Effects of chlorinated polyfluoroalkyl ether sulfonate in comparison with perfluoroalkyl acids on gene profiles and stemness in human mesenchymal stem cells[J]. Chemosphere, 2019, 237:124402 |
Liu W, Qin H, Pan Y F, et al. Low concentrations of perfluorooctane sulfonate repress osteogenic and enhance adipogenic differentiation of human mesenchymal stem cells[J]. Toxicology and Applied Pharmacology, 2019, 367:82-91 |
Tian Y P, Zhou Y, Miao M H, et al. Determinants of plasma concentrations of perfluoroalkyl and polyfluoroalkyl substances in pregnant women from a birth cohort in Shanghai, China[J]. Environment International, 2018, 119:165-173 |
Khalil N, Chen A M, Lee M, et al. Association of perfluoroalkyl substances, bone mineral density, and osteoporosis in the US population in NHANES 2009-2010[J]. Environmental Health Perspectives, 2016, 124(1):81-87 |
Gao Y, Fu J J, Cao H M, et al. Differential accumulation and elimination behavior of perfluoroalkyl acid isomers in occupational workers in a manufactory in China[J]. Environmental Science & Technology, 2015, 49(11):6953-6962 |
Yang C, Tibbitt M W, Basta L, et al. Mechanical memory and dosing influence stem cell fate[J]. Nature Materials, 2014, 13(6):645-652 |
Ye K, Wang X, Cao L P, et al. Matrix stiffness and nanoscale spatial organization of cell-adhesive ligands direct stem cell fate[J]. Nano Letters, 2015, 15(7):4720-4729 |
李曦. 骨质疏松症相关表型的全基因组关联研究——单变量、双变量、通路及基因相互作用分析[D]. 长沙:湖南师范大学, 2011:80 Li X. Genome-wide association study for osteoporosis related phenotypes-Univariate, bivariate, pathway and gene-gene interaction analyses[D]. Changsha:Hunan Normal University, 2011:80(in Chinese) |
Yoshida K, Sanada M, Shiraishi Y, et al. Frequent pathway mutations of splicing machinery in myelodysplasia[J]. Nature, 2011, 478(7367):64-69 |
Vanden Heuvel J P, Thompson J T, Frame S R, et al. Differential activation of nuclear receptors by perfluorinated fatty acid analogs and natural fatty acids:A comparison of human, mouse, and rat peroxisome proliferator-activated receptor-alpha, -beta, and -gamma, liver X receptor-beta, and retinoid X receptor-alpha[J]. Toxicological Sciences, 2006, 92(2):476-489 |
Li C H, Ren X M, Ruan T, et al. Chlorinated polyfluorinated ether sulfonates exhibit higher activity toward peroxisome proliferator-activated receptors signaling pathways than perfluorooctanesulfonate[J]. Environmental Science & Technology, 2018, 52(5):3232-3239 |
Kramer I, Halleux C, Keller H, et al. Osteocyte wnt/β-catenin signaling is required for normal bone homeostasis[J]. Molecular and Cellular Biology, 2010, 30(12):3071-3085 |