Acute particulate matter affects cardiovascular autonomic modulation and IFN-γ methylation in healthy volunteers

doi:10.1016/j.envres.2017.10.036

Environmental Research

Volume 161, February 2018, Pages 97-103

https://doi.org/10.1016/j.envres.2017.10.036 Get rights and content

Highlights

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In healthy subjects, acute exposure to PM affects vagal autonomic control of the heart.
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PM exposure increases methylation of a pro-inflammatory gene, i.e. methylation of interferon γ (IFN- γ).
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PM per se is able to trigger autonomic deregulation and inflammation in a dose-dependent manner.

Abstract

Aims

Air particulate matter (PM) is associated with increased cardiovascular morbidity and mortality. Altered autonomic functions play a key role in PM-induced cardiovascular disease. However, previous studies have not address the impact of PM on sympathetic and parasympathetic control of heart function, independently, and using controlled conditions, i.e., increasing titration of PM of known composition, in absence of other potential confounding factors. To fill this gap, here we used symbolic analysis that is capable of detecting non-mutual changes of the two autonomic branches, thus considering them as independent, and concentrations of PM as they could be measured at peak levels in Milan during a polluted winter day.

Methods and results

In this randomized, cross-over study, we enrolled 12 healthy subjects who underwent two random sessions: inhalation of filtered air mixture or inhalation of filtered air containing particulate mixture (PM 10, PM 2.5, PM 1.0 and PM 0.5 µm). ECG and respiration for autonomic analysis and blood sample for DNA Methylation were collected at baseline (T1), after air exposure (T2) and after 2 h (T3). Spectral and symbolic analysis of heart rate variability (HRV) were performed for autonomic control of cardiac function, while alterations in DNA methylation of candidate genes were used to index pro-inflammatory modifications. In the PM expose group, autonomic analysis revealed a significant decrease of 2UV%, index of parasympathetic modulation (14% vs 9%, p = 0.0309), while DNA analysis showed a significant increase of interferon γ (IFN- γ) methylation, from T1 to T3. In a mixed model using T1, T2 and T3, fine and ultrafine PM fractions showed significant associations with IFN- γ methylation and parasympathetic modulation.

Conclusions

Our study shows, for the first time, that in healthy subjects, acute exposure to PM affects parasympathetic control of heart function and it increases methylation of a pro-inflammatory gene (i.e. methylation of interferon γ). Thus, our study suggests that, even in absence of other co-factors and in otherwise healthy individuals, PM per se is sufficient to trigger parasympathetic dysautonomia, independently from changes in sympathetic control, and inflammation, in a dose-dependent manner.

Introduction

How air pollution affects human health has been the subject of an intense investigation during the last decade (Dominici et al., 2006, Pope et al., 2004, Brook et al., 2010, Pieters et al., 2012). Studies have highlighted the contribution of autonomic dysfunction in the cardiovascular disorders caused or favored by particular matter in the inhaled air (Lipsett et al., 2006). In fact, air pollutants can cause an activation of pulmonary reflexes and pass through the pulmonary epithelium in the circulation, triggering changes of the sympathovagal balance (Miller et al., 2007). This state is characterized by a predominant sympathetic modulation and a decreased vagal control, a condition notoriously associated with increased cardiovascular risk (Creason et al., 2001, Gold et al., 2000). Retrospective studies have shown a significant association dose-response behavior between particulate matter (PM) exposition and alterations of heart rate variability (HRV) in healthy subjects (Creason et al., 2001, Vallejo et al., 2006) as well as in patients with cardiorespiratory (Gold et al., 2000, Vallejo et al., 2006, Park et al., 2005) and metabolic diseases (Huang et al., 2012a). In addition, changes in the coagulation pathway, namely the balance between thrombotic and fibrinolytic mechanisms (Mills et al., 2005), in the inflammatory state (Behndig et al., 2006) and in the metabolic insulin sensitivity (Brook et al., 2013) have also been described.

The pathophysiological mechanisms underlying these multifactorial systemic changes induced by PM are still unclear. This lack of knowledge may stem from the difficulty to evaluate the effects of acute exposure to PM in experimental controlled human models (Mills et al., 2011, Bhaskaran et al., 2011). Moreover, the response to such a broad stimulus, as air pollution exposition, is determined in part through a genotypic-phenotypic interaction that still needs to be elucidated. Epigenetics represents a possible link between genomic coding and phenotype expression that is influenced by both underlying genetic and environmental factors (Baccarelli and Bollati, 2009). Among epigenetic mechanisms, DNA methylation is the best understood one. In mammals, this covalent modification occurs primarily in CpG dinucleotides to form 5-methylcytosines (Handy et al., 2011), and CpG hypermethylation is generally associated with gene silencing. DNA-methylation levels may change over an individual’s lifetime after exposure to different pollutants, and they have been shown to regulate biological processes underlying cardiovascular diseases (Baccarelli et al., 2010). Moreover, animal models have proved that DNA methylation has a critical role in the development of cardiovascular diseases (Baccarelli et al., 2010, Chen et al., 2001).

Despite increasing evidence supporting particulate matter and air pollution as major culprits for cardiovascular affections displaying major pro-inflammatory alterations, the vast majority of previous investigations were conducted in real world scenarios, i.e., in settings whereby many possible confounding factors may intervene and are not checked for. This problem is particularly acute when autonomic dysfunction after exposure to pollutants was examined.

Therefore, in order to fill this gap, here we sought to determine the impact of titrated, increasing exposure to particulate matter of known composition, independently from other confounding cofactors, on cardiac autonomic functions and DNA-methylation, as a major index of epigenetic modifications, in young otherwise healthy individuals.

Section snippets

Study population

We enrolled 12 young healthy males, non-smokers, without any past medical history. They underwent a complete physical examination to exclude any overt cardiovascular, respiratory or metabolic disorder. None of the subjects was under chronic drug treatment and did not practice agonistic physical activity (more than 2 times of physical activity per week). All the volunteers lived in Milan or in Milan county area, and had therefore comparable levels of outdoor baseline air pollution.

Statistical analysis

Standard descriptive statistics was used to summarize baseline characteristic of patients and spectral, symbolic and methylation parameters. Data were expressed as the mean ± SD or as the median and interquartile range (Q1-Q3) as appropriate. Methylation measurements were expressed as the mean of the methylation measured in each CpG considered. A two way ANOVA was applied to evaluate differences among the spectral, symbolic and methylation parameters at the three time points, for each

Results

All the volunteers were young healthy subjects (mean age 25.1 ± 2.2 yr, BMI range 18–28). Basal heart rate (HR) and systolic arterial pressure (SAP) were within normality range (73.4 ± 8.3 bpm and 115.4 ± 6.2 mmHg respectively).

Discussion

How air particulate matter (PM) affects cardiac function, and cardiac autonomic balance in particular, remains ill-defined.

Several epidemiological studies showed that air PM is linked to cardiovascular morbidity and mortality both in healthy and diseased subjects (Dominici et al., 2006, Pope et al., 2004, Brook et al., 2010). Different pathophysiological mechanisms have been postulated to play a key role in this association, such as an altered inflammatory response (Behndig et al., 2006), a

Declaration section

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The Internal Review Board of L. Sacco Hospital (IRB number 2015/ST/008) approved the protocol and all the volunteers signed an informed consent before the beginning of the experiments.
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Please contact author for data requests.
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Consent for publication: Not applicable
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Disclosures: All authors declare no disclosures.
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Sources of Funding: Dr. Bollati received support from the EU Programme “Ideas” (ERC-2011-StG 282413). Dr. Baccarelli received support from the R01ES025225 from National Institute of

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¹: Both authors equally contributed to the manuscript.

View full text

Acute particulate matter affects cardiovascular autonomic modulation and IFN-γ methylation in healthy volunteers

Highlights

Abstract

Aims

Methods and results

Conclusions

Introduction

Section snippets

Study population

Statistical analysis

Results

Discussion

Declaration section

Sci. Total Environ.

Am. J. Cardiol.

Environ. Res.

Neurosci. Biobehav. Rev.

Neuron

Auton. Neurosci.

Epigenetics and environmental chemicals

Curr. Opin. Pediatr.

Cardiovascular epigenetics: basic concepts and results from animal and human studies

Circ. Cardiovasc. Genet.

Airway antioxidant and inflammatory responses to diesel exhaust exposure in healthy humans

Eur. Respir. J.

Cardiovascular consequences of air pollution: what are the mechanisms?

Heart

Air pollution and gene-specific methylation in the Normative Aging Study: association, effect modification, and mediation analysis

Epigenetics

Particulate matter air pollution and cardiovascular disease: an update to the scientific statement from the American Heart Association

Circulation

Mice deficient in methylenetetrahydrofolate reductase exhibit hyperhomocysteinemia and decreased methylation capacity, with neuropathology and aortic lipid deposition

Hum. Mol. Genet.

Particulate matter and heart rate variability among elderly retirees: the Baltimore 1998 PM study

J. Expo. Anal. Environ. Epidemiol.

Fine particulate air pollution and hospital admission for cardiovascular and respiratory diseases

J. Am. Med. Assoc.

Heart rate variability and DNA methylation levels are altered after short-term metal fume exposure among occupational welders: a repeated-measures panel study

BMC Public Health

Ambient pollution and heart rate variability

Circulation