Influences of repeated exposure to low levels of TiO 2 nanoparticles on Kruppel‐like factors in 3D Caco‐2 spheroids and mouse intestines
Influences of repeated exposure to low levels of TiO 2 nanoparticles on Kruppel‐like factors in 3D Caco‐2 spheroids and mouse intestines
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重复暴露于低水平的 TiO 2 纳米粒子对 3D Caco™2 球体和小鼠肠道中 Kruppel™ 样因子的影响
DOI：
10.1002/jat.4420
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发表时间：
2022
影响因子：
3.3
通讯作者：
Yi Cao
中科院分区：
文献类型：
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作者：
W;i Cao;Mingkang Liu;Canyang Wang;Guoxing Jing;Yi Cao
Kruppel样因子(KLF)是一组转录因子，参与许多基本生物学过程的调节，最近的研究表明，即使在非细胞毒性浓度下，纳米粒(NPs)也能够以不同的模式改变KLF。在这项研究中，我们反复将3D Caco-2球体和小鼠暴露于最常用的金属氧化物纳米粒子之一的TiO2纳米粒子中，并基于RNA测序研究KLF信号通路的变化。尽管纳米二氧化钛的内化在体外没有引起细胞毒性，但在7 天内重复暴露于15.7 ng/mlTiO2纳米颗粒可增加KLF4，但降低KLF6。一致地，KLF4/KLF6调节的基因本体论术语被改变，包括那些涉及基因表达调节的术语。我们进一步证实，重复暴露于15.7 ng/mlTiO2NPs后，KLF4和原癌基因bHLH转录因子(MYC)的表达增加，而KLF6和激活转录因子3(ATF3)的表达降低。但随着NP浓度的增加，这些基因的表达呈下降趋势。给小鼠灌胃4.39和43.9 mg/kg的纳米二氧化钛(每天一次，连续5天)，我们观察到KLF4、KLF6、Myc和ATF3的表达增加，并伴有肠道的形态变化。我们的结论是，在体外和体内，重复暴露于低水平的TiO2NPs改变了肠道细胞中的KLF信号通路。
Kruppel‐like factors (KLFs) are a set of transcription factors (TFs) involved in the regulation of many basic biological processes, and recent studies suggested that nanoparticles (NPs) were capable to change KLFs in different models even at non‐cytotoxic concentrations. In this study, we repeatedly exposed 3D Caco‐2 spheroids and mice to TiO2NPs, one of the most frequently used metal oxide NPs, and investigated the changes of KLF‐signaling pathways based on RNA‐sequencing. Although the internalization of TiO2NPs did not induce cytotoxicity in vitro, repeated exposure (three times within 7 days) to 15.7 ng/ml TiO2NPs increased KLF4 but decreased KLF6. Consistently, KLF4/KLF6‐regulated gene ontology terms were altered, including those involved in the regulation of gene expression. We further verified that repeated exposure to 15.7 ng/ml TiO2NPs increased the expression of KLF4 and proto‐oncogene, bHLH transcription factor (MYC), but decreased the expression of KLF6 and activating transcription factor 3 (ATF3). But with the increase of NP concentrations, the expression of these genes was decreased. In mice following intragastrical exposure to 4.39 and 43.9 mg/kg TiO2NPs (once a day for 5 continuous days), we observed increased expression of klf4, klf6, myc, and atf3, along with morphological changes of intestines. We concluded that repeated exposure to low levels of TiO2NPs altered KLF‐signaling pathways in intestinal cells both in vitro and in vivo.