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Characterizing the Low-Dose Effects of Methylmercury on the Early Stages of Embryo Development Using Cultured Human Embryonic Stem Cells
Environmental Health Perspectives ( IF 10.4 ) Pub Date : 2021-7-30 , DOI: 10.1289/ehp7349
Bai Li 1 , Cunye Qiao 2 , Xiaolei Jin 3 , Hing Man Chan 1
Affiliation  

Abstract

Background:

Global concerns of methylmercury (MeHg) exposure have been raised, especially on its effects on pregnant women. Recent epidemiological studies have revealed associations between maternal blood/hair MeHg concentrations, adverse pregnancy outcomes, and developmental deficits. However, the underlying mechanisms remain unclear.

Objectives:

In this study, we characterized the effects of MeHg exposure on undifferentiated human embryonic stem cells (hESCs) and extrapolated the effects to human embryonic development.

Methods:

hESCs were exposed to 0, 1, 5, 10, 50, 100 or 200nM MeHg for 24 h or 6 d. Cell adherence and colony formation and expansion were examined under the microscope. Cell attachment, viability/proliferation, apoptosis, stress response, cell cycle, autophagy, and expression of cell lineage marker genes and proteins were measured at the end of exposures.

Results:

Our results indicated that exposure to nanomolar concentrations of MeHg was associated with a) higher levels of reactive oxygen species (ROS) and hemeoxygenase-1 (HO-1), suggesting increased stress and adaptive responses; b) lower cellular adhesion, viability/proliferation, and colony formation and expansion; c) higher levels of apoptosis, reflected by higher cleaved caspase-3 expression and Annexin V binding; d) higher levels of cytoskeleton protein α-tubulin expression; e) higher rates of G1/S phase cell cycle arrest; and f) autophagy inhibition, as shown by a lower LC3BII/LC3BI ratio and accumulation of SQSTM1 (p62). These outcomes were accompanied by higher expressions of self-renewal genes or proteins or both, including OCT4, SOX2, NANOG, and cytokine receptor IL6ST, as well as pluripotency and the cell fate regulator cyclin D1.

Discussion:

These results revealed that under the selection pressure of exposure to low doses of MeHg, some hESCs underwent apoptosis, whereas others adapted and survived with enhanced self-renewal gene expression and specific morphological phenotypes. Findings from the present study provide in vitro evidence that low doses of MeHg adversely affect hESCs when exposed during a period of time that models embryonic pre-, during, and early postimplantation stages. https://doi.org/10.1289/EHP7349



中文翻译:

使用培养的人类胚胎干细胞表征甲基汞对胚胎发育早期阶段的低剂量影响

摘要

背景:

全球对甲基汞 (MeHg) 暴露的担忧已引起人们的关注,尤其是其对孕妇的影响。最近的流行病学研究揭示了母体血液/头发甲基汞浓度、不良妊娠结局和发育缺陷之间的关联。然而,潜在的机制仍不清楚。

目标:

在这项研究中,我们描述了甲基汞暴露对未分化的人类胚胎干细胞 (hESCs) 的影响,并推断了对人类胚胎发育的影响。

方法:

hESCs 暴露于 0、1、5、10、50、100 或200纳米甲基汞 24 小时或 6 天。在显微镜下检查细胞粘附和集落形成和扩张。在暴露结束时测量细胞附着、活力/增殖、细胞凋亡、应激反应、细胞周期、自噬以及细胞谱系标记基因和蛋白质的表达。

结果:

我们的研究结果表明,暴露于纳摩尔浓度的 MeHg 与a ) 更高水平的活性氧 (ROS) 和 hemeoxygenase-1 (HO-1) 相关,表明压力和适应性反应增加;b ) 降低细胞粘附、活力/增殖以及集落形成和扩张;c ) 更高水平的细胞凋亡,这反映在更高的切割 caspase-3 表达和膜联蛋白 V 结合上;d ) 更高水平的细胞骨架蛋白α-微管蛋白表达; e ) 更高的 G1/S 期细胞周期停滞率;f ) 自噬抑制,如较低的 LC3BII/LC3BI 比率和 SQSTM1 (p62) 的积累所示。这些结果伴随着自我更新基因或蛋白质或两者的更高表达,包括 OCT4、SOX2、NANOG 和细胞因子受体 IL6ST,以及多能性和细胞命运调节因子 cyclin D1。

讨论:

这些结果表明,在暴露于低剂量 MeHg 的选择压力下,一些 hESCs 经历了细胞凋亡,而另一些则适应并存活,增强了自我更新基因表达和特定的形态表型。本研究的结果提供了体外证据,表明在模拟胚胎植入前、植入期间和植入后早期阶段的一段时间内暴露低剂量的甲基汞会对 hESC 产生不利影响。https://doi.org/10.1289/EHP7349

更新日期:2021-08-01
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