Pulmonary toxicity of inhaled nano-sized cerium oxide aerosols in Sprague–Dawley rats

Chang Guo; Sarah Robertson; Ralf J.M. Weber; Alison Buckley; James Warren; Alan Hodgson; Joshua Z. Rappoport; Konstantin Ignatyev; Kirsty Meldrum; Isabella Römer; Sameirah Macchiarulo; James Kevin Chipman; Tim Marczylo; Martin O. Leonard; Timothy W. Gant; Mark R. Viant; Rachel Smith

doi:10.1080/17435390.2018.1554751

Pulmonary toxicity of inhaled nano-sized cerium oxide aerosols in Sprague–Dawley rats

Chang Guo^*, Sarah Robertson, Ralf J.M. Weber, Alison Buckley, James Warren, Alan Hodgson, Joshua Z. Rappoport, Konstantin Ignatyev, Kirsty Meldrum, Isabella Römer, Sameirah Macchiarulo, James Kevin Chipman, Tim Marczylo, Martin O. Leonard, Timothy W. Gant, Mark R. Viant, Rachel Smith

^*Corresponding author for this work

Cell & Developmental Biology

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

39 Scopus citations

Abstract

Cerium oxide nanoparticles (CeO₂NPs), used in some diesel fuel additives to improve fuel combustion efficiency and exhaust filter operation, have been detected in ambient air and concerns have been raised about their potential human health impact. The majority of CeO₂NP inhalation studies undertaken to date have used aerosol particles of larger sizes than the evidence suggests are emitted from vehicles using such fuel additives. Hence, the objective of this study was to investigate the effects of inhaled CeO₂NP aerosols of a more environmentally relevant size, utilizing a combination of methods, including untargeted multi-omics to enable the broadest possible survey of molecular responses and synchrotron X-ray spectroscopy to investigate cerium speciation. Male Sprague–Dawley rats were exposed by nose-only inhalation to aerosolized CeO₂NPs (mass concentration 1.8mg/m³, aerosol count median diameter 40nm) for 3h/d for 4 d/week, for 1 or 2 weeks and sacrificed at 3 and 7d post-exposure. Markers of inflammation changed significantly in a dose- and time-dependent manner, which, combined with results from lung histopathology and gene expression analyses suggest an inflammatory response greater than that seen in studies using micron-sized ceria aerosols. Lipidomics of lung tissue revealed changes to minor lipid species, implying specific rather than general cellular effects. Cerium speciation analysis indicated a change in Ce³⁺/Ce⁴⁺ ratio within lung tissue. Collectively, these results in conjunction with earlier studies emphasize the importance of aerosol particle size on toxicity determination. Furthermore, the limited effect resolution within 7d suggested the possibility of longer-term effects.

Original language	English (US)
Pages (from-to)	733-750
Number of pages	18
Journal	Nanotoxicology
Volume	13
Issue number	6
DOIs	https://doi.org/10.1080/17435390.2018.1554751
State	Published - Jul 3 2019

Funding

This study was funded by the UK’s Natural Environment Research Council and Medical Research Council as part of the FABLE project (From Airborne exposures to BioLogical Effects) (NE/I008314), with support from Public Health England. The authors thank Dr Jennifer Kirwan and Lorraine Wallace (University of Birmingham) for assistance with the multi-omics data collection. Transmission electron microscopy was performed by Mr Lennell Reynolds at the Northwestern University Center for Advanced Microscopy, generously supported by NCI CCSG P30 CA060553 awarded to the Robert H Lurie Comprehensive Cancer Center. The authors thank Diamond Light Source for access to beamline I18 (proposal SP12583-1) that contributed to the results presented here. This study was funded by the UK?s Natural Environment Research Council and Medical Research Council as part of the FABLE project (From Airborne exposures to BioLogical Effects) (NE/I008314), with support from Public Health England. The authors thank Dr Jennifer Kirwan and Lorraine Wallace (University of Birmingham) for assistance with the multi-omics data collection. Transmission electron microscopy was performed by Mr Lennell Reynolds at the Northwestern University Center for Advanced Microscopy, generously supported by NCI CCSG P30 CA060553 awarded to the Robert H Lurie Comprehensive Cancer Center. The authors thank Diamond Light Source for access to beamline I18 (proposal SP12583-1) that contributed to the results presented here.

Keywords

Nanoparticle
cerium
inhalation
omics
rat

ASJC Scopus subject areas

Biomedical Engineering
Toxicology

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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Cite this

Guo, C., Robertson, S., Weber, R. J. M., Buckley, A., Warren, J., Hodgson, A., Rappoport, J. Z., Ignatyev, K., Meldrum, K., Römer, I., Macchiarulo, S., Chipman, J. K., Marczylo, T., Leonard, M. O., Gant, T. W., Viant, M. R., & Smith, R. (2019). Pulmonary toxicity of inhaled nano-sized cerium oxide aerosols in Sprague–Dawley rats. Nanotoxicology, 13(6), 733-750. https://doi.org/10.1080/17435390.2018.1554751

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title = "Pulmonary toxicity of inhaled nano-sized cerium oxide aerosols in Sprague–Dawley rats",

abstract = "Cerium oxide nanoparticles (CeO2NPs), used in some diesel fuel additives to improve fuel combustion efficiency and exhaust filter operation, have been detected in ambient air and concerns have been raised about their potential human health impact. The majority of CeO2NP inhalation studies undertaken to date have used aerosol particles of larger sizes than the evidence suggests are emitted from vehicles using such fuel additives. Hence, the objective of this study was to investigate the effects of inhaled CeO2NP aerosols of a more environmentally relevant size, utilizing a combination of methods, including untargeted multi-omics to enable the broadest possible survey of molecular responses and synchrotron X-ray spectroscopy to investigate cerium speciation. Male Sprague–Dawley rats were exposed by nose-only inhalation to aerosolized CeO2NPs (mass concentration 1.8mg/m3, aerosol count median diameter 40nm) for 3h/d for 4 d/week, for 1 or 2 weeks and sacrificed at 3 and 7d post-exposure. Markers of inflammation changed significantly in a dose- and time-dependent manner, which, combined with results from lung histopathology and gene expression analyses suggest an inflammatory response greater than that seen in studies using micron-sized ceria aerosols. Lipidomics of lung tissue revealed changes to minor lipid species, implying specific rather than general cellular effects. Cerium speciation analysis indicated a change in Ce3+/Ce4+ ratio within lung tissue. Collectively, these results in conjunction with earlier studies emphasize the importance of aerosol particle size on toxicity determination. Furthermore, the limited effect resolution within 7d suggested the possibility of longer-term effects.",

keywords = "Nanoparticle, cerium, inhalation, omics, rat",

author = "Chang Guo and Sarah Robertson and Weber, {Ralf J.M.} and Alison Buckley and James Warren and Alan Hodgson and Rappoport, {Joshua Z.} and Konstantin Ignatyev and Kirsty Meldrum and Isabella R{\"o}mer and Sameirah Macchiarulo and Chipman, {James Kevin} and Tim Marczylo and Leonard, {Martin O.} and Gant, {Timothy W.} and Viant, {Mark R.} and Rachel Smith",

note = "Publisher Copyright: {\textcopyright} 2019, {\textcopyright} 2019 Crown Copyright. Reproduced with the permission of Public Health England. Published by Informa UK Limited, trading as Taylor & Francis Group.",

year = "2019",

month = jul,

day = "3",

doi = "10.1080/17435390.2018.1554751",

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Guo, C, Robertson, S, Weber, RJM, Buckley, A, Warren, J, Hodgson, A, Rappoport, JZ, Ignatyev, K, Meldrum, K, Römer, I, Macchiarulo, S, Chipman, JK, Marczylo, T, Leonard, MO, Gant, TW, Viant, MR & Smith, R 2019, 'Pulmonary toxicity of inhaled nano-sized cerium oxide aerosols in Sprague–Dawley rats', Nanotoxicology, vol. 13, no. 6, pp. 733-750. https://doi.org/10.1080/17435390.2018.1554751

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T1 - Pulmonary toxicity of inhaled nano-sized cerium oxide aerosols in Sprague–Dawley rats

AU - Guo, Chang

AU - Robertson, Sarah

AU - Weber, Ralf J.M.

AU - Buckley, Alison

AU - Warren, James

AU - Hodgson, Alan

AU - Rappoport, Joshua Z.

AU - Ignatyev, Konstantin

AU - Meldrum, Kirsty

AU - Römer, Isabella

AU - Macchiarulo, Sameirah

AU - Chipman, James Kevin

AU - Marczylo, Tim

AU - Leonard, Martin O.

AU - Gant, Timothy W.

AU - Viant, Mark R.

AU - Smith, Rachel

PY - 2019/7/3

Y1 - 2019/7/3

N2 - Cerium oxide nanoparticles (CeO2NPs), used in some diesel fuel additives to improve fuel combustion efficiency and exhaust filter operation, have been detected in ambient air and concerns have been raised about their potential human health impact. The majority of CeO2NP inhalation studies undertaken to date have used aerosol particles of larger sizes than the evidence suggests are emitted from vehicles using such fuel additives. Hence, the objective of this study was to investigate the effects of inhaled CeO2NP aerosols of a more environmentally relevant size, utilizing a combination of methods, including untargeted multi-omics to enable the broadest possible survey of molecular responses and synchrotron X-ray spectroscopy to investigate cerium speciation. Male Sprague–Dawley rats were exposed by nose-only inhalation to aerosolized CeO2NPs (mass concentration 1.8mg/m3, aerosol count median diameter 40nm) for 3h/d for 4 d/week, for 1 or 2 weeks and sacrificed at 3 and 7d post-exposure. Markers of inflammation changed significantly in a dose- and time-dependent manner, which, combined with results from lung histopathology and gene expression analyses suggest an inflammatory response greater than that seen in studies using micron-sized ceria aerosols. Lipidomics of lung tissue revealed changes to minor lipid species, implying specific rather than general cellular effects. Cerium speciation analysis indicated a change in Ce3+/Ce4+ ratio within lung tissue. Collectively, these results in conjunction with earlier studies emphasize the importance of aerosol particle size on toxicity determination. Furthermore, the limited effect resolution within 7d suggested the possibility of longer-term effects.

AB - Cerium oxide nanoparticles (CeO2NPs), used in some diesel fuel additives to improve fuel combustion efficiency and exhaust filter operation, have been detected in ambient air and concerns have been raised about their potential human health impact. The majority of CeO2NP inhalation studies undertaken to date have used aerosol particles of larger sizes than the evidence suggests are emitted from vehicles using such fuel additives. Hence, the objective of this study was to investigate the effects of inhaled CeO2NP aerosols of a more environmentally relevant size, utilizing a combination of methods, including untargeted multi-omics to enable the broadest possible survey of molecular responses and synchrotron X-ray spectroscopy to investigate cerium speciation. Male Sprague–Dawley rats were exposed by nose-only inhalation to aerosolized CeO2NPs (mass concentration 1.8mg/m3, aerosol count median diameter 40nm) for 3h/d for 4 d/week, for 1 or 2 weeks and sacrificed at 3 and 7d post-exposure. Markers of inflammation changed significantly in a dose- and time-dependent manner, which, combined with results from lung histopathology and gene expression analyses suggest an inflammatory response greater than that seen in studies using micron-sized ceria aerosols. Lipidomics of lung tissue revealed changes to minor lipid species, implying specific rather than general cellular effects. Cerium speciation analysis indicated a change in Ce3+/Ce4+ ratio within lung tissue. Collectively, these results in conjunction with earlier studies emphasize the importance of aerosol particle size on toxicity determination. Furthermore, the limited effect resolution within 7d suggested the possibility of longer-term effects.

KW - Nanoparticle

KW - cerium

KW - inhalation

KW - omics

KW - rat

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Pulmonary toxicity of inhaled nano-sized cerium oxide aerosols in Sprague–Dawley rats

Abstract

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Keywords

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UN SDGs

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