Silica-coated magnetic-nanoparticle-induced cytotoxicity is reduced in microglia by glutathione and citrate identified using integrated omics

Particle and Fibre Toxicology

Man Jeong Paik¹  Chan Seo¹  Dong-Kug Choi²  Seong Ho Kang³  Gwang Lee⁴  Haewoon Seo⁵  Sang-Wook Kim⁵  Balachandran Manavalan⁶  Jee Min Chung⁶  Tae Hwan Shin⁶  Shaherin Basith⁶  A Young Kim⁶  Da Yeon Lee⁶  Yup Kang⁶  Eun Joo Baik⁶  M. Maral Mouradian⁷  Ju Yeon Lee⁸  Jin Young Kim⁸ 

[1]College of Pharmacy, Sunchon National University, 255 Jungang-ro, 57922, Suncheon, Republic of Korea

[2]Department of Biotechnology, College of Biomedical and Health Science, Konkuk University, 268 Chungwondaero, 27478, Chungju, Republic of Korea

[3]Department of Chemistry, Graduate School, Kyung Hee University, 17104, Yongin-si, Gyeonggi-do, Republic of Korea

[4]Department of Applied Chemistry and Institute of Natural Sciences, Kyung Hee University, 17104, Yongin-si, Gyeonggi-do, Republic of Korea

[5]Department of Molecular Science and Technology, Ajou University, 16499, Suwon-si, Gyeonggi-do, Republic of Korea

[6]Department of Physiology, Ajou University School of Medicine, 16499, Suwon-si, Gyeonggi-do, Republic of Korea

[7]Department of Molecular Science and Technology, Ajou University, 206 World cup-ro, 16499, Suwon, Republic of Korea

[8]Department of Physiology, Ajou University School of Medicine, 206 World cup-ro, 16499, Suwon, Republic of Korea

[9]RWJMS Institute for Neurological Therapeutics, Rutgers Biomedical and Health Sciences, and Department of Neurology, Robert Wood Johnson Medical School, Rutgers University, 08854, Piscataway, NJ, USA

[10]Research Center of Bioconvergence Analysis, Korea Basic Science Institute, 162 Yeongudanji-ro, 28119, Cheongju, Republic of Korea

关键词: Silica-coated magnetic nanoparticles;    Nanotoxicity;    Integrated omics;    Microglia;    Machine learning;   

DOI  :  10.1186/s12989-021-00433-y

来源: Springer

【 摘 要 】

BackgroundNanoparticles have been utilized in brain research and therapeutics, including imaging, diagnosis, and drug delivery, owing to their versatile properties compared to bulk materials. However, exposure to nanoparticles leads to their accumulation in the brain, but drug development to counteract this nanotoxicity remains challenging. To date, concerns have risen about the potential toxicity to the brain associated with nanoparticles exposure via penetration of the brain blood barrier to address this issue.MethodsHere the effect of silica-coated-magnetic nanoparticles containing the rhodamine B isothiocyanate dye [MNPs@SiO2(RITC)] were assessed on microglia through toxicological investigation, including biological analysis and integration of transcriptomics, proteomics, and metabolomics. MNPs@SiO2(RITC)-induced biological changes, such as morphology, generation of reactive oxygen species, intracellular accumulation of MNPs@SiO2(RITC) using transmission electron microscopy, and glucose uptake efficiency, were analyzed in BV2 murine microglial cells. Each omics data was collected via RNA-sequencing-based transcriptome analysis, liquid chromatography-tandem mass spectrometry-based proteome analysis, and gas chromatography- tandem mass spectrometry-based metabolome analysis. The three omics datasets were integrated and generated as a single network using a machine learning algorithm. Nineteen compounds were screened and predicted their effects on nanotoxicity within the triple-omics network.ResultsIntracellular reactive oxygen species production, an inflammatory response, and morphological activation of cells were greater, but glucose uptake was lower in MNPs@SiO2(RITC)-treated BV2 microglia and primary rat microglia in a dose-dependent manner. Expression of 121 genes (from 41,214 identified genes), and levels of 45 proteins (from 5918 identified proteins) and 17 metabolites (from 47 identified metabolites) related to the above phenomena changed in MNPs@SiO2(RITC)-treated microglia. A combination of glutathione and citrate attenuated nanotoxicity induced by MNPs@SiO2(RITC) and ten other nanoparticles in vitro and in the murine brain, protecting mostly the hippocampus and thalamus.ConclusionsCombination of glutathione and citrate can be one of the candidates for nanotoxicity alleviating drug against MNPs@SiO2(RITC) induced detrimental effect, including elevation of intracellular reactive oxygen species level, activation of microglia, and reduction in glucose uptake efficiency. In addition, our findings indicate that an integrated triple omics approach provides useful and sensitive toxicological assessment for nanoparticles and screening of drug for nanotoxicity.Graphical Abstract

【 授权许可】

CC BY