Journal of Environmental Protection, 2013, 4, 114-122
http://dx.doi.org/10.4236/jep.2013.48A1014 Published Online August 2013 (http://www.scirp.org/journal/jep)
Air Pollution and Epigenetics
Aleena Syed, Kinjal Hew, Arunima Kohli, Greg Knowlton, Kari C. Nadeau
Department of Pediatrics, Division of Immunology, Allergy and Rheumatology, Stanford University School of Medicine, Stanford,
USA.
Received May 25th, 2013; revised June 29th, 2013; accepted July 26th, 2013
Copyright © 2013 Aleena Syed et al. This is an open access article distributed under the Creative Commons Attribution License,
which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
ABSTRACT
Air pollution is a global problem with far-reaching environmental impacts. Exposure has been linked to a number of
different adverse health effects. Understanding the impact of ambient air pollution is complicated given the diversity of
both the pollutants involved as well as the complexity of associated diseases. While we see a positive correlation be-
tween levels of exposure and health issues, the mechanisms of pathogenesis are still under investigation. The study of
epigenetic regulation as it relates to disease is emerging as an exciting new way to interpret the possible effects of am-
bient air pollution on DNA. In this review we provide an overview of epigenetic modifications as well as an analysis of
how epigenetic mechanisms are involved in the adverse effects associated with the most common components of ambi-
ent air pollution.
Keywords: Air Pollution; Epigenetics; DNA Methylation; Histone Acetylation; microRNA; PAH; DEP; Ozone
1. Introduction
Recent epidemiological studies have shown that ambient
air pollution exposure is associated with increased mor-
tality and higher incidence of respiratory diseases such as
asthma, chronic obstructive pulmonary disease, and can-
cer [1]. Adverse impacts of air pollutant exposure have a
profound effect on morbidity and mortality; according to
one study, ambient air pollution caused 6% of total mor-
tality, or more than 40,000 attributable cases, per year
[2].
In general, the worldwide trend is towards a reduction
in the concentrations of air pollutants because of increas-
ingly strong restrictions from local governments and in-
ternational organizations. In developing countries, rising
concentrations of air pollutants pose an imminent threat
to public health, and even in countries that have made the
improvements necessary to meet World Health Organiza-
tion (WHO) air quality standards, the adverse health ef-
fects of air pollutants remain problematic [3,4].
Major air pollutants that have been linked to adverse
health outcomes include polycyclic aromatic hydrocar-
bons (PAH), ozone, particulate matter (PM) and diesel
exhaust particles (DEP), and cigarette smoke [5-8]. Al-
though studies have found an associative link between
ambient air pollution and the incidence of respiratory
diseases, the exact, causative mechanisms of these air
pollutants are not yet fully understood. Recently, numer-
ous publications have linked induction of diseases such
as asthma via ambient air pollution exposure to epige-
netic mechanisms, among others [9-12]. Epigenetics is
defined as the study of heritable changes in gene expres-
sion that do not affect underlying DNA sequences. The
most common epigenetic mechanisms include DNA me-
thylation, histone modifications, and microRNA (miRNA)
[13]. This review aims to provide a brief overview of
epigenetic modifications (summarized in Figure 1) and
explain the mechanisms through which the primary types
of ambient air pollution can lead to adverse health ef-
fects.
2. Epigenetic Mechanisms
2.1. DNA Methylation
DNA methylation is necessary for regulating normal gene
expression and can be greatly impacted by environmental
factors. Methylation changes are reversible and mediated
by DNA methyltransferase (DNMT) and demethylase.
The addition of methyl groups generally occurs at cyto-
sine residues adjacent to guanine nucleotides (CpG sites)
within enhancer regions of candidate genes. The addition
of methyl groups (methylation) prevents transcription,
silencing gene expression. By contrast, the removal of
methyl groups (demethylation) allows transcription

Air Pollution and Epigenetics 115
Figure 1. Epigenetic mechanisms involved in air pollutant
induced adverse health effects.
factor binding, activating and enhancing gene expression.
Methylation changes are dynamic and have been impli-
cated in the natural course of mammalian development
[14]. Environmental factors like ambient air pollution can
affect global methylation patterns. Some of these epige-
netic changes have been linked to disease.
2.2. Histone Acetylation
Histones are highly alkaline proteins that arrange DNA
into structures known as nucleosomes. These nucleosomes
function like spools around which the DNA coils, playing
an important role in the regulation of gene accessibility
[15]. Modifications to the histones therefore alter this
regulation. Several potential modification mechanisms
exist, including: 1) Acetylation, whereby acetyltrans-
ferases add an acetyl group to lysine residues in the his-
tone tail, neutralizing their positive charge and therefore
decreasing histones’ affinity for DNA and increasing
transcription; 2) Methylation, which—similarly to DNA
methylation—involves the transfer of a methyl group by
methyltransferases to or from lysine or arginine to create
an unmodified, mono-, di-, or tri-methylated state, with
certain modifications (H3K4me and H3K36me) associ-
ated with activation of transcription and others associated
with repression of transcription (H3K9 and H3K27); 3)
Phosphorylation, the addition of a phosphate group,
which increases the negative charge of the histone and
therefore increases repulsion between the histone and the
DNA strand, increasing accessibility of the DNA; and 4)
Ubiquitylation, in which a ubiquitin protein (76 amino
acids) is added to a lysine side chain, with varying effects
on transcription that seem to be context-dependent [15]
[16]. There appears to be cross-talk not only between
these mechanisms of histone modification, but also be-
tween histone modification and other epigenetic mecha-
nisms, i.e., DNA methylation and micro RNA [15,16].
2.3. microRNAs
MicroRNAs (miRNAs) are an abundant class of single-
stranded small non-coding RNAs, approximately 19 - 22
nucleotides long, which regulate gene expression post-
transciptionally. miRNAs typically function by nega-
tively regulating mRNA processing, stability, and trans-
lation and thereby represent a novel layer in regulation of
flow of genetic information and cellular functions.
miRNAs are encoded in genomic DNA and are tran-
scribed by RNA polymerase II into long primary tran-
scripts called pri-miRNA. This pri-miRNA is sequen-
tially processed in the cell nucleus and then in the cyto-
plasm to generate mature active miRNA [17]. Recent
evidence suggests that miRNA expression maybe impli-
cated in several developmental, inflammatory, apoptotic,
and cellular signal transduction pathways affecting mul-
tiple disease pathogenesis, including cardiovascular dis-
ease, cancer, metabolic diseases, lung development, and
respiratory disease, etc. [18-25].
3. Common Air Pollutants
3.1. Polycyclic Aromatic Hydrocarbons (PAH)
Polycyclic aromatic hydrocarbons (PAHs) represent a
complex class of environmental pollutants derived from
the incomplete combustion of organic compounds. These
relatively stable compounds are comprised of multiple,
fused, benzene rings. The major sources of PAH include
burning of biomass, wildfires, and vehicular emissions
[26,27]. The primary sources of PAH production vary
from country to country, with developing nations respon-
sible for greater emissions than developed nations due in
large part to disparities in production technology [27].
Exposure to PAH is most significant in urban regions
marked by high levels of both industrial development as
well as traffic [26,27]; significant global contributors
include China, India, and Brazil [27].
Several studies have assessed occupational health risks
in individuals exposed to disproportionate levels of PAHs,
such as traffic controllers and industrial workers [28-31].
These studies show that PAH can be a potent carcinogen
and has also been linked to adverse respiratory effects
[26,27,32,33]. Additionally, PAH exposure has been as-
sociated with the activation of DNA damage signaling,
with multiple PAHs exerting more extensive damage than
one polycyclic compound alone [34].
PAH exposure can begin in the womb and, through
epigenetic modifications, can have long-lasting effects.
Increased maternal exposure to PAH has been associated
with increased DNA methylation of the asthma related
gene acyl-CoA synthestase long-chain family member 3
(ACSL3) and subsequent increases in the prevalence of
childhood asthma [8]. In another study, in vitro exposure
was associated with hypermethylation of the asthma-

Air Pollution and Epigenetics
116
related gene interferon-gamma (IFN-γ) and consequent
decreases in its expression. IFN-γ is thought to play a
protective role in asthma and allergic disease; thus, de-
creases in expression may be pathogenic [35]. Exposure
to ambient air pollution (which includes PAHs) has been
linked to increased methylation in the forkhead box pro-
tein 3 (FOX P3) locus of regulatory T cells (Treg), and
subsequent functional deficits that could contribute to
asthma pathogenesis [36]. High levels of PAH exposure
in coke oven workers has been correlated with hy-
pomethylation of the O6-methyl-guanine-DNA methyl-
transferase (MGMT), contributing to genomic instability
in lymphocytes [28], which may in turn increase the risk
of carcinogenesis.
PAH appears to alter methylation patterns, which
could account for the far-reaching impact of both pre-
and postnatal chronic exposure to PAH. However, it is
still not clear how PAH actually alters methylation. One
hypothesis is that these epigenetic changes are mediated
via the aryl hydrocarbon receptor (AhR). AhRs are ex-
pressed on several cell types and act as an environmental
sensor for toxicity. Activation of AhR signals a number
of pathways involved in inflammation and the immune
response [37]. The effects of AhR activation appear to be
ligand-dependent; thus, different PAHs may have varied
effects. Binding of the PAH phenanthrene to AhR on the
surface of Treg cells results in increased methylation of
the FOXP3 locus. This methylation diminishes the sup-
pressive function of Treg and appears to convert them to
T helper type 2 cells (Th2) [38], producing an inflamma-
tory response. Overactivation of Th2 cells and deficits in
natural regulatory mechanisms have both been linked to
allergic disorders [39]. This imbalance may be induced
through PAH-mediated activation of AhR.
3.2. Ozone
Ground-level ozone is one of six criteria pollutants for
which National Ambient Air Quality Standards (NAAQS)
are set by the United States Environmental Protection
Agency, with the current standard set at 0.075 ppm/8h.
Epidemiological studies have demonstrated a clear
pathologic association between ambient ozone levels and
respiratory health, including respiratory allergies, lung
function deficits, increased prevalence of asthma, and
hospital admissions [40-42]. A recent study showed that
ozone inhalation contributed to both human morbidity
and mortality and each 10 parts per billion (ppb) increase
in ozone was associated with approximately a 0.52%
increase in mortality [43].
Despite the non-antigenic nature of ozone, recent evi-
dence suggests that ozone may indirectly modulate adap-
tive immunity by promoting the activation of antigen
presenting cells [44-46]. Toll-like Receptor (TLR) 4 has
been identified as an essential susceptibility gene for the
inflammatory and physiologic effects of ozone exposure
in certain mouse strains, and is an important clue to the
link between ozone and microbial immunity [47,48]. Re-
cent evidence in intestinal epithelial cells suggests that
TLR4 gene expression downregualted via epigenetic
modifications including histone deacetylation and DNA
methylation to prevent excessive inflammatory responses
[49]. Although, a similar mechanism of regulation of
TLR responses post ozone exposure might be at play in
the lung epithelial cells no studies thus far have demon-
strated this. More recently multiple miRNAs have been
implicated in the regulation of TLR4 signaling pathway
[50-56]. TLR signaling pathways consist of both MyD88
dependent and independent pathways [57]. MyD88 de-
pendent pathway signals through IRAK1 and TRAF6
leading to nuclear translocation of NFkB and activation
of AP-1. Both IRAK1 and TRAF6 are targets of miR-
146 [51]. The MyD88 independent pathway signals
through TRIF, inducing IRF transcription factors result-
ing in type 1 interferon production. TRIF and another
adaptor TAB2 in this pathway have known to be regu-
lated by miR-155 [50,58].
3.3. Particulate Matter (PM) and Deisel Exhaust
Particles (DEP)
Ambient PM has been associated with adverse health
outcomes but the mechanisms linking PM inhalation to
adverse health are not completely understood. A mouse
model study using intranasal sensitization to Aspergillus
fumigates and inhaled DEP exposure showed changes in
DNA methylation involved in two important genes in-
volved in asthma, IL-4 and IFN-γ, which positively cor-
related with increased total IgE secretion, which is in-
volved in asthma pathogenesis [59]. In humans, a recent
profiling study of 141 subjects showed that exposure to
airborne PM, particularly black carbon and sulfate were
significantly associated with changes in DNA methyla-
tion pattern of genes involved in asthma [60]. In a study
of steel plant workers exposed to PM < 10 µm, research-
ers showed significant alterations in blood DNA methy-
lation both globally in the Alu and LINE-1 repetitive
elements, involved in immune inflammatory response, as
well as gene-specific methylation of iNOS promoter [10].
Oxidative and nitrosative stress have been implicated in
mediating airway inflammation involved in asthma de-
velopment and fractional concentration of exhaled nitric
oxide (FeNO) has been used a biomarker to predict air-
way inflammation and asthma development.
Multiple studies show evidence of PM with ozone ex-
posure linked to higher levels of FeNO, particularly in
children [61-63]. The first study to show evidence linking
PM exposure induced epigenetic modification with phe-
notype expression showed a significant association be-
tween exposure to short term (7 days) of PM < 2.5 µm

Air Pollution and Epigenetics 117
with lower NOS2 methylation and correlation with FeNO
levels [64]. A global methylation profiling study, using
mice to mimic long term exposure of humans to ambient
particulate air pollution near steel mills and major high-
ways, showed hypermethylation in sperm DNA, which
persisted even after exposure ceased. These mice also
showed more DNA damage and higher frequencies in
DNA mutations compared to mice exposed to filtered air,
indicating potential increase in mutagenicity [65]. In vitro
studies of bronchial epithelial cells using the BEAS-2B
cell line showed that exposure to DEP resulted in histone
modification including selective degradation of histone
deacetylase (HDAC) 1 and activation of histone acetyl-
transferases (HAT) p300 as well as increased acetylation
of histone H4 in the promoter region of cyclooxy-
genase-2 (COX-2), an inflammatory mediator. Expres-
sion of COX-2 was increased with DEP exposure indi-
cating that DEP exposure resulted in histone modifica-
tions resulting in increased inflammation [66]. In another
profiling study evaluating PM exposure effects on
miRNA expression using a microarray approach, re-
searchers found four PM-sensitive miRNAs that were
expressed differentially post exposure compared to base-
line (miR-421, miR-146a, miR-29a, and miR-let7g).
Upon further analyzing miRNA expression and candidate
inflammatory genes, the authors concluded that exposure
to PM for 3 days resulted in inflammatory gene regula-
tion through PM responsive miRNAs [67].
3.4. Cigarette Smoke
Cigarette smoke, both primary and secondary, is one of
the more widely studied environmental exposures, par-
ticularly with regard to gene-environment interactions.
Exposure to cigarette smoke has been associated with the
development and exacerbation of several diseases, most
prominently respiratory diseases such as COPD, asthma,
and lung cancer, as well as cardiovascular disease and
other cancers [68]. The mechanisms of these relation-
ships are not fully understood, but it seems that epigenet-
ics may play a major role in mediating the effects of
cigarette smoke on human health.
A landmark study published in 2005 found that in-
creased maternal and grandmaternal smoking was associ-
ated with increased asthma in children [69], suggesting a
generational effect consistent with epigenetic modifica-
tion. Indeed, several studies have associated in utero ex-
posure to cigarette smoke via maternal smoking with
global changes to DNA methylation [70-72] as well as
with alterations in the methylation of specific genes im-
plicated in growth [73], processing of toxicants and car-
cinogens [74,75], and cancer and immune functions [76].
Maternal smoking during pregnancy has also been asso-
ciated with downregulation of miRNA implicated in
growth and development [77].
Cigarette smoke exposure, both primary and secondary,
has also been associated with alterations in DNA methy-
lation, with global changes observed [78] as well as
changes in genes relevant to asthma [13,79], cardiovas-
cular disease [80], lung cancer [81-83], COPD [80],
bladder cancer [84,85], and colorectal cancer [86] among
others, with some suggestions of differences between
current and former smokers [87].
Similar alterations due to smoke exposure have also
been observed in histone modifications, including reduc-
tion of histone deacetylases (specifically histone deace-
tylases 2 and 3) that have implications in COPD and
asthma [88-91], and phosphorylation associated with
generation of double-stranded DNA breaks [92,93], as
well as methylation [82], and acetylation and phospho-
acetylation [94,95]. Many histone modifications have
been studied in the context of changes in behavior of the
protein complex NF-κB, which is important for control of
DNA transcription and has been found to be upregulated
when histone deacetylases are reduced [96].
Smoke exposure has also been found to be associated
with changes in micro RNA expression. Differences in
plasma miRNA expression have been found between
smokers and nonsmokers [97], as well as decreases in
global miRNA expression in smokers versus nonsmokers
[98,99]. Exposure to cigarette smoke condensate in cul-
ture has been associated with increased oncomir miRNA
[100], and decreased tumor suppressor miRNA [101];
nicotine exposure has also been found to alter miRNA
expression in adult human stem cells, with detrimental
effects on regenerative potential [102]. Overall, these
changes seem to suggest a potential mechanistic link to
cancer more than any other disease associated with ciga-
rette smoking.
It is important to note that cigarette smoke contains
hundreds of compounds, including such common envi-
ronmental pollutants as PM2.5, PM10, PAHs, cadmium,
lead, and arsenic. This suggests that it is important to
consider potential modulating effects of cigarette smoke
exposure on the impacts of these other pollutants. Vari-
ous studies have found that cigarette smoke exposure
modulates both clinical symptoms and methylation pat-
terns associated with air pollution exposures, exacerbat-
ing disease phenotypes [103,104].
4. Conclusion
Recent efforts have been made to curb the global produc-
tion of air pollutants, but we are only beginning to un-
cover their impact. Here we outline the adverse health
effects associated with ambient air pollution and suggest
the involvement of epigenetic modifications, including
DNA methylation, histone acetylation, and microRNAs.
Many of these epigenetic changes are thought to be heri-
table; thus, adverse events associated with ambient air

Air Pollution and Epigenetics
118
pollution can have long-lasting, transgenerational impacts.
Genetics have already been implicated in the pathogene-
sis of many disorders, like asthma and cancer that are
also subsequently linked to ambient air pollution expo-
sure. The study of genetics and epigenetics is vital to the
understanding of ambient air pollution and could be use-
ful in identifying biomarkers for those individuals most
likely to develop health problems in response to expo-
sure.
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