Science for Life Laboratory, Department of Environmental Science, Stockholm University, 114 18 Stockholm, Sweden; Stockholm University Center for Circular and Sustainable Systems (SUCCeSS), Stockholm University, 106 91 Stockholm, Sweden.
Science for Life Laboratory, Department of Environmental Science, Stockholm University, 114 18 Stockholm, Sweden; Stockholm University Center for Circular and Sustainable Systems (SUCCeSS), Stockholm University, 106 91 Stockholm, Sweden.
Sci Total Environ. 2024 Nov 1;949:174864. doi: 10.1016/j.scitotenv.2024.174864. Epub 2024 Jul 20.
DNA methylation plays a pivotal role in cancer. The ubiquitous contaminant perfluorooctanesulfonic acid (PFOS) has been epidemiologically associated with breast cancer, and can induce proliferation and malignant transformation of normal human breast epithelial cells (MCF-10A), but the information about its effect on DNA methylation is sparse. The aim of this study was to characterize the whole-genome methylome effects of PFOS in our breast cell model and compare the findings with previously demonstrated DNA methylation alterations in breast tumor tissues. The DNA methylation profile was assessed at single CpG resolution in MCF-10A cells treated with 1 μM PFOS for 72 h by using Enzymatic Methyl sequencing (EM-seq). We found 12,591 differentially methylated CpG-sites and 13,360 differentially methylated 100 bp tiles in the PFOS exposed breast cells. These differentially methylated regions (DMRs) overlapped with 2406 genes of which 494 were long non-coding RNA and 1841 protein coding genes. We identified 339 affected genes that have been shown to display altered DNA methylation in breast cancer tissue and several other genes related to cancer development. This includes hypermethylation of GACAT3, DELEC1, CASC2, LCIIAR, MUC16, SYNE1 and hypomethylation of TTN and KMT2C. DMRs were also found in estrogen receptor genes (ESR1, ESR2, ESRRG, ESRRB, GREB1) and estrogen responsive genes (GPER1, EEIG1, RERG). The gene ontology analysis revealed pathways related to cancer phenotypes such as cell adhesion and growth. These findings improve the understanding of PFOS's potential role in breast cancer and illustrate the value of whole-genome methylome analysis in uncovering mechanisms of chemical effects, identifying biomarker candidates, and strengthening epidemiological associations, potentially impacting risk assessment.
DNA 甲基化在癌症中起着关键作用。普遍存在的污染物全氟辛烷磺酸（PFOS）已被流行病学与乳腺癌相关联，并且可以诱导正常人类乳腺上皮细胞（MCF-10A）的增殖和恶性转化，但有关其对 DNA 甲基化影响的信息却很少。本研究的目的是在我们的乳腺细胞模型中描述 PFOS 对全基因组甲基组的影响，并将这些发现与先前在乳腺肿瘤组织中证明的 DNA 甲基化改变进行比较。通过使用酶促甲基测序（EM-seq），在 MCF-10A 细胞中用 1 μM PFOS 处理 72 小时后，以单个 CpG 分辨率评估 DNA 甲基化谱。我们发现，在暴露于 PFOS 的乳腺细胞中，有 12,591 个差异甲基化 CpG 位点和 13,360 个差异甲基化 100bp 条带。这些差异甲基化区域（DMRs）与 2406 个基因重叠，其中 494 个是长非编码 RNA，1841 个是蛋白编码基因。我们鉴定了 339 个受影响的基因，这些基因在乳腺癌组织和其他与癌症发展相关的基因中显示出 DNA 甲基化的改变。这包括 GACAT3、DELEC1、CASC2、LCIIAR、MUC16、SYNE1 的高甲基化和 TTN 和 KMT2C 的低甲基化。在雌激素受体基因（ESR1、ESR2、ESRRG、ESRRB、GREB1）和雌激素反应基因（GPER1、EEIG1、RERG）中也发现了 DMRs。基因本体论分析揭示了与癌症表型相关的途径，如细胞粘附和生长。这些发现提高了对 PFOS 在乳腺癌中潜在作用的认识，并说明了全基因组甲基组分析在揭示化学效应机制、鉴定生物标志物候选物以及加强潜在影响风险评估的流行病学关联方面的价值。
