Impact of long-term exposure to PM2.5 on peripheral blood gene expression pathways involved in cell signaling and immune response

Jelle Vlaanderen; Roel Vermeulen; Matthew Whitaker; Marc Chadeau-Hyam; Jouke Jan Hottenga; Eco de Geus; Gonneke Willemsen; Brenda W.J.H. Penninx; Rick Jansen; Dorret I. Boomsma

doi:10.1016/j.envint.2022.107491

Impact of long-term exposure to PM_2.5 on peripheral blood gene expression pathways involved in cell signaling and immune response

Jelle Vlaanderen^*, Roel Vermeulen, Matthew Whitaker, Marc Chadeau-Hyam, Jouke Jan Hottenga, Eco de Geus, Gonneke Willemsen, Brenda W.J.H. Penninx, Rick Jansen, Dorret I. Boomsma

^*Corresponding author for this work

Research output: Contribution to Journal › Article › Academic › peer-review

Abstract

Background: Exposure to ambient air pollution, even at low levels, is a major environmental health risk. The peripheral blood transcriptome provides a potential avenue for the elucidation of ambient air pollution related biological perturbations. We assessed the association between long-term estimates for seven priority air pollutants and perturbations in peripheral blood transcriptomics data collected in the Dutch National Twin Register (NTR) and Netherlands Study of Depression and Anxiety (NESDA) cohorts. Methods: In both the discovery (n = 2438) and replication (n = 1567) cohort, outdoor concentration of 7 air pollutants (NO₂, NO_x, particulate matter (PM_2.5, PM_2.5abs, PM₁₀, PM_coarse), and ultrafine particles) was predicted with land use regression models. Gene expression was assessed by Affymetrix U219 arrays. Multi-variable univariate mixed-effect models were applied to test for an association between the air pollutants and the transcriptome. Functional analysis was conducted in DAVID. Results: In the discovery cohort, we observed for 335 genes (374 probes with FDR < 5 %) a perturbation in peripheral blood gene expression that was associated with long-term average levels of PM_2.5. For 69 genes pooled effect estimates from the NTR and NESDA cohorts were significant. Identified genes play a role in biological pathways related to cell signaling and immune response. Sixty-two out of 69 genes had a similar direction of effect in an analysis in which we regressed the probes on differential PM_2.5 exposure within monozygotic twin pairs, indicating that the observed differences in gene expression were likely driven by differences in air pollution, rather than by confounding by genetic factors. Conclusion: Our results indicate that PM_2.5 can elicit a response in cell signaling and the immune system, both hallmarks of environmental diseases. The differential effect that we observed between air pollutants may aid in the understanding of differential health effects that have been observed with these exposures.

Original language	English
Article number	107491
Journal	Environment International
Volume	168
DOIs	https://doi.org/10.1016/j.envint.2022.107491
Publication status	Published - Oct 2022

Bibliographical note

Funding Information:
Funding: This work was supported by the European Union’s Horizon 2020 research and innovation programme under grant agreement No 874627 (EXPANSE) and by the US National Institute of Mental Health (RC2 MH089951, PI Sullivan) as part of the American Recovery and Reinvestment Act of 2009. The Netherlands Study of Depression and Anxiety (NESDA) and the Netherlands Twin Register (NTR) acknowledge funding by the Netherlands Organization for Scientific Research (MagW/ZonMW grants 904-61-090, 985-10-002,904-61-193,480-04-004, 400-05-717, 912-100-20; Spinozapremie 56-464-14192; Geestkracht program grant 10-000-1002); Biobanking and Biomolecular Resources Research Infrastructure (BBMRI-NL); the European Science Foundation (EU/QLRT-2001-01254); the European Community's Seventh Framework Program (FP7/2007-2013); ENGAGE (HEALTH-F4-2007-201413); and the European Research Council (ERC, 230374).

Funding Information:
Funding: This work was supported by the European Union's Horizon 2020 research and innovation programme under grant agreement No 874627 (EXPANSE) and by the US National Institute of Mental Health (RC2 MH089951, PI Sullivan) as part of the American Recovery and Reinvestment Act of 2009. The Netherlands Study of Depression and Anxiety (NESDA) and the Netherlands Twin Register (NTR) acknowledge funding by the Netherlands Organization for Scientific Research (MagW/ZonMW grants 904-61-090, 985-10-002,904-61-193,480-04-004, 400-05-717, 912-100-20; Spinozapremie 56-464-14192; Geestkracht program grant 10-000-1002); Biobanking and Biomolecular Resources Research Infrastructure (BBMRI-NL); the European Science Foundation (EU/QLRT-2001-01254); the European Community's Seventh Framework Program (FP7/2007-2013); ENGAGE (HEALTH-F4-2007-201413); and the European Research Council (ERC, 230374).

Publisher Copyright:
© 2022 The Author(s)

Funding

Funding: This work was supported by the European Union’s Horizon 2020 research and innovation programme under grant agreement No 874627 (EXPANSE) and by the US National Institute of Mental Health (RC2 MH089951, PI Sullivan) as part of the American Recovery and Reinvestment Act of 2009. The Netherlands Study of Depression and Anxiety (NESDA) and the Netherlands Twin Register (NTR) acknowledge funding by the Netherlands Organization for Scientific Research (MagW/ZonMW grants 904-61-090, 985-10-002,904-61-193,480-04-004, 400-05-717, 912-100-20; Spinozapremie 56-464-14192; Geestkracht program grant 10-000-1002); Biobanking and Biomolecular Resources Research Infrastructure (BBMRI-NL); the European Science Foundation (EU/QLRT-2001-01254); the European Community's Seventh Framework Program (FP7/2007-2013); ENGAGE (HEALTH-F4-2007-201413); and the European Research Council (ERC, 230374). Funding: This work was supported by the European Union's Horizon 2020 research and innovation programme under grant agreement No 874627 (EXPANSE) and by the US National Institute of Mental Health (RC2 MH089951, PI Sullivan) as part of the American Recovery and Reinvestment Act of 2009. The Netherlands Study of Depression and Anxiety (NESDA) and the Netherlands Twin Register (NTR) acknowledge funding by the Netherlands Organization for Scientific Research (MagW/ZonMW grants 904-61-090, 985-10-002,904-61-193,480-04-004, 400-05-717, 912-100-20; Spinozapremie 56-464-14192; Geestkracht program grant 10-000-1002); Biobanking and Biomolecular Resources Research Infrastructure (BBMRI-NL); the European Science Foundation (EU/QLRT-2001-01254); the European Community's Seventh Framework Program (FP7/2007-2013); ENGAGE (HEALTH-F4-2007-201413); and the European Research Council (ERC, 230374).

Funders	Funder number
BBMRI-NL
Biobanking and Biomolecular Resources Research Infrastructure
ENGAGE	HEALTH-F4-2007-201413
Spinozapremie	10-000-1002, 56-464-14192
National Institute of Mental Health	RC2MH089951
Horizon 2020 Framework Programme
Seventh Framework Programme	FP7/2007-2013
European Research Council	230374
European Science Foundation	EU/QLRT-2001-01254
Nederlandse Organisatie voor Wetenschappelijk Onderzoek	912-100-20, 985-10-002,904-61-193,480-04-004, 904-61-090, 400-05-717
Horizon 2020	874627

Keywords

Air pollution
Biological pathways
Cell signaling
Immune system
Molecular epidemiology
Transcriptomics

UN SDGs

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

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10.1016/j.envint.2022.107491

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Cite this

Vlaanderen, J., Vermeulen, R., Whitaker, M., Chadeau-Hyam, M., Hottenga, J. J., de Geus, E., Willemsen, G., Penninx, B. W. J. H., Jansen, R., & Boomsma, D. I. (2022). Impact of long-term exposure to PM_2.5 on peripheral blood gene expression pathways involved in cell signaling and immune response. Environment International, 168, Article 107491. https://doi.org/10.1016/j.envint.2022.107491

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title = "Impact of long-term exposure to PM2.5 on peripheral blood gene expression pathways involved in cell signaling and immune response",

abstract = "Background: Exposure to ambient air pollution, even at low levels, is a major environmental health risk. The peripheral blood transcriptome provides a potential avenue for the elucidation of ambient air pollution related biological perturbations. We assessed the association between long-term estimates for seven priority air pollutants and perturbations in peripheral blood transcriptomics data collected in the Dutch National Twin Register (NTR) and Netherlands Study of Depression and Anxiety (NESDA) cohorts. Methods: In both the discovery (n = 2438) and replication (n = 1567) cohort, outdoor concentration of 7 air pollutants (NO2, NOx, particulate matter (PM2.5, PM2.5abs, PM10, PMcoarse), and ultrafine particles) was predicted with land use regression models. Gene expression was assessed by Affymetrix U219 arrays. Multi-variable univariate mixed-effect models were applied to test for an association between the air pollutants and the transcriptome. Functional analysis was conducted in DAVID. Results: In the discovery cohort, we observed for 335 genes (374 probes with FDR < 5 %) a perturbation in peripheral blood gene expression that was associated with long-term average levels of PM2.5. For 69 genes pooled effect estimates from the NTR and NESDA cohorts were significant. Identified genes play a role in biological pathways related to cell signaling and immune response. Sixty-two out of 69 genes had a similar direction of effect in an analysis in which we regressed the probes on differential PM2.5 exposure within monozygotic twin pairs, indicating that the observed differences in gene expression were likely driven by differences in air pollution, rather than by confounding by genetic factors. Conclusion: Our results indicate that PM2.5 can elicit a response in cell signaling and the immune system, both hallmarks of environmental diseases. The differential effect that we observed between air pollutants may aid in the understanding of differential health effects that have been observed with these exposures.",

keywords = "Air pollution, Biological pathways, Cell signaling, Immune system, Molecular epidemiology, Transcriptomics",

author = "Jelle Vlaanderen and Roel Vermeulen and Matthew Whitaker and Marc Chadeau-Hyam and Hottenga, {Jouke Jan} and {de Geus}, Eco and Gonneke Willemsen and Penninx, {Brenda W.J.H.} and Rick Jansen and Boomsma, {Dorret I.}",

note = "Funding Information: Funding: This work was supported by the European Union{\textquoteright}s Horizon 2020 research and innovation programme under grant agreement No 874627 (EXPANSE) and by the US National Institute of Mental Health (RC2 MH089951, PI Sullivan) as part of the American Recovery and Reinvestment Act of 2009. The Netherlands Study of Depression and Anxiety (NESDA) and the Netherlands Twin Register (NTR) acknowledge funding by the Netherlands Organization for Scientific Research (MagW/ZonMW grants 904-61-090, 985-10-002,904-61-193,480-04-004, 400-05-717, 912-100-20; Spinozapremie 56-464-14192; Geestkracht program grant 10-000-1002); Biobanking and Biomolecular Resources Research Infrastructure (BBMRI-NL); the European Science Foundation (EU/QLRT-2001-01254); the European Community's Seventh Framework Program (FP7/2007-2013); ENGAGE (HEALTH-F4-2007-201413); and the European Research Council (ERC, 230374). Funding Information: Funding: This work was supported by the European Union's Horizon 2020 research and innovation programme under grant agreement No 874627 (EXPANSE) and by the US National Institute of Mental Health (RC2 MH089951, PI Sullivan) as part of the American Recovery and Reinvestment Act of 2009. The Netherlands Study of Depression and Anxiety (NESDA) and the Netherlands Twin Register (NTR) acknowledge funding by the Netherlands Organization for Scientific Research (MagW/ZonMW grants 904-61-090, 985-10-002,904-61-193,480-04-004, 400-05-717, 912-100-20; Spinozapremie 56-464-14192; Geestkracht program grant 10-000-1002); Biobanking and Biomolecular Resources Research Infrastructure (BBMRI-NL); the European Science Foundation (EU/QLRT-2001-01254); the European Community's Seventh Framework Program (FP7/2007-2013); ENGAGE (HEALTH-F4-2007-201413); and the European Research Council (ERC, 230374). Publisher Copyright: {\textcopyright} 2022 The Author(s)",

year = "2022",

month = oct,

doi = "10.1016/j.envint.2022.107491",

language = "English",

volume = "168",

journal = "Environment International",

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TY - JOUR

T1 - Impact of long-term exposure to PM2.5 on peripheral blood gene expression pathways involved in cell signaling and immune response

AU - Vlaanderen, Jelle

AU - Vermeulen, Roel

AU - Whitaker, Matthew

AU - Chadeau-Hyam, Marc

AU - Hottenga, Jouke Jan

AU - de Geus, Eco

AU - Willemsen, Gonneke

AU - Penninx, Brenda W.J.H.

AU - Jansen, Rick

AU - Boomsma, Dorret I.

N1 - Funding Information: Funding: This work was supported by the European Union’s Horizon 2020 research and innovation programme under grant agreement No 874627 (EXPANSE) and by the US National Institute of Mental Health (RC2 MH089951, PI Sullivan) as part of the American Recovery and Reinvestment Act of 2009. The Netherlands Study of Depression and Anxiety (NESDA) and the Netherlands Twin Register (NTR) acknowledge funding by the Netherlands Organization for Scientific Research (MagW/ZonMW grants 904-61-090, 985-10-002,904-61-193,480-04-004, 400-05-717, 912-100-20; Spinozapremie 56-464-14192; Geestkracht program grant 10-000-1002); Biobanking and Biomolecular Resources Research Infrastructure (BBMRI-NL); the European Science Foundation (EU/QLRT-2001-01254); the European Community's Seventh Framework Program (FP7/2007-2013); ENGAGE (HEALTH-F4-2007-201413); and the European Research Council (ERC, 230374). Funding Information: Funding: This work was supported by the European Union's Horizon 2020 research and innovation programme under grant agreement No 874627 (EXPANSE) and by the US National Institute of Mental Health (RC2 MH089951, PI Sullivan) as part of the American Recovery and Reinvestment Act of 2009. The Netherlands Study of Depression and Anxiety (NESDA) and the Netherlands Twin Register (NTR) acknowledge funding by the Netherlands Organization for Scientific Research (MagW/ZonMW grants 904-61-090, 985-10-002,904-61-193,480-04-004, 400-05-717, 912-100-20; Spinozapremie 56-464-14192; Geestkracht program grant 10-000-1002); Biobanking and Biomolecular Resources Research Infrastructure (BBMRI-NL); the European Science Foundation (EU/QLRT-2001-01254); the European Community's Seventh Framework Program (FP7/2007-2013); ENGAGE (HEALTH-F4-2007-201413); and the European Research Council (ERC, 230374). Publisher Copyright: © 2022 The Author(s)

PY - 2022/10

Y1 - 2022/10

N2 - Background: Exposure to ambient air pollution, even at low levels, is a major environmental health risk. The peripheral blood transcriptome provides a potential avenue for the elucidation of ambient air pollution related biological perturbations. We assessed the association between long-term estimates for seven priority air pollutants and perturbations in peripheral blood transcriptomics data collected in the Dutch National Twin Register (NTR) and Netherlands Study of Depression and Anxiety (NESDA) cohorts. Methods: In both the discovery (n = 2438) and replication (n = 1567) cohort, outdoor concentration of 7 air pollutants (NO2, NOx, particulate matter (PM2.5, PM2.5abs, PM10, PMcoarse), and ultrafine particles) was predicted with land use regression models. Gene expression was assessed by Affymetrix U219 arrays. Multi-variable univariate mixed-effect models were applied to test for an association between the air pollutants and the transcriptome. Functional analysis was conducted in DAVID. Results: In the discovery cohort, we observed for 335 genes (374 probes with FDR < 5 %) a perturbation in peripheral blood gene expression that was associated with long-term average levels of PM2.5. For 69 genes pooled effect estimates from the NTR and NESDA cohorts were significant. Identified genes play a role in biological pathways related to cell signaling and immune response. Sixty-two out of 69 genes had a similar direction of effect in an analysis in which we regressed the probes on differential PM2.5 exposure within monozygotic twin pairs, indicating that the observed differences in gene expression were likely driven by differences in air pollution, rather than by confounding by genetic factors. Conclusion: Our results indicate that PM2.5 can elicit a response in cell signaling and the immune system, both hallmarks of environmental diseases. The differential effect that we observed between air pollutants may aid in the understanding of differential health effects that have been observed with these exposures.

AB - Background: Exposure to ambient air pollution, even at low levels, is a major environmental health risk. The peripheral blood transcriptome provides a potential avenue for the elucidation of ambient air pollution related biological perturbations. We assessed the association between long-term estimates for seven priority air pollutants and perturbations in peripheral blood transcriptomics data collected in the Dutch National Twin Register (NTR) and Netherlands Study of Depression and Anxiety (NESDA) cohorts. Methods: In both the discovery (n = 2438) and replication (n = 1567) cohort, outdoor concentration of 7 air pollutants (NO2, NOx, particulate matter (PM2.5, PM2.5abs, PM10, PMcoarse), and ultrafine particles) was predicted with land use regression models. Gene expression was assessed by Affymetrix U219 arrays. Multi-variable univariate mixed-effect models were applied to test for an association between the air pollutants and the transcriptome. Functional analysis was conducted in DAVID. Results: In the discovery cohort, we observed for 335 genes (374 probes with FDR < 5 %) a perturbation in peripheral blood gene expression that was associated with long-term average levels of PM2.5. For 69 genes pooled effect estimates from the NTR and NESDA cohorts were significant. Identified genes play a role in biological pathways related to cell signaling and immune response. Sixty-two out of 69 genes had a similar direction of effect in an analysis in which we regressed the probes on differential PM2.5 exposure within monozygotic twin pairs, indicating that the observed differences in gene expression were likely driven by differences in air pollution, rather than by confounding by genetic factors. Conclusion: Our results indicate that PM2.5 can elicit a response in cell signaling and the immune system, both hallmarks of environmental diseases. The differential effect that we observed between air pollutants may aid in the understanding of differential health effects that have been observed with these exposures.

KW - Air pollution

KW - Biological pathways

KW - Cell signaling

KW - Immune system

KW - Molecular epidemiology

KW - Transcriptomics

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