Genomic DNA methylation signatures in different tissues after ambient air particulate matter exposure

doi:10.1016/j.ecoenv.2019.04.049

Ecotoxicology and Environmental Safety

Volume 179, 15 September 2019, Pages 175-181

https://doi.org/10.1016/j.ecoenv.2019.04.049 Get rights and content

Highlights

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Acute PM exposure down-regulated global DNA methylation in lung, heart and blood.
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Chronic PM exposure resulted in reduced global DNA methylation in most tissues.
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The global DNA hypomethylation could relate to down-regulation of Dnmt1.

Abstract:

DNA methylation (5-mc) is one of the several epigenetic markers, and is generally associated with the inhibition of gene expression. Both hyper and hypo DNA methylation are associated with the diseases. Exposure to fine particles with a diameter of 2.5 μm or less (PM_2.5) is a pervasive risk factor for cardiopulmonary mortality, metabolic disorders, cognition damage, and etc.. Recent reports pointed toward that these diseases were associated with the altered DNA methylation level of some specific-gene, potentially suggesting that the DNA methylation alteration was involved in the health hazard derived from the PM_2.5 exposure. In this study, we systematically investigated the global DNA methylation level of most tissues, including lung, heart, testis, thymus, spleen, epididymal fat, hippocampus, kidney, live, after short and long term PM_2.5 exposure. After acute PM_2.5 exposure, the global hypo-methylation in DNA was observed in lung and heart. Notably, after chronic PM_2.5 exposure, level of global DNA methylation decreased in most organs which included lung, testis, thymus, spleen, epididymal fat, hippocampus and blood. The present study systematically demonstrated the global DNA methylation changes by PM_2.5 exposure, and put forward a possible orientation for further exploring the effects of ambient air particles exposure on the specific organs.

Introduction

The Particulate Matter has been a major global public health problem that was classified as a carcinogen to humans of the IARC group I (Lim et al., 2012). Increasing evidence indicates that PM_2.5 exposure is associated with nearly all kinds of diseases, such as cardiovascular diseases (Franklin et al., 2015), diabetes mellitus (Rao et al., 2015), reproductive effects (Yan et al., 2016) and nervous system diseases (JC Chen et al., 2015a), and etc.. These diseases involve in a variety of tissues and organs, including lung (Gharibvand et al., 2017), heart (Ruckerl et al., 2006), brain (JC Chen et al., 2015a), and etc.. Although the exact etiology is still unclear, we can often find reports about the alterations of DNA methylation in some specific genes when these diseases occurred (Bind et al., 2014; R Chen et al., 2015b; Zhang et al., 2017).

DNA methylation is one of the earliest found modification pathways and most widely studied form of epigenetic modification. According to the augment of the methyl groups to DNA, it can influence the activity of DNA without changing the sequence. Furthermore, it regulates the expression of genes through the changes of chromatin structure, DNA conformation, DNA stability, and DNA-protein interactions by adding methyl to the DNA molecule. The appropriate regulation processes of DNA methylation maintain the normal physiological process of mammals. Once the abnormal methylation/demethylation occurs, diseases even tumors could be initiated. The global DNA methylation in cells or tissues could reveal the correlations between overall methylation status in certain biological processes and diseases (Dunn, 2003). Evidences showed the linkage between particulate matter (PM) exposure and DNA methylation changes (Brook et al., 2010). PM inhalation may decrease global DNA methylation and affect many biomarkers in blood (Baccarelli et al., 2009; Chen et al., 2016), as well as hypomethylation in some pro-inflammatory and inflammatory genes (Cantone et al., 2017; Wang et al., 2016). Due to the limitation of human experiment, the previous studies mainly reported the alteration of global DNA methylation in blood, and there were few reports on the effect of air particle exposure to global DNA methylation level in other tissues. Therefore, in our study, chambers for animal were used to control exposure (short and long term) to exam the effects of PM_2.5 on the global DNA methylation in some main tissues in the context of the real-world air pollution mixture.

In the present study, we focused on the variation of the global DNA methylation in major tissues of mice, including lung, heart, testis, thymus, spleen, epididymal fat, hippocampus, kidney, liver and blood, after being exposed to short and long term real-world PM. Our work will provide an orientation for further investigating the influence of PM_2.5 exposure to DNA methylation in specific organs. It is the first time to analyze DNA methylation of 10 main tissues of body after real-world PM exposure, which can help to understand the possible health effects from ambient air particles on multiple organs and systems comprehensively.

Section snippets

Ethics

All animal experimentations were conducted in compliance with the guidelines of ethical human being and animal research. The study protocol was approved by the Medicine Animal Care and Use Committee at Chinese Research Academy of Environmental Sciences (CRAES) before commencement of experiments.

Exposure protocol

The same set of chambers was used as before for animal exposure experiments (Wei et al., 2016). Briefly, the two stainless steel chambers (1.2 × 0.8 × 1.2 m) for animal exposure were paralleled at the

Pathological changes in the lungs

After acute PM_2.5 exposure, the lung of mice performed acute inflammation response, presenting as irregular alveolar cavity shape, thickened alveolar septa and inflammatory cell infiltration and a slight alveolar wall capillary congestion (Fig. 1a and b). After chronic exposure, in addition to the inflammatory response, the lung displayed alveolar wall telangiectasia, congestive and capillary decrease in unfiltered group compared to the filtered group (Fig. 1c and d). Furthermore, we found that

Discussion

DNA maintains the normal growth and development of the organisms through accurate transcription and translation process. Epigenetic modifications, typified by DNA methylation, play a significant role in life. DNA methylation can silence gene expression by blocking the interaction of transcription factors with regulatory regions of the gene (Comb and Goodman, 1990). Controversy, hypomethylation of DNA in promoter region can cause the over-expression of genes. Decreases in global DNA methylation

Conclusion

In both acute and chronic PM exposure, the quantities of DNA methylation decreased in many tissues, especially in lung and blood. The Dnmt1 interfered by PM exposure might be the main reason. To the best of our knowledge, there is no other studies reported the global DNA methylation in the main organs under PM exposure. The reduced DNA methylation level could activate the expression of some harmful genes, such as oncogene, cytokines, and etc., then lead to the adverse effect on health. The DNA

Notes

The authors declare no competing financial interest.

Acknowledgments

This work was supported by grants from the National Natural Science Foundation of China (21477119) and the fundamental research funds for central public welfare research institutes of china (2016YSKY-021) and cooperative research program of Institute of Nature and Environmental Technology, Kanazawa University, Japan (17037). The funders had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript.

References (44)

L. Cantone et al.
Particulate matter exposure is associated with inflammatory gene methylation in obese subjects
Environ. Res.
(2017)
R. Chen et al.
DNA hypomethylation and its mediation in the effects of fine particulate air pollution on cardiovascular biomarkers: a randomized crossover trial
Environ. Int.
(2016)
R. Ding et al.
Characteristics of DNA methylation changes induced by traffic-related air pollution
Mutat. Res. Genet. Toxicol. Environ. Mutagen
(2016)
R. Franco et al.
Oxidative stress, DNA methylation and carcinogenesis
Cancer Lett.
(2008)
B.A. Franklin et al.
Air pollution and cardiovascular disease
Curr. Probl. Cardiol.
(2015)
S.S. Lim et al.
A comparative risk assessment of burden of disease and injury attributable to 67 risk factors and risk factor clusters in 21 regions, 1990-2010: a systematic analysis for the global burden of disease study 2010
Lancet
(2012)
X. Liu et al.
The reproductive toxicology of male sd rats after pm2.5 exposure mediated by the stimulation of endoplasmic reticulum stress
Chemosphere
(2017)
M. Okano et al.
DNA methyltransferases dnmt3a and dnmt3b are essential for de novo methylation and mammalian development
Cell
(1999)
M.P. Turunen et al.
Epigenetics and atherosclerosis
Biochim. Biophys. Acta
(2009)
C. Wang et al.
Personal exposure to fine particulate matter and blood pressure: a role of angiotensin converting enzyme and its DNA methylation
Environ. Int.
(2016)

S. Zaina et al.

Nutrition and aberrant DNA methylation patterns in atherosclerosis: more than just hyperhomocysteinemia?

J. Nutr.

(2005)

A. Baccarelli et al.

Epigenetics and environmental chemicals

Curr. Opin. Pediatr.

(2009)

A. Baccarelli et al.

Rapid DNA methylation changes after exposure to traffic particles

Am. J. Respir. Crit. Care Med.

(2009)

A. Baccarelli et al.

Repetitive element DNA methylation and circulating endothelial and inflammation markers in the va normative aging study

Epigenetics

(2010)

A. Bellavia et al.

DNA hypomethylation, ambient particulate matter, and increased blood pressure: findings from controlled human exposure experiments

J Am Heart Assoc

(2013)

M.-A. Bind et al.

Air pollution and gene-specific methylation in the normative aging study: association, effect modification, and mediation analysis

Epigenetics

(2014)

S. Braber et al.

Inflammatory changes in the airways of mice caused by cigarette smoke exposure are only partially reversed after smoking cessation

Respir. Res.

(2010)

C.V. Breton et al.

Particulate matter, DNA methylation in nitric oxide synthase, and childhood respiratory disease

Environ. Health Perspect.

(2012)

R.D. Brook et al.

Particulate matter air pollution and cardiovascular disease an update to the scientific statement from the american heart association

Circulation

(2010)

F. Cetta et al.

Linking environmental particulate matter with genetic alterations

Environ. Health Perspect.

(2009)

J.C. Chen et al.

Ambient air pollution and neurotoxicity on brain structure: evidence from women's health initiative memory study

Ann. Neurol.

(2015)

R. Chen et al.

Fine particulate matter constituents, nitric oxide synthase DNA methylation and exhaled nitric oxide

Environ. Sci. Technol.

(2015)

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Genomic DNA methylation signatures in different tissues after ambient air particulate matter exposure

Highlights

Abstract:

Introduction

Section snippets

Ethics

Exposure protocol

Pathological changes in the lungs

Discussion

Conclusion

Notes

Acknowledgments

Environ. Res.

Environ. Int.

Mutat. Res. Genet. Toxicol. Environ. Mutagen

Cancer Lett.

Curr. Probl. Cardiol.

Lancet

Chemosphere

Cell

Biochim. Biophys. Acta

Environ. Int.

J. Nutr.

Epigenetics and environmental chemicals

Curr. Opin. Pediatr.

Rapid DNA methylation changes after exposure to traffic particles

Am. J. Respir. Crit. Care Med.

Repetitive element DNA methylation and circulating endothelial and inflammation markers in the va normative aging study

Epigenetics

DNA hypomethylation, ambient particulate matter, and increased blood pressure: findings from controlled human exposure experiments

J Am Heart Assoc

Air pollution and gene-specific methylation in the normative aging study: association, effect modification, and mediation analysis

Epigenetics

Inflammatory changes in the airways of mice caused by cigarette smoke exposure are only partially reversed after smoking cessation

Respir. Res.

Particulate matter, DNA methylation in nitric oxide synthase, and childhood respiratory disease

Environ. Health Perspect.

Particulate matter air pollution and cardiovascular disease an update to the scientific statement from the american heart association

Circulation

Linking environmental particulate matter with genetic alterations

Environ. Health Perspect.

Ambient air pollution and neurotoxicity on brain structure: evidence from women's health initiative memory study

Ann. Neurol.

Fine particulate matter constituents, nitric oxide synthase DNA methylation and exhaled nitric oxide

Environ. Sci. Technol.