Department of Pharmaceutical Sciences and Experimental Therapeutics, College of Pharmacy, The University of Iowa, Iowa City, IA 52242, United States of America.
Department of Chemistry, The University of Iowa, Iowa City, IA 52245, United States of America.
Toxicol In Vitro. 2021 Feb;70:105031. doi: 10.1016/j.tiv.2020.105031. Epub 2020 Oct 17.
The increasing appearance of engineered nanomaterials in broad biomedical and industrial sectors poses an escalating health concern from unintended exposure with unknown consequences. Routine in vitro assessments of nanomaterial toxicity are a vital component to addressing these mounting health concerns; however, despite the known role of cell-cell and cell-matrix contacts in governing cell survival, these physical interactions are generally ignored. Herein, we demonstrate that exposure to amorphous silica particles destabilizes mitochondrial membrane potential, stimulates reactive oxygen species (ROS) production and promotes cytotoxicity in SH-SY5Y human neuroblastoma through mechanisms that are potently matrix dependent, with SH-SY5Y cells plated on the softest matrix displaying a near complete recovery in viability compared to dose-matched cells plated on tissue-culture plastic. Cells on the softest matrix (3 kPa) further displayed a 50% reduction in ROS production and preserved mitochondrial membrane potential. The actin cytoskeleton is mechanosensitive and closely related to ROS production. SH-SY5Y cells exposed to a 100 μg/mL dose of 50 nm silica particles displayed distinct cytoskeletal aberrations and a 70% increase in cell stiffness. Overall, this study establishes that the mechanical environment can significantly impact silica nanoparticle toxicity in SH-SY5Y cells. The mechanobiochemical mechanisms behind this regulation, which are initiated at the cell-matrix interface to adjust cytoskeletal structure and intracellular tension, demand specific attention for a comprehensive understanding of nanotoxicity.
越来越多的工程纳米材料出现在广泛的生物医学和工业领域，这对人们造成了越来越大的健康担忧，因为人们对这些纳米材料的潜在暴露及其未知后果知之甚少。常规的体外纳米材料毒性评估是解决这些日益严重的健康问题的重要组成部分；然而，尽管细胞-细胞和细胞-基质接触在控制细胞存活方面的作用已被广泛认识，但这些物理相互作用通常被忽视。本文研究表明，无定形二氧化硅颗粒会破坏线粒体膜电位，刺激活性氧（ROS）的产生，并通过强烈依赖基质的机制促进人神经母细胞瘤 SH-SY5Y 的细胞毒性，与在组织培养塑料上培养的细胞相比，在最柔软的基质上培养的 SH-SY5Y 细胞的活力几乎完全恢复。在最柔软的基质（3kPa）上培养的细胞进一步显示 ROS 生成减少 50%，线粒体膜电位得到保留。细胞骨架是对机械敏感的，与 ROS 的产生密切相关。暴露于 100μg/mL 50nm 二氧化硅颗粒的 SH-SY5Y 细胞表现出明显的细胞骨架异常和细胞刚性增加 70%。总的来说，这项研究表明，机械环境可以显著影响 SH-SY5Y 细胞中二氧化硅纳米颗粒的毒性。这种调节背后的机械生物化学机制始于细胞-基质界面，以调整细胞骨架结构和细胞内张力，需要特别注意，以全面了解纳米毒性。
