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

Tae Hwan Shin; Balachandran Manavalan; Da Yeon Lee; Shaherin Basith; Chan Seo; Man Jeong Paik; Sang Wook Kim; Haewoon Seo; Ju Yeon Lee; Jin Young Kim; A. Young Kim; Jee Min Chung; Eun Joo Baik; Seong Ho Kang; Dong Kug Choi; Yup Kang; M. Maral Mouradian; Gwang Lee

doi:10.1186/s12989-021-00433-y

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

Tae Hwan Shin, Balachandran Manavalan, Da Yeon Lee, Shaherin Basith, Chan Seo, Man Jeong Paik, Sang Wook Kim, Haewoon Seo, Ju Yeon Lee, Jin Young Kim, A. Young Kim, Jee Min Chung, Eun Joo Baik, Seong Ho Kang, Dong Kug Choi, Yup Kang, M. Maral Mouradian, Gwang Lee

Robert Wood Johnson Medical School (RWJMS), Neurology

Rutgers, The State University

Research output: Contribution to journal › Article › peer-review

Abstract

Background: Nanoparticles 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. Methods: Here 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. Results: Intracellular 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. Conclusions: Combination 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: [Figure not available: see fulltext.]

Original language	American English
Article number	42
Journal	Particle and Fibre Toxicology
Volume	18
Issue number	1
DOIs	https://doi.org/10.1186/s12989-021-00433-y
State	Published - Dec 2021

ASJC Scopus subject areas

Toxicology
Health, Toxicology and Mutagenesis

Keywords

Integrated omics
Machine learning
Microglia
Nanotoxicity
Silica-coated magnetic nanoparticles

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10.1186/s12989-021-00433-y

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Shin, T. H., Manavalan, B., Lee, D. Y., Basith, S., Seo, C., Paik, M. J., Kim, S. W., Seo, H., Lee, J. Y., Kim, J. Y., Kim, A. Y., Chung, J. M., Baik, E. J., Kang, S. H., Choi, D. K., Kang, Y., Maral Mouradian, M., & Lee, G. (2021). Silica-coated magnetic-nanoparticle-induced cytotoxicity is reduced in microglia by glutathione and citrate identified using integrated omics. Particle and Fibre Toxicology, 18(1), Article 42. https://doi.org/10.1186/s12989-021-00433-y

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

abstract = "Background: Nanoparticles 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. Methods: Here 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. Results: Intracellular 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. Conclusions: Combination 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: [Figure not available: see fulltext.]",

keywords = "Integrated omics, Machine learning, Microglia, Nanotoxicity, Silica-coated magnetic nanoparticles",

author = "Shin, \{Tae Hwan\} and Balachandran Manavalan and Lee, \{Da Yeon\} and Shaherin Basith and Chan Seo and Paik, \{Man Jeong\} and Kim, \{Sang Wook\} and Haewoon Seo and Lee, \{Ju Yeon\} and Kim, \{Jin Young\} and Kim, \{A. Young\} and Chung, \{Jee Min\} and Baik, \{Eun Joo\} and Kang, \{Seong Ho\} and Choi, \{Dong Kug\} and Yup Kang and \{Maral Mouradian\}, M. and Gwang Lee",

note = "Publisher Copyright: {\textcopyright} 2021, The Author(s).",

year = "2021",

month = dec,

doi = "10.1186/s12989-021-00433-y",

language = "American English",

volume = "18",

journal = "Particle and Fibre Toxicology",

issn = "1743-8977",

publisher = "BioMed Central Ltd",

number = "1",

}

Shin, TH, Manavalan, B, Lee, DY, Basith, S, Seo, C, Paik, MJ, Kim, SW, Seo, H, Lee, JY, Kim, JY, Kim, AY, Chung, JM, Baik, EJ, Kang, SH, Choi, DK, Kang, Y, Maral Mouradian, M & Lee, G 2021, 'Silica-coated magnetic-nanoparticle-induced cytotoxicity is reduced in microglia by glutathione and citrate identified using integrated omics', Particle and Fibre Toxicology, vol. 18, no. 1, 42. https://doi.org/10.1186/s12989-021-00433-y

TY - JOUR

T1 - Silica-coated magnetic-nanoparticle-induced cytotoxicity is reduced in microglia by glutathione and citrate identified using integrated omics

AU - Shin, Tae Hwan

AU - Manavalan, Balachandran

AU - Lee, Da Yeon

AU - Basith, Shaherin

AU - Seo, Chan

AU - Paik, Man Jeong

AU - Kim, Sang Wook

AU - Seo, Haewoon

AU - Lee, Ju Yeon

AU - Kim, Jin Young

AU - Kim, A. Young

AU - Chung, Jee Min

AU - Baik, Eun Joo

AU - Kang, Seong Ho

AU - Choi, Dong Kug

AU - Kang, Yup

AU - Maral Mouradian, M.

AU - Lee, Gwang

PY - 2021/12

Y1 - 2021/12

N2 - Background: Nanoparticles 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. Methods: Here 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. Results: Intracellular 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. Conclusions: Combination 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: [Figure not available: see fulltext.]

AB - Background: Nanoparticles 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. Methods: Here 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. Results: Intracellular 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. Conclusions: Combination 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: [Figure not available: see fulltext.]

KW - Integrated omics

KW - Machine learning

KW - Microglia

KW - Nanotoxicity

KW - Silica-coated magnetic nanoparticles

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UR - http://www.scopus.com/inward/citedby.url?scp=85120610555&partnerID=8YFLogxK

U2 - 10.1186/s12989-021-00433-y

DO - 10.1186/s12989-021-00433-y

M3 - Article

C2 - 34819099

SN - 1743-8977

VL - 18

JO - Particle and Fibre Toxicology

JF - Particle and Fibre Toxicology

IS - 1

M1 - 42

ER -

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

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Keywords

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