Department of Pharmaceutical Sciences, Irma Lerma Rangel College of Pharmacy , Texas A&M Health Science Center , 312 REYN, MS 1114 , College Station , Texas 77843 , United States.
Chem Res Toxicol. 2019 Oct 21;32(10):2016-2027. doi: 10.1021/acs.chemrestox.9b00198. Epub 2019 Sep 20.
Organic compounds have been linked to adverse pregnancy complications. Perfluorooctanesulfonic acid (PFOS), a man-made fluorosurfactant and global pollutant, has been shown to induce oxidative stress in various cell types. Oxidative stress plays a key role in leading several placental diseases including preeclampsia (PE), gestational diabetes, spontaneous abortion, preterm labor, and intrauterine growth restriction. Recently, epigenetic regulation such as histone modifications, DNA methylation, and microRNAs (miRNAs), are shown to be associated with oxidative stress as well as pregnancy complications such as PE. However, whether PFOS exerts its detrimental effects in the placenta through epigenetics remains to be unveiled. Therefore, we aimed to investigate the effect of PFOS-induced reactive oxygen species (ROS) generation in first trimester human trophoblast cell line (HTR-8/SV) and whether epigenetic regulation is involved in this process. When treated with a range of PFOS doses at 24 and 48 h, even at 10 μM, it significantly increased the ROS production and decreased gene and protein expression, respectively, of the DNA methyltransferases DNMT1 ( < 0.001; < 0.05), DNMT3A ( < 0.001; < 0.05), and DNMT3B ( < 0.01; < 0.01) and the sirtuins, for example, SIRT1 ( < 0.001; < 0.001) and SIRT3 ( < 0.001; < 0.05), while reducing global DNA methylation ( < 0.01) and increasing protein lysine acetylation ( < 0.001) as compared to vehicle controls. Interestingly, PFOS (10 μM) significantly increased miR29-b ( < 0.01), which has been previously reported to be associated with PE. The observed epigenetic effects were shown to be dependent on the expression of miR-29b, as knockdown of miR-29b significantly alters the gene and protein expression of DNMT1, DNMT3A, DNMT3B, SIRT1, and SIRT3 and ROS production as well as global DNA methylation and protein acetylation. This study provides for the first time a novel insight into PFOS-induced ROS generation via regulation of sets of the interactive epigenetic circuit in the placenta, which may lead to pregnancy complications.
有机化合物与不良妊娠并发症有关。全氟辛烷磺酸（PFOS），一种人造氟表面活性剂和全球性污染物，已被证明会在各种细胞类型中诱导氧化应激。氧化应激在导致几种胎盘疾病（包括子痫前期（PE）、妊娠糖尿病、自然流产、早产和宫内生长受限）中起着关键作用。最近，表观遗传调控，如组蛋白修饰、DNA 甲基化和 microRNAs（miRNAs），已被证明与氧化应激以及子痫前期等妊娠并发症有关。然而，PFOS 是否通过表观遗传途径对胎盘产生有害影响仍有待揭示。因此，我们旨在研究 PFOS 诱导的活性氧（ROS）生成在第一孕期人滋养层细胞系（HTR-8/SV）中的作用，以及表观遗传调控是否参与这一过程。当用一系列 PFOS 剂量（24 和 48 小时）处理时，即使在 10 μM 时，它也显著增加了 ROS 的产生，并分别降低了 DNA 甲基转移酶 DNMT1（<0.001；<0.05）、DNMT3A（<0.001；<0.05）和 DNMT3B（<0.01；<0.01）以及沉默调节蛋白，例如 SIRT1（<0.001；<0.001）和 SIRT3（<0.001；<0.05）的基因和蛋白表达，同时降低了整体 DNA 甲基化（<0.01）并增加了蛋白质赖氨酸乙酰化（<0.001）与载体对照相比。有趣的是，PFOS（10 μM）显著增加了 miR29-b（<0.01），这之前已被报道与 PE 有关。观察到的表观遗传效应依赖于 miR-29b 的表达，因为 miR-29b 的敲低显著改变了 DNMT1、DNMT3A、DNMT3B、SIRT1 和 SIRT3 的基因和蛋白表达以及 ROS 的产生以及整体 DNA 甲基化和蛋白质乙酰化。这项研究首次提供了一个新的见解，即 PFOS 通过调节胎盘内相互作用的表观遗传电路来诱导 ROS 的产生，这可能导致妊娠并发症。
