Transcriptional profiling identifies physicochemical properties of nanomaterials that are determinants of the in vivo pulmonary response

Sabina Halappanavar; Anne Thoustrup Saber; Nathalie Decan; Keld Alstrup Jensen; Dongmei Wu; Nicklas Raun Jacobsen; Charles Guo; Jacob Rogowski; Ismo K. Koponen; Marcus Levin; Anne Mette Madsen; Rambabu Atluri; Valentinas Snitka; Renie K. Birkedal; David Rickerby; Andrew Williams; Håkan Wallin; Carole L Yauk; Ulla Vogel

doi:10.1002/em.21936

Transcriptional profiling identifies physicochemical properties of nanomaterials that are determinants of the in vivo pulmonary response

Sabina Halappanavar, Anne Thoustrup Saber, Nathalie Decan, Keld Alstrup Jensen, Dongmei Wu, Nicklas Raun Jacobsen, Charles Guo, Jacob Rogowski, Ismo K. Koponen, Marcus Levin, Anne Mette Madsen, Rambabu Atluri, Valentinas Snitka, Renie K. Birkedal, David Rickerby, Andrew Williams, Håkan Wallin, Carole L Yauk, Ulla Vogel

Department of Public Health

46 Citations (Scopus)

Abstract

We applied transcriptional profiling to elucidate the mechanisms associated with pulmonary responses to titanium dioxide (TiO2 ) nanoparticles (NPs) of different sizes and surface coatings, and to determine if these responses are modified by NP size, surface area, surface modification, and embedding in paint matrices. Adult C57BL/6 mice were exposed via single intratracheal instillations to free forms of TiO2 NPs (10, 20.6, or 38 nm in diameter) with different surface coatings, or TiO2 NPs embedded in paint matrices. Controls were exposed to dispersion medium devoid of NPs. TiO2 NPs were characterized for size, surface area, chemical impurities, and agglomeration state in the exposure medium. Pulmonary transcriptional profiles were generated using microarrays from tissues collected one and 28 d postexposure. Property-specific pathway effects were identified. Pulmonary protein levels of specific inflammatory cytokines and chemokines were confirmed by ELISA. The data were collapsed to 659 differentially expressed genes (P ≤ 0.05; fold change ≥ 1.5). Unsupervised hierarchical clustering of these genes revealed that TiO2 NPs clustered mainly by postexposure timepoint followed by particle type. A pathway-based meta-analysis showed that the combination of smaller size, large deposited surface area, and surface amidation contributes to TiO2 NP gene expression response. Embedding of TiO2 NP in paint dampens the overall transcriptional effects. The magnitude of the expression changes associated with pulmonary inflammation differed across all particles; however, the underlying pathway perturbations leading to inflammation were similar, suggesting a generalized mechanism-of-action for all TiO2 NPs. Thus, transcriptional profiling is an effective tool to determine the property-specific biological/toxicity responses induced by nanomaterials.

Original language	English
Journal	Environmental and Molecular Mutagenesis
Volume	56
Issue number	2
Pages (from-to)	245-264
Number of pages	20
ISSN	0893-6692
DOIs	https://doi.org/10.1002/em.21936
Publication status	Published - 1 Mar 2015

Keywords

Animals
Gene Expression Regulation
Inflammation
Lung
Metal Nanoparticles
Mice
Oxidative Stress
Proteomics
Tissue Array Analysis
Titanium

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10.1002/em.21936

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Halappanavar, S., Saber, A. T., Decan, N., Jensen, K. A., Wu, D., Jacobsen, N. R., Guo, C., Rogowski, J., Koponen, I. K., Levin, M., Madsen, A. M., Atluri, R., Snitka, V., Birkedal, R. K., Rickerby, D., Williams, A., Wallin, H., Yauk, C. L., & Vogel, U. (2015). Transcriptional profiling identifies physicochemical properties of nanomaterials that are determinants of the in vivo pulmonary response. Environmental and Molecular Mutagenesis, 56(2), 245-264. https://doi.org/10.1002/em.21936

Transcriptional profiling identifies physicochemical properties of nanomaterials that are determinants of the in vivo pulmonary response. / Halappanavar, Sabina; Saber, Anne Thoustrup; Decan, Nathalie et al.

In: Environmental and Molecular Mutagenesis, Vol. 56, No. 2, 01.03.2015, p. 245-264.

Research output: Contribution to journal › Journal article › Research › peer-review

Halappanavar, S, Saber, AT, Decan, N, Jensen, KA, Wu, D, Jacobsen, NR, Guo, C, Rogowski, J, Koponen, IK, Levin, M, Madsen, AM, Atluri, R, Snitka, V, Birkedal, RK, Rickerby, D, Williams, A, Wallin, H, Yauk, CL & Vogel, U 2015, 'Transcriptional profiling identifies physicochemical properties of nanomaterials that are determinants of the in vivo pulmonary response', Environmental and Molecular Mutagenesis, vol. 56, no. 2, pp. 245-264. https://doi.org/10.1002/em.21936

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abstract = "We applied transcriptional profiling to elucidate the mechanisms associated with pulmonary responses to titanium dioxide (TiO2 ) nanoparticles (NPs) of different sizes and surface coatings, and to determine if these responses are modified by NP size, surface area, surface modification, and embedding in paint matrices. Adult C57BL/6 mice were exposed via single intratracheal instillations to free forms of TiO2 NPs (10, 20.6, or 38 nm in diameter) with different surface coatings, or TiO2 NPs embedded in paint matrices. Controls were exposed to dispersion medium devoid of NPs. TiO2 NPs were characterized for size, surface area, chemical impurities, and agglomeration state in the exposure medium. Pulmonary transcriptional profiles were generated using microarrays from tissues collected one and 28 d postexposure. Property-specific pathway effects were identified. Pulmonary protein levels of specific inflammatory cytokines and chemokines were confirmed by ELISA. The data were collapsed to 659 differentially expressed genes (P ≤ 0.05; fold change ≥ 1.5). Unsupervised hierarchical clustering of these genes revealed that TiO2 NPs clustered mainly by postexposure timepoint followed by particle type. A pathway-based meta-analysis showed that the combination of smaller size, large deposited surface area, and surface amidation contributes to TiO2 NP gene expression response. Embedding of TiO2 NP in paint dampens the overall transcriptional effects. The magnitude of the expression changes associated with pulmonary inflammation differed across all particles; however, the underlying pathway perturbations leading to inflammation were similar, suggesting a generalized mechanism-of-action for all TiO2 NPs. Thus, transcriptional profiling is an effective tool to determine the property-specific biological/toxicity responses induced by nanomaterials.",

keywords = "Animals, Gene Expression Regulation, Inflammation, Lung, Metal Nanoparticles, Mice, Oxidative Stress, Proteomics, Tissue Array Analysis, Titanium",

author = "Sabina Halappanavar and Saber, {Anne Thoustrup} and Nathalie Decan and Jensen, {Keld Alstrup} and Dongmei Wu and Jacobsen, {Nicklas Raun} and Charles Guo and Jacob Rogowski and Koponen, {Ismo K.} and Marcus Levin and Madsen, {Anne Mette} and Rambabu Atluri and Valentinas Snitka and Birkedal, {Renie K.} and David Rickerby and Andrew Williams and H{\aa}kan Wallin and Yauk, {Carole L} and Ulla Vogel",

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AU - Halappanavar, Sabina

AU - Saber, Anne Thoustrup

AU - Decan, Nathalie

AU - Jensen, Keld Alstrup

AU - Wu, Dongmei

AU - Jacobsen, Nicklas Raun

AU - Guo, Charles

AU - Rogowski, Jacob

AU - Koponen, Ismo K.

AU - Levin, Marcus

AU - Madsen, Anne Mette

AU - Atluri, Rambabu

AU - Snitka, Valentinas

AU - Birkedal, Renie K.

AU - Rickerby, David

AU - Williams, Andrew

AU - Wallin, Håkan

AU - Yauk, Carole L

AU - Vogel, Ulla

PY - 2015/3/1

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N2 - We applied transcriptional profiling to elucidate the mechanisms associated with pulmonary responses to titanium dioxide (TiO2 ) nanoparticles (NPs) of different sizes and surface coatings, and to determine if these responses are modified by NP size, surface area, surface modification, and embedding in paint matrices. Adult C57BL/6 mice were exposed via single intratracheal instillations to free forms of TiO2 NPs (10, 20.6, or 38 nm in diameter) with different surface coatings, or TiO2 NPs embedded in paint matrices. Controls were exposed to dispersion medium devoid of NPs. TiO2 NPs were characterized for size, surface area, chemical impurities, and agglomeration state in the exposure medium. Pulmonary transcriptional profiles were generated using microarrays from tissues collected one and 28 d postexposure. Property-specific pathway effects were identified. Pulmonary protein levels of specific inflammatory cytokines and chemokines were confirmed by ELISA. The data were collapsed to 659 differentially expressed genes (P ≤ 0.05; fold change ≥ 1.5). Unsupervised hierarchical clustering of these genes revealed that TiO2 NPs clustered mainly by postexposure timepoint followed by particle type. A pathway-based meta-analysis showed that the combination of smaller size, large deposited surface area, and surface amidation contributes to TiO2 NP gene expression response. Embedding of TiO2 NP in paint dampens the overall transcriptional effects. The magnitude of the expression changes associated with pulmonary inflammation differed across all particles; however, the underlying pathway perturbations leading to inflammation were similar, suggesting a generalized mechanism-of-action for all TiO2 NPs. Thus, transcriptional profiling is an effective tool to determine the property-specific biological/toxicity responses induced by nanomaterials.

AB - We applied transcriptional profiling to elucidate the mechanisms associated with pulmonary responses to titanium dioxide (TiO2 ) nanoparticles (NPs) of different sizes and surface coatings, and to determine if these responses are modified by NP size, surface area, surface modification, and embedding in paint matrices. Adult C57BL/6 mice were exposed via single intratracheal instillations to free forms of TiO2 NPs (10, 20.6, or 38 nm in diameter) with different surface coatings, or TiO2 NPs embedded in paint matrices. Controls were exposed to dispersion medium devoid of NPs. TiO2 NPs were characterized for size, surface area, chemical impurities, and agglomeration state in the exposure medium. Pulmonary transcriptional profiles were generated using microarrays from tissues collected one and 28 d postexposure. Property-specific pathway effects were identified. Pulmonary protein levels of specific inflammatory cytokines and chemokines were confirmed by ELISA. The data were collapsed to 659 differentially expressed genes (P ≤ 0.05; fold change ≥ 1.5). Unsupervised hierarchical clustering of these genes revealed that TiO2 NPs clustered mainly by postexposure timepoint followed by particle type. A pathway-based meta-analysis showed that the combination of smaller size, large deposited surface area, and surface amidation contributes to TiO2 NP gene expression response. Embedding of TiO2 NP in paint dampens the overall transcriptional effects. The magnitude of the expression changes associated with pulmonary inflammation differed across all particles; however, the underlying pathway perturbations leading to inflammation were similar, suggesting a generalized mechanism-of-action for all TiO2 NPs. Thus, transcriptional profiling is an effective tool to determine the property-specific biological/toxicity responses induced by nanomaterials.

KW - Animals

KW - Gene Expression Regulation

KW - Inflammation

KW - Lung

KW - Metal Nanoparticles

KW - Mice

KW - Oxidative Stress

KW - Proteomics

KW - Tissue Array Analysis

KW - Titanium

U2 - 10.1002/em.21936

DO - 10.1002/em.21936

M3 - Journal article

C2 - 25504612

SN - 0893-6692

VL - 56

SP - 245

EP - 264

JO - Environmental and Molecular Mutagenesis

JF - Environmental and Molecular Mutagenesis

IS - 2

ER -

Transcriptional profiling identifies physicochemical properties of nanomaterials that are determinants of the in vivo pulmonary response

Abstract

Keywords

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