Program in Molecular and Integrative Physiological Sciences, Departments of Environmental Health, and Genetics & Complex Diseases, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, 02115, USA.
Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, 02115, USA.
Sci Rep. 2020 Apr 3;10(1):5934. doi: 10.1038/s41598-020-62594-8.
Arsenic (As) exposure adversely affects neurodevelopment in children. Accumulation of misfolded proteins in cells exposed to As leads to endoplasmic reticulum (ER) stress response, which, if not relieved, results in cell death. Despite the potential role of ER stress for As-induced neurotoxicity, the underlying mechanisms remain poorly understood. Here we aimed to investigate the roles of microRNA(miR)-124, a novel ER stress suppressor, in As-induced ER stress response and cytotoxicity in neural cells. We further aimed to link these in vitro findings to neurodevelopmental outcomes in children who were exposed to As. Using Quantitative RT-PCR and Cyquant assay, we showed that miR-124 protects against As-induced cytotoxicity in neural cells with concomitant suppression of As-induced ER stress. In addition, As-induced cytotoxicity was exacerbated in miR-124 knockout cells generated by CRISPR-based gene editing compared scramble control. Furthermore, we identified two miR-124 SNPs rs67543816 (p = 0.0003) and rs35418153 (p = 0.0004) that are significantly associated with a mental composite score calculated from the Bayley Scales of Infant Development III in Bangladesh children. Our study reveals As-induced ER stress as a crucial mechanism underlying the toxic effects of As on neural cell function and neurodevelopment and identifies miR-124 as a potential preventative and therapeutic target against detrimental effects of As exposure in children.
砷（As）暴露会对儿童的神经发育产生不良影响。暴露于 As 的细胞中错误折叠的蛋白质积累会导致内质网（ER）应激反应，如果不能得到缓解，则会导致细胞死亡。尽管 ER 应激在 As 诱导的神经毒性中具有潜在作用，但相关机制仍知之甚少。在这里，我们旨在研究 microRNA（miR）-124 在 As 诱导的 ER 应激反应和神经细胞细胞毒性中的作用，miR-124 是一种新型的 ER 应激抑制剂。我们进一步旨在将这些体外发现与接触 As 的儿童的神经发育结果联系起来。通过定量 RT-PCR 和 Cyquant 测定，我们表明 miR-124 可防止 As 诱导的神经细胞细胞毒性，同时抑制 As 诱导的 ER 应激。此外，与 scramble 对照相比，基于 CRISPR 的基因编辑产生的 miR-124 敲除细胞中，As 诱导的细胞毒性加剧。此外，我们确定了两个 miR-124 SNPs rs67543816（p=0.0003）和 rs35418153（p=0.0004）与孟加拉国儿童的贝利婴幼儿发育量表 III 计算的心理综合评分显著相关。我们的研究揭示了 As 诱导的 ER 应激是 As 对神经细胞功能和神经发育产生毒性作用的关键机制，并确定了 miR-124 作为针对儿童接触 As 有害影响的潜在预防和治疗靶点。
