Deciphering per- and polyfluoroalkyl substances mode of action: comparative gene expression analysis in human liver spheroids.

IF 4.1 3区 医学 Q2 TOXICOLOGY
Andrea Rowan-Carroll, Matthew J Meier, Carole L Yauk, Andrew Williams, Karen Leingartner, Lauren Bradford, Luigi Lorusso, Ella Atlas
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Abstract

Understanding the mechanisms by which environmental chemicals cause toxicity is necessary for effective human health risk assessment. High-throughput transcriptomics (HTTr) can be used to inform risk assessment on toxicological mechanisms, hazards, and potencies. We applied HTTr to elucidate the molecular mechanisms by which per- and polyfluoroalkyl substances (PFAS) cause liver perturbations. We contrasted transcriptomic profiles of PFOA, PFBS, PFOS, and PFDS against transcriptomic profiles from established liver-toxic and non-toxic reference compounds, alongside peroxisome proliferator-activated receptors (PPARs) agonists. Our analysis was conducted on metabolically competent 3-D human liver spheroids produced from primary cells from 10 donors. Pathway analysis showed that PFOS and PFDS perturb many of the same pathways as the known liver-toxic compounds in the spheroids, and that the cholesterol biosynthesis pathways are significantly affected by exposure to these compounds. PFOA alters lipid metabolism-related pathways but its expression profile does not closely match reference compounds. PFBS upregulates many degradation-related pathways and targets many of the same pathways as the PPAR agonists and acetaminophen. Our transcriptional analysis does not support the claim that these PFAS are DNA-damaging in this model. A multidimensional scaling (MDS) analysis revealed that PFOS, PFOA, and PFDS cluster together in the same multidimensional space as liver-damaging compounds, whereas PFBS clusters more closely with the non-liver-damaging compounds. Benchmark concentration-response modeling predicts that all the PFAS are bioactive in the liver. Overall, our results show that these PFAS produce unique transcriptional changes but also alter pathways associated with established liver-toxic chemicals in this liver spheroid model.

解读PFAS的作用方式:人肝球体中基因表达的比较分析。
了解环境化学品产生毒性的机制对于有效地评估人类健康风险是必要的。高通量转录组学(HTTr)可用于毒理学机制、危害和效力的风险评估。我们应用HTTr来阐明全氟和多氟烷基物质(PFAS)引起肝脏扰动的分子机制。我们将PFOA、PFBS、PFOS和PFDS的转录组谱与已建立的肝毒性和无毒参比化合物以及过氧化物酶体增殖激活受体(ppar)激动剂的转录组谱进行了对比。我们的分析是对来自10个供体的原代细胞产生的具有代谢能力的3-D人肝球体进行的。途径分析表明,PFOS和PFDS扰乱了球体中许多与已知肝毒性化合物相同的途径,并且暴露于这些化合物会显著影响胆固醇的生物合成途径。PFOA改变脂质代谢相关途径,但其表达谱与参考化合物不密切匹配。PFBS上调了许多与降解相关的途径,并且靶向许多与PPAR激动剂和对乙酰氨基酚相同的途径。我们的转录分析不支持这些PFAS在该模型中破坏DNA。多维尺度分析显示,全氟辛烷磺酸、全氟辛酸和PFDS与肝损伤化合物聚集在同一多维空间;而PFBS与非肝损伤化合物的聚集更紧密。基准浓度反应模型预测所有PFAS在肝脏中具有生物活性。总体而言,我们的研究结果表明,这些PFAS产生独特的转录变化,但也改变了与肝脏球形模型中已建立的肝毒性化学物质相关的途径。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Toxicological Sciences
Toxicological Sciences 医学-毒理学
CiteScore
7.70
自引率
7.90%
发文量
118
审稿时长
1.5 months
期刊介绍: The mission of Toxicological Sciences, the official journal of the Society of Toxicology, is to publish a broad spectrum of impactful research in the field of toxicology. The primary focus of Toxicological Sciences is on original research articles. The journal also provides expert insight via contemporary and systematic reviews, as well as forum articles and editorial content that addresses important topics in the field. The scope of Toxicological Sciences is focused on a broad spectrum of impactful toxicological research that will advance the multidisciplinary field of toxicology ranging from basic research to model development and application, and decision making. Submissions will include diverse technologies and approaches including, but not limited to: bioinformatics and computational biology, biochemistry, exposure science, histopathology, mass spectrometry, molecular biology, population-based sciences, tissue and cell-based systems, and whole-animal studies. Integrative approaches that combine realistic exposure scenarios with impactful analyses that move the field forward are encouraged.
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