1 Department of Dental Medicine, The First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou, China.
2 Department of Occupational and Environmental Health, School of Public Health, Guangdong Pharmaceutical University, Guangzhou, China.
Hum Exp Toxicol. 2019 Jul;38(7):833-845. doi: 10.1177/0960327119842273. Epub 2019 Apr 12.
In the development of dental fluorosis, oxidative stress is considered as the key mechanism. Endoplasmic reticulum (ER) stress can induce oxidative stress and activate the important antioxidative factor nuclear factor erythroid 2-related factor 2 (Nrf2) in a PKR-like ER kinase (PERK)-dependent manner, but combining ER stress and oxidative stress, the role of PERK-Nrf2 signaling pathway involved in fluoride-regulated ameloblasts is not fully defined. Here, we studied the effect of fluoride on PERK-Nrf2 signaling pathway in mouse ameloblasts. We found that low-dose and continuous fluoride exposure increased binding immunoglobulin protein expression and activated PERK-activating transcription factor 4 signaling pathway. Meanwhile, the expression of Nrf2 and its target genes (glutamylcysteine synthetase and glutathione S-transferase-P1) enhanced following ER stress. Tunicamycin increased the expression of PERK, leading to Nrf2 nuclear import, and tauroursodeoxycholate suppressed Nrf2 activation through PERK during ER stress, indicating that PERK activation is required for Nrf2 nuclear entry. Furthermore, tert-butylhydroquinone triggered the overexpression of Nrf2 to reduce ER stress, but luteolin inhibited Nrf2 nuclear localization to elevate ER stress. In summary, this study proved that fluoride under certain dose can induce ER stress and promote Nrf2 nuclear import via PERK activation and suggested that antioxidation mechanism mediated by PERK-Nrf2 can alleviate fluoride-induced ER stress effectively.
在氟斑牙的发生发展过程中，氧化应激被认为是关键机制。内质网（ER）应激可以诱导氧化应激，并通过 PKR 样 ER 激酶（PERK）依赖性方式激活重要的抗氧化因子核因子红细胞 2 相关因子 2（Nrf2），但结合 ER 应激和氧化应激，氟调节成釉细胞中 PERK-Nrf2 信号通路的作用尚未完全确定。在这里，我们研究了氟化物对小鼠成釉细胞中 PERK-Nrf2 信号通路的影响。我们发现，低剂量和持续的氟暴露增加了结合免疫球蛋白蛋白的表达，并激活了 PERK-激活转录因子 4 信号通路。同时，在 ER 应激下，Nrf2 及其靶基因（谷氨酰半胱氨酸合成酶和谷胱甘肽 S-转移酶-P1）的表达增强。衣霉素增加了 PERK 的表达，导致 Nrf2 核内易位，而牛磺熊脱氧胆酸通过 PERK 在 ER 应激时抑制 Nrf2 的激活，表明 PERK 的激活是 Nrf2 核内进入所必需的。此外，叔丁基对苯二酚引发 Nrf2 的过表达以减轻 ER 应激，但木犀草素通过抑制 Nrf2 的核定位来升高 ER 应激。总之，本研究证明了在一定剂量下氟化物可以通过 PERK 激活诱导 ER 应激，并促进 Nrf2 核内易位，并表明 PERK-Nrf2 介导的抗氧化机制可以有效缓解氟化物诱导的 ER 应激。
