体外筛选未充分研究的全氟辛烷磺酸,重点关注脂质代谢干扰。

IF 4.8 2区 医学 Q1 TOXICOLOGY Archives of Toxicology Pub Date : 2024-07-02 DOI:10.1007/s00204-024-03814-2
Lackson Kashobwe, Faezeh Sadrabadi, Albert Braeuning, Pim E. G. Leonards, Thorsten Buhrke, Timo Hamers
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引用次数: 0

摘要

全氟烷基和多氟烷基物质(PFAS)是一种人造化学品,被广泛应用于许多工业领域。接触 PFAS 与多种健康风险有关,包括婴儿出生体重下降、肝中毒、脂质代谢紊乱和免疫反应下降。我们利用体外细胞模型筛选了六种研究较少的全氟辛烷磺酰胺(PFOSA)、全氟戊酸(PFPeA)、全氟丙酸(PFPrA)、6:2 氟代醇(6:2 FTOH)、6:全氟丙酸(PFPrA)、6:2 氟特醇(6:2 FTOH)、6:2 氟特磺酸(6:2 FTSA)和 8:2 氟特磺酸(8:2 FTSA)],以检测它们激活核受体和导致脂质代谢相关基因差异表达的能力。同时进行细胞毒性试验,以排除观察到的不同基因表达是由于细胞毒性引起的。根据细胞毒性试验和基因表达研究结果,全氟辛烷磺酸比其他测试过的全氟辛烷磺酸更有效。全氟辛烷磺酸会降低参与胆汁酸合成和解毒、胆固醇合成、胆汁酸和胆固醇转运以及脂质代谢调节的关键基因的基因表达。除 6:2 FTOH 和 8:2 FTSA 外,所有测试的 PFAS 都会降低 PPARA 基因的表达。报告基因分析还显示,8:2 FTSA 能使类脂质 X 受体(FXR)发生转录。基于这项研究,PFOSA、6:2 FTSA 和 8:2 FTSA 被列为进一步研究的优先对象,以确认和了解它们对肝脏脂质代谢可能产生的影响。
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In vitro screening of understudied PFAS with a focus on lipid metabolism disruption

Per- and polyfluoroalkyl substances (PFAS) are man-made chemicals used in many industrial applications. Exposure to PFAS is associated with several health risks, including a decrease in infant birth weight, hepatoxicity, disruption of lipid metabolism, and decreased immune response. We used the in vitro cell models to screen six less studied PFAS [perfluorooctane sulfonamide (PFOSA), perfluoropentanoic acid (PFPeA), perfluoropropionic acid (PFPrA), 6:2 fluorotelomer alcohol (6:2 FTOH), 6:2 fluorotelomer sulfonic acid (6:2 FTSA), and 8:2 fluorotelomer sulfonic acid (8:2 FTSA)] for their capacity to activate nuclear receptors and to cause differential expression of genes involved in lipid metabolism. Cytotoxicity assays were run in parallel to exclude that observed differential gene expression was due to cytotoxicity. Based on the cytotoxicity assays and gene expression studies, PFOSA was shown to be more potent than other tested PFAS. PFOSA decreased the gene expression of crucial genes involved in bile acid synthesis and detoxification, cholesterol synthesis, bile acid and cholesterol transport, and lipid metabolism regulation. Except for 6:2 FTOH and 8:2 FTSA, all tested PFAS downregulated PPARA gene expression. The reporter gene assay also showed that 8:2 FTSA transactivated the farnesoid X receptor (FXR). Based on this study, PFOSA, 6:2 FTSA, and 8:2 FTSA were prioritized for further studies to confirm and understand their possible effects on hepatic lipid metabolism.

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来源期刊
Archives of Toxicology
Archives of Toxicology 医学-毒理学
CiteScore
11.60
自引率
4.90%
发文量
218
审稿时长
1.5 months
期刊介绍: Archives of Toxicology provides up-to-date information on the latest advances in toxicology. The journal places particular emphasis on studies relating to defined effects of chemicals and mechanisms of toxicity, including toxic activities at the molecular level, in humans and experimental animals. Coverage includes new insights into analysis and toxicokinetics and into forensic toxicology. Review articles of general interest to toxicologists are an additional important feature of the journal.
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