Department of Bioengineering, Cancer Center at Illinois, Micro and Nanotechnology Laboratory, University of Illinois at Urbana-Champaign, Urbana, IL, 61801, USA; Biomedical Research Center in Mills Breast Cancer Institute, Carles Foundation Hospital, Urbana, IL, 61801, USA.
Department of Bioengineering, Cancer Center at Illinois, Micro and Nanotechnology Laboratory, University of Illinois at Urbana-Champaign, Urbana, IL, 61801, USA; Biomedical Research Center in Mills Breast Cancer Institute, Carles Foundation Hospital, Urbana, IL, 61801, USA.
Food Chem Toxicol. 2020 Jul;141:111358. doi: 10.1016/j.fct.2020.111358. Epub 2020 Apr 18.
Perfluorooctanoic acid (PFOA) is a persistent and widespread industry-made chemical. Emerging evidence indicates that PFOA exposure could be meditated through DNA methylation, yet, the molecular mechanisms governing the epigenetic states have not been well established. In this study, we investigated the epigenetic alterations and inhibitory mechanisms upon PFOA exposure by identifying changes related to DNA methyltransferase (DNMT) with fluorescence correlation spectroscopy and stimulated emission depletion nanoscopy in human breast epithelial cells (MCF7). PFOA exposure at 100 and 200 μM altered the mobility of DNMT3A and inhibited the enzymatic activity of DNMT, resulting in global DNA demethylation. Moreover, PFOA significantly altered the heterochromatin organization, as noted by the distribution profile of histone 3 lysine 9 tri-methylation (H3K9me3) at 200 and 400 μM exposure levels with super-resolution microscopy. An increased redistribution around the periphery of the nucleus was noted with a more diffused distribution beyond the 200 μM exposure. Overall, exposure of PFOA resulted in DNA demethylation accompanied by altered expression patterns of DNMT1 and DNMT3A. These findings provided new insights on the epigenetic alterations and revealed an altered heterochromatin packaging upon exposure to PFOA, implicating a mechanistic mode of action of DNA demethylation through direct impacts on DNMTs and increasing susceptibility to diseases such as cancer.
全氟辛酸 (PFOA) 是一种持久且广泛存在的工业制造化学物质。新出现的证据表明，PFOA 暴露可能通过 DNA 甲基化来介导，然而，调节表观遗传状态的分子机制尚未得到很好的建立。在这项研究中，我们通过荧光相关光谱法和受激发射损耗纳米显微镜，在人乳腺上皮细胞 (MCF7) 中鉴定与 DNA 甲基转移酶 (DNMT) 相关的变化，研究了 PFOA 暴露引起的表观遗传改变和抑制机制。100 和 200 μM 的 PFOA 暴露改变了 DNMT3A 的迁移率，并抑制了 DNMT 的酶活性，导致全基因组去甲基化。此外，PFOA 还显著改变了异染色质的组织，这可以从组蛋白 3 赖氨酸 9 三甲基化 (H3K9me3) 在 200 和 400 μM 暴露水平下的分布模式中看出，采用超分辨率显微镜。在超过 200 μM 暴露时，核周围的重新分布明显增加，且分布更为弥散。总的来说，PFOA 的暴露导致 DNA 去甲基化，同时伴随着 DNMT1 和 DNMT3A 的表达模式改变。这些发现为表观遗传改变提供了新的见解，并揭示了 PFOA 暴露后异染色质包装的改变，暗示了通过直接影响 DNMTs 导致 DNA 去甲基化的作用机制，并增加了患癌症等疾病的易感性。
