International Journal of

Molecular Sciences

Review
The Impact of Nutrition and Environmental
Epigenetics on Human Health and Disease
Céline Tiffon
French National Cancer Institute, 92100 Boulogne-Billancourt, France; [email protected];
Tel. +33-(0)1-4110-1614




Received: 26 September 2018; Accepted: 29 October 2018; Published: 1 November 2018


Abstract: Environmental epigenetics describes how environmental factors affect cellular epigenetics
and, hence, human health. Epigenetic marks alter the spatial conformation of chromatin to
regulate gene expression. Environmental factors with epigenetic effects include behaviors, nutrition,
and chemicals and industrial pollutants. Epigenetic mechanisms are also implicated during
development in utero and at the cellular level, so environmental exposures may harm the fetus by
impairing the epigenome of the developing organism to modify disease risk later in life. By contrast,
bioactive food components may trigger protective epigenetic modifications throughout life, with early
life nutrition being particularly important. Beyond their genetics, the overall health status of an
individual may be regarded as an integration of many environmental signals starting at gestation
and acting through epigenetic modifications. This review explores how the environment affects the
epigenome in health and disease, with a particular focus on cancer. Understanding the molecular
effects of behavior, nutrients, and pollutants might be relevant for developing preventative strategies
and personalized heath programs. Furthermore, by restoring cellular differentiation, epigenetic drugs
could represent a potential strategy for the treatment of many diseases including cancer.

Keywords: epigenetic marks; signal integration; molecular mechanisms; nutrients; endocrine

disruptors; mammary gland; personalized health

1. Introduction

1.1. A Brief Introduction to Epigenetics

Epigenetics refers to the control of gene expression via mechanisms not directly related to the
DNA coding sequence [1]. As a result, all cells in an organism have very different phenotypes despite
having the same genome. Epigenetics modulates and regulates gene expression through various
epigenomic “marks”, the term given to chemical compounds added to DNA or histone proteins and
recognized by enzymes that either lay down or remove the specific mark. These marks change the
spatial conformation of chromatin: either compacting it, thereby preventing the binding of transcription
factors to the DNA, or opening it, allowing transcription factor binding and usually upregulating
cellular processes.
DNA methylation—the addition of methyl groups to the 5-carbons of cytosine residues in CpG
islands to give rise to 5-methylcytosines—works together with histone modifications to regulate
gene expression. DNA methylation tends to act at promoters to induce gene silencing, while histone
acetylation usually unwinds chromatin. DNA methylation is catalyzed by enzymes in the DNA
methyltransferase (DNMT) family, which recruit functional complexes containing DNA methylation
domains, leading to transcriptional inhibition or maintaining a repressive chromatin state.
Histone acetylation is associated with transcriptional activity and an open chromatin state [2,3].
Acetylation of histone tails is controlled by two enzyme families: histone acetyltransferases (HATs),

Int. J. Mol. Sci. 2018, 19, 3425; doi:10.3390/ijms19113425 www.mdpi.com/journal/ijms

Int. J. Mol. Sci. 2018, 19, 3425 2 of 19

which transfer an acetyl group, and histone deacetylases (HDACs) [4–6], which remove acetyl groups.
Other epigenetic marks are also described and include histone post-translational modifications such
as methylation, ubiquitination, sumoylation, phosphorylation, biotinylation, and ADP-ribosylation,
which either promote or suppress gene expression. The pattern of these marks on histone tails is often
referred to as the histone code, which dictates the binding of effector proteins that in turn results in
specific cellular processes.
Non-coding RNAs (ncRNAs) are another type of specific epigenetic mark that mediate various
intracellular processes [7]. A ncRNA is a functional RNA molecule transcribed from DNA but not
translated into protein. The best characterized ncRNAs are microRNAs (miRNAs), which are short,
single-stranded, 19–24 nucleotide ncRNAs. miRNAs regulate gene silencing at the transcriptional
and/or translational level of protein-coding genes [8]. Long non-coding RNAs (lncRNAs) are another
subset of RNAs over 200 nucleotides in length that function as chromatin remodelers, transcriptional
regulators, and post-transcriptional regulators. Many lncRNAs complex with chromatin-modifying
proteins to recruit their catalytic activity to specific genomic sites, thereby modifying chromatin
states and influencing gene expression. With little or no protein-coding potential, lncRNAs instead
participate in various intracellular processes [7], and recent studies have identified that certain lncRNAs
are specifically associated with certain cancers [9].
With the development of high-resolution sequencing and high-throughput technologies, a large
number of biologically functional ncRNAs have now been identified [10]. In addition, there is crosstalk
between DNA methylation and histone modifications [11]; for example, histone methyltransferases,
histone demethylases, and accessory proteins interact and coordinate the chromatin state and DNA
methylation and methylation status of histones are tightly associated [12]. Moreover, various ncRNAs
are also closely associated with other epigenetic marks, which form extensive crosstalk throughout the
cell, or the “epigenetic network” [7]. There is now plenty of evidence that the epigenetic control of the
genome is far more complicated than first thought and involves multiple epigenetic mechanisms and
their interactions [12,13].
More recently, histone variants, mostly of canonical histones H2A, H2B, and H3, with specific
properties have been identified in humans and other higher eukaryotes. Most of them are H2A
variants, among which macroH2A1 generates alternative splice isoforms, i.e., macroH2A1.1 and
macroH2A1.2. MacroH2A1 isoforms appear to be critical regulators of chromatin structure and
chromatin dynamics during cellular senescence, regeneration, and fasting [14,15]. The function of
these histone variant proteins and their molecular mechanisms in health and during an organism’s
lifespan are reviewed in [14]. The discovery of histone variants and their diversity has added further
complexity to context-dependent biological systems and their regulation, such as during health,
aging, and in pathological conditions including cancer. This is an area of ongoing research, since
chromatin dynamics throughout life are likely to change and the epigenome suffers from a progressive
loss in configuration during aging [15]. The resulting abnormal chromatin state during aging is
characterized by different incorporated histone variants, nucleosome remodeling, altered histone
modification patterns, and altered DNA methylation patterns, resulting in the recruitment of different
chromatin modifiers, abnormal gene expression patterns, and genomic instability. Among the multiple
different variants of histone H2A, macroH2A has been implicated in aging; its level increases in an
age-dependent manner during replicative senescence in cultured human fibroblast cells and also in
several tissues of aged mice and primates [15].

1.2. Environmental Epigenetics

These active or repressive marks are also dependent on lifestyle and environmental factors.
“Environmental epigenetics” refers to how environmental exposures affect epigenetic changes [16].
Life experiences, habits, and our environment shape what and who we are by virtue of their impact
on our epigenome and health; for instance, although identical twins share the same genome and
are superficially phenotypically similar, they are unique individuals with definable differences.
Int. J. Mol. Sci. 2018, 19, 3425 3 of 19

These differences result from distinct gene expression influenced by epigenetic factors. Behavior,
nutrition, and exposure to toxins and pollutants are among the lifestyle factors known to be associated
with epigenetic modifications. For example, nutrition is a key environmental exposure from gestation
to death that impacts our health by influencing epigenetic phenomena. In another example, recent
epidemiological data suggest that the increased incidence of cancer observed in the developed world
since the 1960s may partly be due to exposure to endocrine-disrupting chemicals (EDCs), to which
humans and wildlife are exposed daily from multiple sources. These are discussed in detail below.

1.3. Cancer: Current Status and Future Prospects

Cancer is the second most common cause of death in most countries and will remain so as
elderly people are most susceptible to cancer and the population is rapidly aging, at least in the
west. While age-standardized cancer mortality rates are projected to decrease in the European Union
(EU) [17,18] and the United States (US) [19,20] due to advances in screening, prevention, and treatment,
the incidence has increased in Europe and the US for testicular and prostate cancers over the last
50 years [21–23]. In the United Kingdom (UK), the combined incidence of all cancers has increased for
all age groups since the early 1990s, with the greatest increase seen in young people aged 0–24 years.
Cancer is a genetic disease characterized by inherited or sporadic mutations in genes that maintain
tissue homeostasis, control the cell cycle, or regulate apoptosis. Cancer is also an epigenetic disease
characterized by mutations in chromatin-remodeling enzymes and epigenome alterations resulting
from aberrant attachment or removal of DNA or histone protein marks. Accumulating evidence
suggests that many adult diseases, including cancers, have epigenetic origins.

1.4. Article Overview

This review explores the effects and consequences of lifestyle and environmental exposures from
gestation and beyond on human health via epigenetic modifications. How epigenetic targets are
affected by lifestyle and environmental factors, especially nutritional factors and chemical exposure,
are discussed in detail. Understanding the underlying molecular mechanisms and deciphering
the signaling pathways involved in environmental epigenetics and disease risk paves the way for
personalized interventions such as personalized nutrition or risk management plans, with cancer used
as the main illustrative model.

2. Nutritional Epigenetics

2.1. Nutritional Epigenetics in Health and Disease

Nutrition is one of the most studied and better understood environmental epigenetic factors.
Associations have been observed between adverse prenatal nutritional conditions, postnatal health,
and increased risk of disease. For instance, at its extreme, the Dutch Famine Birth Cohort resulting
from the Dutch Famine of 1944–1945 has been used to study the effects of starvation during pregnancy
and subsequent health and developmental outcomes including, but not limited to, increased risk of
type II diabetes mellitus, cardiovascular disease, metabolic disorders, and decreased cognitive function
in later life [24–26]. The first months of pregnancy seem to have the greatest effect on disease risk;
children conceived during the Dutch Famine tended to have smaller-than-usual offspring, suggesting
that effects may persist and impact our children and even beyond. It seems likely that the fetus
epigenetically adapts in response to a limited supply of nutrients. In humans, persistent epigenetic
differences associated with prenatal exposure to famine have been ascribed to a lower degree of
methylation of a gene implicated in insulin metabolism than their unexposed siblings [27].
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The evidence for transgenerational effects of poor maternal diet on human populations with
respect to metabolic outcomes was examined in [28]. There is evidence from historical records that
the grandchildren of women exposed to famine and other dietary alterations during pregnancy
are more likely to experience health complications than their control counterparts. The potential
molecular mechanisms of transgenerational inheritance suggest methylation of gametes via the
paternal and maternal lineage [28]. Indeed, further transmission via the paternal line is highly
likely to occur via epigenetic modulation of the spermatozoan nucleus. Two examples from historical
cohorts illustrate this transgenerational transmission via the paternal lineage. One showed that female
grandchildren (F2) from the paternal grandmother (F0) who experienced poor food availability during
her own growth were at higher risk of cardiovascular mortality. The second more recent example
showed that adult grand-offspring whose fathers were exposed to famine in utero had higher BMIs
than a control population. The evidence that both maternal and paternal diets influence metabolic
phenotypes in offspring in mammals through epigenetic information transmission is reviewed in [29].
Over molecular mechanisms with respect to the fetal origins of adult disease have been suggested
including mitochondrial dysfunction and oxidative stress as among the earliest events described in
offspring exposed to nutrient restriction [29].
Nutrition in early life induces long-term changes in DNA methylation that impact on individual
health and age-related diseases throughout life [11,30]. Nutrients can either act directly by inhibiting
epigenetic enzymes such as DNMT, HDAC, or HAT or by altering the availability of substrate necessary
for those enzymatic reactions. This in turn modifies the expression of critical genes and impacting on
our overall health and longevity (see [12,31] for reviews).
A number of studies have reported the epigenetic effects of diet on phenotype and susceptibility to
diseases throughout life. Folate metabolism is linked to phenotypic changes through DNA methylation,
as folate, a water-soluble B vitamin, is a source of one-carbon for the synthesis of AdoMet, which is
necessary for DNA methylation [12,30,31]. Other methyl donor nutrients such as choline can also alter
the DNA methylation status and subsequently impact gene expression [12]. Maternal methyl donor
nutrient availability in early pregnancy is essential for proper fetal development, with consequences
for health and disease susceptibility or cancer in the children throughout life. In one animal study,
a maternal diet restricted in methyl nutrients during periconception affected DNA methylation patterns
in offspring and was the cause of altered phenotypes [12].
Conversely, dietary restriction but without severe nutritional deprivation has been shown in
several models to extend lifespan [32]. Calorie restriction has an anti-inflammatory effect through
the inhibitory effects of critical genes not limited to NF-κB [12]. From the epigenetic standpoint,
there is clear crosstalk between DNA methylation and histone modifications [11], suggesting that
the chromatin structure may also determine DNA methylation [11]. In this context of epigenetic
interactions, sirtuin 1, a NAD+ -dependent HDAC whose substrate specificity includes histone proteins,
has been suggested to be activated by some dietary components (for example resveratrol, a type of
natural phenol present in grape skins). Sirtuin 1 mediates some of the effects of dietary restriction
that delay or reverse some of the physiological changes associated with aging through effects on DNA
methylation [32].
Diets high in these methyl-donating nutrients can rapidly impact gene expression, especially
during early development when the epigenome is first established, and can have long-lasting effects in
adult life. Studies in animals have reported that diets poor in methyl-donating folate or choline
before or just after birth cause permanent hypomethylation of parts of the genome. In adults,
a methyl-deficient diet decreases DNA methylation, but the changes are reversible when methyl is
added back into the diet. Further, depending on the dietary supplements received by a pregnant mouse,
her offspring may have a different phenotype due to differential gene methylation. In an example
of epigenome-modifying chemicals, bisphenol A (BPA) is widely used to manufacture numerous
plastic products including containers. The pups of adult mice fed BPA were more likely to have an
unhealthy phenotype (yellow/obese, prone to cancer and diabetes) compared to those born from
Int. J. Mol. Sci. 2018, 19, 3425 5 of 19

mothers fed BPA with supplemented methyl-rich nutrients like folic acid and vitamin B12 (brown,
thin and healthy). In this case, maternal nutrient supplementation counteracted the negative effects
of chemical exposure, underscoring the importance of a good diet rich in fruit and vegetables and
other high-quality foods. Methyl-donating nutrients act as co-substrates for methyl group transfers;
the pool of available methyl donors is an important regulator of both DNA and histone methylation
capacity [33] and their production is also dependent on BPA’s epigenetic effects. In this mouse model,
altered DNA hypomethylation could be alleviated by folic acid as a dietary methyl donor.
Another striking example of the effects of early diets on epigenetics with consequences on
the phenotype can be found in honey bees. The sterile worker bee differentiates from the fertile
queen depending on the larval diet through epigenetic changes in DNA methylation patterns.
Larvae designated to become queens are fed exclusively with royal jelly, which contains epigenetically
active ingredients that silences a key gene which itself silences a group of queen genes [12].
Furthermore, DNA methylation changes occur during ageing, and it has become evident that early life
nutrition can modulate DNA methylation and influence longevity, in particular by inducing long-term
changes in DNA methylation and other marks that affect susceptibility to a range of ageing-associated
diseases [11]; that is, a form of “cellular memory” (see [32] for a review). In this regard, the lifespan of
a queen bee is up to twenty times that of a worker.

2.2. Nutritional Epigenetics and Cancer

Folic acid and vitamin B12 are two examples of epigenetically active ingredients that play
important roles in DNA metabolism and the maintenance of DNA methylation patterns via chemical
reaction of a methyl product. In one in vivo study, dietary folate intake was positively correlated with
p16 tumor suppressor gene expression, a critical cancer-associated gene with frequent silencing DNA
methylation of its promoter [12]. Altered p16 gene expression was observed in aged mouse colons,
consistent with the known decrease in DNMT expression with aging.
Low folate intake has been associated with hypomethylation and an increased risk of colorectal
and pancreatic cancers [9,34]. There is a growing body of epidemiological evidence that folate
modulates anticarcinogenic properties through epigenetic changes, as folate deficiency reduces the
potential for DNA methylation, and abnormal DNA methylation is associated with many types of
cancer. Diets rich in fruits and vegetables containing natural anti-oxidants can protect against cancer.
The potential epigenetic effects of several nutritional components in addition to folate, mostly derived
from vegetables, have been examined in a number of studies, which have shown reductions in DNA
hypermethylation of critical genes resulting in tumor suppression [32,35]. For example, green tea
contains polyphenols, which are natural compounds widely distributed in plant foods and with many
biological activities including inhibition of DNA methylation.
A variety of dietary factors are potential HDAC and HAT modulators. Some, such as sulforaphane,
an isothiocyanate found in broccoli sprouts, or diallyl disulfide, an organosulfur compound in garlic,
have been shown to act as HDAC inhibitors [9,35], a class of epigenetic therapeutic described further
below. Such epigenetic drugs have been used to treat cancers in clinical trials due to their mode of
action in restoring cancer cell differentiation and rendering tumors more sensitive to conventional
therapies [36]. Several in vitro studies using these compounds have shown anti-carcinogenic
effects associated with HDAC inhibition and histone acetylation [12,37,38]. Table 1 summarizes
some dietary components considered to have protective effects against cancer through different
epigenetic modifications.
As noted above, miRNAs can regulate DNA methylation and histone modifications, but promoter
methylation or histone acetylation can also modulate miRNA expression as part of a complex network
with feed-forward and feedback loops. Dysregulated miRNA expression is associated with the
development or progression of human cancers through alterations in cell proliferation and apoptosis,
but methyl- and folate-deficient diets can also result in aberrant miRNA expression to exert similar,
pro-cancer effects [12]. Specifically, miR-222 has been considered a potential biomarker of nutritional
Int. J. Mol. Sci. 2018, 19, 3425 6 of 19

status in humans and is implicated in obesity. Certain dietary components may protect against cancer
through miRNA regulation, such as curcumin and retinoic acid [12], the former present in some plants
and commonly used as a dietary supplement and food flavoring, and the latter present in any vitamin
A-rich food.

Table 1. A summary of some dietary components considered to have protective effects against cancer.

Nutrient Food Origin Epigenetic Role

Sesame seeds, brazil nuts, fish,
Methionine SAM synthesis
peppers, spinach
Leafy vegetables, sunflower seeds,
Folic Acid Methionine synthesis
baker’s yeast, liver
Vitamin B12 Meat, liver, shellfish, milk Methionine synthesis
Meats, whole grain products,
Vitamin B6 Methionine synthesis
vegetables, nuts
Popular dietary supplement pill; Enzymes transfer methyl groups
SAM-e (SAM)
unstable in food from SAM directly to the DNA
Egg yolks, liver, soy, cooked beef,
Choline Methyl donor to SAM
chicken, veal and turkey
Wheat, spinach, shellfish, and Break down the toxic byproducts
Betaine
sugar beets of SAM synthesis
Removes acetyl groups from
Resveratrol Red wine histones, improving health (shown
in lab mice)
Increased methylation, cancer
Genistein Soy, soy products
prevention, unknown mechanism
Increased histone acetylation
Sulforaphane Broccoli
turning on anti-cancer genes
Increased histone acetylation
A compound produced in the
turning on ‘protective’ genes,
Butyrate intestine when dietary fiber
increased lifespan (shown in the
is fermented
lab in flies)
Increased histone acetylation
Diallyl sulphide (DADS) Garlic
turning on anti-cancer genes

Dietary patterns, not only individual nutrients, also influence behavior and phenotype in offspring.
For example, Western diets tend to be high in saturated fats, red meats, and empty carbohydrates but
low in fresh fruits and vegetables, whole grains, seafood, and poultry. This diet has been linked to
many diseases including hypertension, heart disease, diabetes, and obesity and it has generally been
linked to an increased risk of cancer [39,40]. In a specific example, nonalcoholic fatty liver disease
(NAFLD) is a major public health concern in western societies. Nonalcoholic steatohepatitis (NASH),
a form of NAFLD, is characterized by lipid accumulation in hepatocytes, inflammatory cell infiltrates,
oxidative stress, and fibrosis and can lead to cirrhosis or hepatocellular carcinoma. The effects of a
Western diet [41] or a high fat diet [42] on NAFLD development has been investigated in rodents.
The risk of NAFLD may increase through an imbalance in fatty acids (FAs) in the Western diet.
For instance, substituting linoleic acid with α-linolenic acid or long chain n-3 polyunsaturated fatty
acids and decreased the n-6:n-3 FA ratio in high fat, high fructose (HFHF) diet-induced NASH [43].
The data from this study showed that decreasing the n-6:n-3 ratio by introducing healthy fats
prevented HFHF-induced NASH by attenuating oxidative stress and inflammation and restoring
the antioxidant state.
Int. J. Mol. Sci. 2018, 19, 3425 7 of 19

Epigenetics, such as DNA methylation, may be involved in the impact the western diet has on
the human body. The effects of maternal Western diet on offspring physical activity, gene expression,
and phenotype were assessed in [44]. Interestingly, differences in F1 female offspring but not in F2
male and female offspring were observed, suggesting that changes in the F1 generation were related
to in utero somatic reprogramming. Epigenetic effects of specific FAs have been investigated in a
number of studies. Eicosapentaenoic acid (EPA) and arachidonic acid (AA) are products of essential
FA metabolism; both FAs are involved in inflammation resolution. EPA has been long regarded as a
protective FA, particularly in the light of the favorable cardiometabolic effects of fish oil. One study [45]
demonstrated a strong association between whole peripheral blood DNA methylation and EPA and AA
in two distinct human cohorts—lactating infants and adult men—of different ages and developmental
stages, thereby linking EPA and AA to DNA hypermethylation. Another study [46] reported that
maternal dyslipidemia caused significant epigenetic changes in placentas and fetal livers and also
increased fetal liver triacylglycerol accumulation. It has been shown from animal experiments that
cardiovascular and metabolic diseases, particularly in males, may develop from alterations in DNA
methylation. A recent study demonstrated how parental diet may affect their offspring’s epigenetic
modifications and lead to the development of cardiovascular and metabolic diseases and impact
central nervous system plasticity [47]. This study demonstrated that mice exposed to a high-fat,
high-sugar diet (HFHSD) prior to and during pregnancy led to DNA modifications of their offspring’s
compensatory renin-angiotensin system (RAS), a hormone system that regulates blood pressure, fluid
retention, and vascular resistance. In adulthood, offspring from HFHSD-exposed dams exhibited
several differences compared to control counterparts including but not limited to a lower level of
angiotensin converting enzyme-2 (ACE2) gene expression in the brain stem, kidney, and cecum and
higher ACE2 gene activity in the hypothalamus. These data suggest that perinatal exposure to HFHSD
resulted in epigenetic modifications of the compensatory brain RAS, potentially affecting plasticity of
neuronal networks leading to autonomic dysfunction in the male offspring.
In conclusion, following a western diet even before the chid’s birth may lead to physiological
dysfunction via epigenetic changes. Further investigations, such as looking at potential
transgenerational transmission in F2 male and female mice by crossing F1 males (offspring from
HFHSD-exposed dams) with regular diet-fed females (and the opposite) would be of particular interest.
In contrast to the Western diet, a number of studies have described the health benefits of
following the Mediterranean diet, which is associated with a reduced risk of heart disease and
cardiovascular mortality as well as overall mortality. The Mediterranean diet traditionally includes
fruits, vegetables, pasta and rice, fish and poultry, whole grains, and healthy fats (monounsaturated
fats and polyunsaturated fats such as beneficial linolenic acid) and discourages red meat and saturated
fats. The favorable effects of a Mediterranean diet as primary prevention of cardiovascular disease
were assessed among persons at high cardiovascular risk [48]. The data from this study revealed that
the incidence of major cardiovascular events was lower in those assigned to a Mediterranean diet
supplemented with extra-virgin olive oil or nuts than among those assigned to a reduced-fat diet [48].
The Mediterranean diet is also associated with a reduced incidence of cancer, and the risk of breast
cancer has been reported to be reduced in women who eat a Mediterranean diet supplemented with
extra-virgin oil and mixed nuts. In relation to breast cancer, one study demonstrated that dietary
patterns affect the mammary gland microbiome, establishing an alternative mechanistic pathway for
breast cancer prevention [49]. The impact of maternal Mediterranean diet adherence during pregnancy
on offspring behaviors has also been investigated, and maternal adherence to a Mediterranean diet
in early pregnancy is associated with positive neurobehavioral outcomes in early childhood and
with sex-dependent methylation differences in the control regions of imprinted genes [50]. Figure 1
summarizes how diet affects the epigenome to modify individual and transgenerational phenotypes.
Int. J. Mol. Sci. 2018, 19, 3425 8 of 19
Int. J. Mol. Sci. 2018, 19, x FOR PEER REVIEW 8 of 18

Figure 1.
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individual and
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3. Chemical Environmental Epigenetics

Environmental pollutants are among the environmental factors with epigenetic effects.
Environmental exposures frequently considered epigenetic toxins include metals, such as arsenic,
Int. J. Mol. Sci. 2018, 19, 3425 9 of 19

3. Chemical Environmental Epigenetics

Environmental pollutants are among the environmental factors with epigenetic effects.
Environmental exposures frequently considered epigenetic toxins include metals, such as arsenic,
particulate matter from air pollution, organic compounds, pesticides, and other endocrine-disrupting
chemicals, the latter reviewed in detail below.

3.1. Endocrine-Disrupting Chemicals (EDCs)

Endocrine-disrupting chemicals (EDCs) represent a group of environmental chemicals that
interfere with hormone signaling pathways. Their actions on the epigenome are described as an
exemplar. Humans and animals are regularly exposed to a wide range of EDCs. There is increasing
evidence to suggest that EDC exposure during early life, in particular during fetal development,
contributes to a variety of diseases, including cancers, which manifest later in life or even in the next
generation. This suggests epigenetic inheritance of EDC-related events. Indeed, it is well established
that epigenetic mechanisms play a central role in these long-lasting effects of EDCs. Moreover, a large
number of studies have demonstrated that EDCs induce epigenetic changes. However, the underlying
mechanisms of action are less well understood.
The effects of EDCs on epigenetics were recently reviewed in [33]. Briefly, the effects of EDCs
can be global, that is, on epigenetic enzyme expression, i.e., DNMTs, HATs, and HDACs. In this case,
for example, EDCs affect DNMT via nuclear hormone receptors such as the estrogen and androgen
receptors or through miRNA expression, the latter being concomitant with other gene expression
changes. The second mode of action of EDCs is gene-specific, regulating locus-specific epigenetic
patterns. For example, EDCs may specifically affect one gene via nuclear receptors, which have been
reported to regulate locus-specific chromatin states by recruiting histone modifiers and changing
DNA methylation patterns by interacting with DNMTs and recruiting them to specific genomic sites.
In addition, EDCs are likely to regulate other ncRNA expression via interference with nuclear receptors,
which have a putative role in the regulation of ncRNA expression.

3.1.1. EDC Exposure Induces Abnormal Development, Behavior, and Disease

The main consequences of environmental exposure to chemicals such as EDCs are adverse effects
on the growth and development of reproductive organs, effects on neuronal differentiation, and an
increase in the combined incidence of all cancers. EDCs are exogenous agents that alter one or more
endocrine system axes and, consequently, impose adverse health effects at the level of the organism,
its progeny, and/or subpopulations [54]. These compounds mimic natural hormones and are reported
to promote a strong hormonal imbalance that causes developmental and reproductive disorders
and tumor formation in children and adults after fetal exposure. An association between industrial
chemicals/drugs and an elevated incidence of neoplasms in experimental animals and humans after
early-stage exposure has also been described. According to the World Health Organization (WHO) [55],
in addition to an elevated incidence of a variety of childhood and adult cancers, many different adult
diseases have fetal origins but the causes have remained obscure. Reproductive disorders including
testicular cancer, impaired semen quality, and the timing of puberty; altered brain and neurocognitive
development; and adverse effects on adipose tissue, the adrenal glands, and the endocrine pancreas can
be caused by prenatal EDC exposure. Sexual differentiation and reproductive functions are specifically
under hormonal control (i.e., androgens and estrogens). Thyroid hormones are of special importance
in brain development and are essential for regulating normal metabolism.
In terms of EDC-associated behavioral disorders, several studies have reported the BPA exposure
affects behavior and development across several generations, including those not even exposed,
depending on the window of exposure and exposure time. Sexual, social, learning, and maternal
behavior changes are all associated with prenatal exposure to very low BPA doses, while exposure at
different ages may also alter behavior. One study investigated the impact of low-dose BPA exposure
Int. J. Mol. Sci. 2018, 19, 3425 10 of 19

on rat development and behavior over three generations, in which one group was not exposed to BPA
and the other two were exposed at different periods of their life [56]. BPA exposure caused changes
and defects over generations, including in unexposed offspring, implicating epigenetic changes.
In particular, non-exposed offspring had body weight increases and changes in taste preferences
compared to treated groups.

3.1.2. EDCs, Epigenetics, and Cancer

Since the 1960s, data from numerous reproductive and developmental toxicity tests have provided
growing evidence of the harmful impact of some environmental substances that interfere with normal
endocrine function in humans.
In 2003, Birnbaum and Fenton [57] reviewed the consequences of exposure to endocrine disruptors
on cancer and development and reported an association between prenatal exposure to diethylstilbestrol
(DES), a synthetic estrogen originally used to prevent miscarriage, with a rare neoplasm, clear cell
adenocarcinoma of the vagina. The data from animal studies of environmental estrogen exposure are
particularly strong and correlate well with the human data. Earlier, McLachlan, et al. [58] demonstrated
that prenatal DES exposure in mice resulted in uterine tumors and genital tract abnormalities in
adulthood. Several other adverse effects of DES were subsequently found both in boys and girls [22,23],
and Palmer, et al. [59] reported that gestational and perinatal exposure of female fetuses to DES
was associated with an increased risk of breast cancer in the children of these exposed women.
It was previously shown that elevated natural estrogen levels during gestation was associated with
an increased incidence of breast cancer in the offspring later in life [60]. The naturally occurring
phytoestrogen genistein found in most soy products has been shown to increase carcinogen-induced
mammary cancers in female rat offspring after maternal genistein injection, suggesting that an elevated
estrogenic environment in utero could enhance subsequent breast cancer risk at maturity [61]. The male
offspring born to mothers treated with DES during pregnancy displayed feminization [62,63] and
developmental malformations of the genital tract, infertility, and obesity [64]. There is also evidence of
second-generation effects of DES on developmental abnormalities and tumorigenesis, as the sons of
women exposed in utero had a higher prevalence of hypospadias than other case-controlled males [55].
Furthermore, experimental studies in rodents had already suggested that the carcinogenic effects
of DES may be transmitted to succeeding generations, suggesting the involvement of epigenetic
changes [65]. While the reproductive performance of the DES (F2) male mice was unaltered,
an increased incidence of reproductive tract tumors was transmitted from the DES “grandmothers” to
subsequent generations. DES (F2) female mice had an increased incidence of malignant reproductive
tract tumors, including uterine adenocarcinomas; however, the fertility of these DES lineage female
mice was not affected by DES exposure of their “grandmothers”, in contrast to the reduced fertility
observed in their mothers (F1 DES-exposed females) [66]. The increased incidences of testicular and
prostate cancers observed in European and American populations over the last 50 years may also be
related to early exposure to environmental estrogens and/or anti-androgens [21–23,67]. Environmental
anti-androgens are also associated with an increased incidence of gynecomastia in adult males, an effect
similar to that observed after exposure to low dose DES during treatment of castration-resistant
prostate cancer [68]. There is also growing evidence for an association between in utero exposure to
various environmental toxins and childhood cancers, in particular brain tumors and hematological
malignancies such as acute lymphoblastic leukemia (ALL), lymphoma, and leukemia [57].
Environmental dioxins, a type of EDC, have been called the most toxic synthetic compounds
and can cause a host of adverse health effects. These pollutants mimic estrogen. As developmental
and reproductive toxins, dioxins can cause immunotoxicity, dermal and hepatic toxicity, endocrine
effects, and cancer [69]. Dioxin, the prototypical dioxin, is a human carcinogen [70,71] that increases
the incidence of all cancers. Lung cancer, hematological cancers, and soft-tissue carcinomas have all
been reported to develop after dioxin exposure. Humans are exposed in real life and on a daily basis to
Int. J. Mol. Sci. 2018, 19, 3425 11 of 19

a mixture of structurally diverse EDCs that induce effects at different doses, at different ages, and on
different target tissues.
Some studies have reported an increased risk of cancers in individuals exposed to high amounts
of polycyclic aromatic hydrocarbons (PAHs), which are organic compounds produced when meats
are grilled or barbecued [72,73] and considered a type of EDC. PAHs have been linked to many
types of cancers in well-established animal models [74]. Some carcinogenic PAHs are genotoxic and
induce mutations that initiate cancer; others are not genotoxic and instead affect cancer promotion or
progression [75]. The pathways that mediate cell signaling for the endocrine disruptions induced by
these chemicals include but is not limited to regulatory mechanisms (chromatin/epigenetic regulation)
and cell function (development/differentiation, immune response/inflammation, apoptosis) [76].
Multiple epidemiological studies of people living in Europe, the United States, and China have linked
in utero exposure to PAHs, through air pollution or parental occupational exposure, with poor fetal
growth, reduced immune function, and poorer neurological development [77–80].
Therefore, there is evidence that EDCs can affect the epigenetic landscape of cells in target tissues
by altering DNA methylation or histone methylation patterns, thereby affecting global gene expression
profiles and transcriptomes. Given that epigenetic patterns can be heritable, these effects have been
observed in successive generations [68].

3.2. Other Toxin Exposures and Epigenetic Effects

While smoking and alcohol consumption mainly cause disease through mutagenic events, both
can also exert cellular effects through epigenetics. Children exposed to prenatal maternal smoking have
epigenetic modifications in buccal mucosal cells. Maternal cigarette smoking during pregnancy has
been investigated with respect to consequences on health, neurodevelopment, behavior, and cognitive
function in infants. Maternal tobacco smoking during pregnancy is associated with respiratory diseases
associated with immune system dysregulation such as asthma and allergies as well as cancer later in
the life of offspring [26,81]. In another example, alcohol use is a risk factor for many cancers including
oral, pharyngeal, laryngeal, esophageal, liver, colorectal, and breast cancer, and the risk of cancer is
dose-dependent. Alcohol has deleterious/hazardous effects on growth, metabolism, and neuronal
development through laying down epigenetic marks at early embryonic exposure, as evidenced by
in vitro and animal studies. These disturbances in the epigenetic landscape may contribute to defects
in certain memory and learning processes as well as malformations and abnormal fetal development.
Numerous studies have reported that both genetic and environmental risk factors also play a role in
the development of alcoholism [82,83].

4. Environmental Epigenetics and Cancer: Breast Cancer as a Specific Example

EDCs affect male mammary gland development [84] with transgenerational effects [85].
Alterations have been described in male and female mammary gland morphogenesis after BPA
exposure that may contribute to breast cancer risk [86,87]. Fetal exposure to the estrogen-mimetic
BPA has recently been shown to trigger epigenetic changes in postnatal and adult rat mammary
glands throughout life and alter gene expression [88]. Indeed, changes in DNA methylation status or
chromatin modifications in BPA-exposed animals may underpin some pre-neoplastic lesions, such as
intraductal hyperplasias and neoplastic lesions. Animals exposed to BPA in utero have an increased
risk of mammary carcinogenesis, which further increases when animals are exposed to a second
carcinogenic stimulus. Dhimolea et al. (2014) showed that in utero BPA exposure altered both
the DNA methylation profile and chromatin remodeling. In particular, increased levels of histone
H3 lysine 4 trimethylation (H3K4me3), an established epigenetic marker of actively transcribed
genes, was observed at the alpha-lactalbumin promoter in BPA-exposed animals. Global changes
in mRNA expression profiles following fetal exposure to BPA were observed at sexual maturity,
together with histological alterations of intraductal hyperplasia and ductal carcinoma in situ (DCIS).
Interestingly, the BPA-treated group showed increased expression of c-Jun and downregulation of
Int. J. Mol. Sci. 2018, 19, 3425 12 of 19

the cyclin-dependent kinase (CDK) inhibitor p57 (Cdkn1c), both known to be involved in cell cycle
regulation. Kim et al. (2014) demonstrated that some environmental chemicals (e.g., methoxychlor
(MXC), an estrogenic pesticide, and triclosan (TCS), a broad-spectrum antibacterial and antifungal
agent widely used in hygiene products) stimulated ovarian cancer growth via upregulation of cyclin D1
and downregulation of p21 [89]. Prenatal exposure to the estrogen-mimetic dioxin delayed mammary
gland proliferation and differentiation following puberty [90] and consequently increased sensitivity
to carcinogens, because terminal end buds undergoing rapid proliferation and differentiation are
more susceptible to tumor initiation [91]. Interestingly, dioxin exposure was associated with delayed
breast development in girls [92]. Similar in utero effects were seen with atrazine (ATR), another
environmental toxin and estrogen mimetic used as an herbicide and the most common member
of the chlorotriazine family, the most heavily used agricultural pesticide. Following in utero
exposure, ATR delayed early mammary gland development in female rat offspring, leading to
increased terminal end buds and prolonging the window of sensitivity to potential carcinogens.
A significant correlation between exposure to estrogens, phytoestrogens, and high fat diets and
breast cancer susceptibility has been reported in several epidemiological studies. For instance,
gestational/lactational exposure to genistein and vinclozolin, a phytoestrogen present in mammalian
diets and an anti-androgenic agricultural fungicide, respectively, altered mammary gland structures
of animals at puberty and in estrous. Epithelial proliferation was increased in EDC-exposed animals,
as evidenced by increased Ki67 mRNA levels, epithelial bridging, ductal branching and hyperplasia,
loss of epithelial cell polarization, and periductal fibrosis. Alterations in mammary gland structures
were profound and particularly affected the terminal end buds, ducts, and lobuloalveolar structures.
These modifications involved epigenomic changes and signatures that may influence subsequent
breast cancer risk [93]. Indeed, a supplemental transcriptomic study showed alterations in genes
related to development, differentiation, morphogenesis, and metabolism in the mammary glands of
EDC-exposed rats compared to those in the mammary glands of controls, as well as accompanying
histological modifications [94].
There are also reports of adult-onset transgenerational disease and histopathological changes (of
the testis, prostate, and kidney) in F3 animals (eliminating the possibility of direct exposure effects)
after exposure of a gestating F0 generation female to plastic-derived chemicals [95]. Vinclozolin
is known to promote transgenerational epigenetic inheritance of adult-onset diseases in the rat by
promoting male germline epigenome reprogramming [96–98]. Subsequently, all tissues propagated
from these sperm have differentially damaged epigenomes and transcriptomes that can then alter
phenotypes and influence the development of adult-onset diseases in subsequent generations [97].

5. The Potential of Epigenetic Drugs

Epigenetic regulation is highly complex. Histone proteins can be modified by several chemical
modifications, while DNA is modified through the introduction of methyl groups to CpG islands.
For each modification, two enzymatic families with competing activities add or remove chemical
groups to affect chromatin structure and thus gene transcription and DNA repair. Interested readers
are referred to an excellent review on the types of histones modifications, DNA methylation, and their
regulating enzymes [99].
Abnormal epigenetic regulation may occur due to mutations in these enzymes or their altered
activity as evidenced in a broad range of solid and hematological malignancies. These events participate
in many diseases, including cancer. Therefore, the discovery of regulatory epigenetic enzymes has
prompted the development of new therapeutic approaches over recent years, mostly in cancer research.
Here we review drugs that acetylate histones and HDAC inhibitors, a primary class of epigenetic
therapy showing good efficacy in cancer.
Histone acetylation is regulated by histone acetyltransferases (HAT) and HDAC, which add
or removing acetyl groups from histone proteins to confer either an open or condensed chromatin
conformation, respectively. Histone acetylation is generally associated with transcriptional activation,
Int. J. Mol. Sci. 2018, 19, 3425 13 of 19

and many genes have been reported to be epigenetically silenced in cancer cells. In addition to histones,
several non-histone proteins including many oncogenes and tumor suppressors such as Myc, p53,
and PTEN are also dynamically acetylated. There are 11 Zn-dependent HDACs, which are subdivided
into four classes: class I comprises HDACs 1, 2, 3, and 8; class IIA HDACs 4, 5, 7, and 9; class IIB
HDACs 6 and 10; and class IV HDAC 11. Class I enzymes are expressed in the nucleus, class IIB in
the cytoplasm, and class IIA shuttle between the cytoplasm and nucleus. HDAC inhibitors act by
inhibiting enzymes responsible for transcriptional repression and silencing, thereby reversing the gene
repression observed in malignancies. They might also help re-establish epigenetic control, such as in
cancer patients with HAT gene mutations indicating decreased tumor acetylation.
These drugs can induce growth arrest, differentiation, and apoptosis in malignant cells. Vorinostat
and romidepsin have been approved by the US Food and Drug Administration for the treatment
of blood cancers, in particular myelodysplastic syndromes, leukemia, and lymphoma, and multiple
HDAC inhibitors are currently in clinical trials for solid tumors [99], some in combination with
either conventional therapies or newer, targeted therapies. However, these drugs have a more
global genomic effect rather than targeting a single molecule or pathway. This continues to pose
significant challenges in dissecting the specific effects of these drugs on histone and non-histone
proteins. Nevertheless, the effects of epigenetic drugs seem to be quite well-tolerated. Furthermore,
these epigenetic drugs have recently offered an exciting novel strategy to reverse immune suppression
and restore T-cell-mediated anti-tumor activity. A summary of the underlying key mechanisms of
epigenetic drugs that ‘prime’ tumors for immunotherapy is presented in [100]. In addition, these drugs
may act as immunomodulatory agents in the treatment of cutaneous T cell lymphoma, in particular by
decreasing the expression and secretion of the immunosuppressive cytokine IL-10 and by increasing
the expression of the pro-inflammatory cytokine IFN-γ [101].

6. Conclusions
The health of an individual depends on the interaction of many environmental factors with its
genetics. Lifestyle factors are likely to affect human health and offspring via epigenetic mechanisms.
Variations in gene expression are influenced by epigenetics, which depends on our life experiences
and habits including nutrition, behavior, and environmental toxin exposures. Chronic environmental
exposures are thought to be partly responsible for the increased rates of all cancers, not only for those
directly exposed, but also for the fetus. Some periods of development are particularly susceptible to
the harmful effects of these toxins. In addition, the combination of toxin, dose, and critical exposure
window must be considered but may be difficult to predict. Following toxin exposure, epigenomic
alterations in the offspring may affect several organs and make the individual more sensitive to
carcinogens during childhood or adulthood and increase disease susceptibility later in life, including
cancer, diabetes, and autism. Epigenetic marks are influenced by the environment and these changes
may be re-established in subsequent generation, or transgenerational epigenetic inheritance. Some of
our traits, behaviors, illnesses, and good and bad experiences leave epigenetic tags that may be
inherited; however, they may also be removed by lifestyle changes.
There is increasing evidence that different epigenetic mechanisms (DNA methylation, histone
modifications, ncRNAs) are interconnected and form an “epigenetic network”. The observed
phenotype—including global health and age-related processes—is the end result of a number of
integrated signals. Lifestyle factors and environmental exposures leave epigenetic marks on our
DNA that impact gene expression; some have protective effects while others are harmful. Fruit- and
vegetable-rich diets may have similar effects on DNA to epigenetic drugs. A deeper understanding
of epigenetic effects and the signaling pathways activated by bioactive food components would
aid in assessing the role and potential benefit of nutrients on our health and reducing cancer
susceptibility. Nutritional epigenetics could be combined with drugs for synergistic effects for
treatment or prophylaxis or be adapted for pregnant woman to reduce the burden of chronic disease
in offspring through an “epigenetically healthy” gestational diet. In both developed and developing
Int. J. Mol. Sci. 2018, 19, 3425 14 of 19

countries, optimizing maternal diet is a challenging public health problem. Future work in the
field of nutrition and epigenetics has the potential to provide significant benefit to public health,
and personalized nutrition could become a part of a patient’s medical program.
The same applies to environmental chemicals. Due to their harmful effects on individuals,
children, and possibly across generations, the impact of chemicals with epigenetic effects has become a
major global public health concern that needs to be addressed. Some checkpoints or key molecules
in the cell at the interface between the cell cycle and differentiation processes are likely to be targets
of chemicals that favor cancer development. Understanding the epigenetic effects of EDCs would
aid in assessing their action and mapping such marks could be used for risk management based on
pathway-based toxicity testing.

7. Take-Home Messages
• Nutrition—in particular maternal diet and dietary patterns—and chemical pollutants are
two important environmental factors that impact human health.
• These factors have a direct impact on the individual by contributing to the pathogenesis of many
diseases, not least cancer.
• Furthermore, these factors probably span generations through epigenetic transmission, making
them a major global public health problem not only for the individual but also future generations
and society.
• Understanding the molecular mechanisms and signaling pathways involved in environmental
epigenetics paves the way for both public health and targeted interventions to reduce their
societal impact.

Funding: This research received no external funding.

Conflicts of Interest: The authors declare no conflict of interest.

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