School of Public Health and Community Medicine, Institute of Medicine, University of Gothenburg, Gothenburg, Sweden.
CANSEARCH Research Laboratory, Faculty of Medicine, University of Geneva, Geneva, Switzerland.
Environ Int. 2020 Mar;136:105446. doi: 10.1016/j.envint.2019.105446. Epub 2020 Jan 8.
Perfluoroalkyl substances (PFAS) are widespread synthetic substances with various adverse health effects. Not much is known about the modes of action of PFAS toxicity, but one likely mechanism is alteration of microRNA expression.
To investigate whether PFAS exposure is associated with altered microRNA expression in serum.
We selected women from the Ronneby cohort, with high exposure to perfluorooctane sulfonic acid (PFOS) and perfluorohexane sulfonic acid (PFHxS), emanating from drinking water contaminated by firefighting foam, and a control group of women from a neighbouring municipality without drinking water contamination. Serum levels of PFAS were analysed using LC/MS/MS. High coverage microRNA expression was analysed by next generation sequencing (NGS) in 53 individuals to screen for microRNAs associated with PFAS exposure. After verification by qPCR, associations between PFAS exposure and expression of 18 selected microRNAs were validated by qPCR in 232 individuals. In silico functional analyses were performed using Ingenuity pathway analysis (IPA).
Three microRNAs were consistently associated with PFAS exposure in the different steps of the study: miR-101-3p, miR-144-3p and miR-19a-3p (all downregulated with increasing exposure). In silico functional analyses suggested that these PFAS-associated microRNAs were annotated to e.g. cardiovascular function and disease, Alzheimer's disease, growth of cancer cell lines and cancer. Seven predicted target genes for the downregulated microRNAs were annotated to PFAS in IPA knowledge database: DNA methyltransferase 3 alpha (DNMT3a), epidermal growth factor receptor (EGFR), 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR), nuclear receptor subfamily 1, group H, member 3 (NR1H3), peroxisome proliferator-activated receptor alpha (PPARα), prostaglandin-endoperoxide synthase 2 (PTGS2), and tumour growth factor alpha (TGFα).
PFAS exposure was associated with downregulation of specific microRNAs. Further, in silico functional analyses suggest potential links between the specific PFAS-associated microRNAs, specific microRNA target genes and possibly also health effects.
全氟烷基物质（PFAS）是广泛存在的合成物质，具有多种不良健康影响。关于 PFAS 毒性的作用机制知之甚少，但一种可能的机制是改变 microRNA 的表达。
研究 PFAS 暴露是否与血清中 microRNA 表达的改变有关。
我们从 Ronneby 队列中选择了一些女性，她们的饮用水受到了来自消防泡沫的污染，水中含有高浓度的全氟辛烷磺酸（PFOS）和全氟己烷磺酸（PFHxS），而对照组的女性来自没有饮用水污染的相邻市镇。使用 LC/MS/MS 分析血清中的 PFAS 水平。通过下一代测序（NGS）在 53 名个体中进行高覆盖率 microRNA 表达分析，以筛选与 PFAS 暴露相关的 microRNAs。通过 qPCR 验证后，在 232 名个体中通过 qPCR 验证了 18 个选定的 microRNA 与 PFAS 暴露之间的关联。使用 Ingenuity 通路分析（IPA）进行了计算机模拟功能分析。
在研究的不同步骤中，有三个 microRNA 与 PFAS 暴露始终相关：miR-101-3p、miR-144-3p 和 miR-19a-3p（随着暴露的增加而下调）。计算机模拟功能分析表明，这些与 PFAS 相关的 microRNA 被注释为心血管功能和疾病、阿尔茨海默病、癌细胞系的生长和癌症等。IPA 知识库中下调的 microRNA 的七个预测靶基因被注释为 PFAS：DNA 甲基转移酶 3α（DNMT3a）、表皮生长因子受体（EGFR）、3-羟基-3-甲基戊二酰基辅酶 A 还原酶（HMGCR）、核受体亚家族 1、组 H、成员 3（NR1H3）、过氧化物酶体增殖物激活受体α（PPARα）、前列腺素内过氧化物合酶 2（PTGS2）和肿瘤生长因子α（TGFα）。
PFAS 暴露与特定 microRNA 的下调有关。此外，计算机模拟功能分析表明，特定的与 PFAS 相关的 microRNA、特定的 microRNA 靶基因之间可能存在联系，并且可能与健康影响也存在联系。
