Various genetic messages are “turned on” (expressed) or
“turned off” (silenced) through epigenetic processes like DNA methylation. When
turned off, it is as if a protein glove covers the DNA message so it can no
longer be read or acted upon. Although epigenetic modification of our genes is
a natural part of our development and well being, these processes can interact
with various chemicals in our environment and in foods and drinks we consume,
leading to the development of disease. Conversely, epigenetic actions of other
compounds in our environment and nutrition are thought to hold the key to providing therapies to fight and prevent disease.
If a genetic mutation for a disease is “turned off” by
epigenetic markers, that particular gene—in
such an instance—cannot cause disease. For example, an individual may have
inherited the genes for a particular disease; if, however, those genes are not
expressed, the disease will not develop. However,
change to the epigenetic markers (of
a mutated gene) could cause the mutated gene to “tune into” and hence develop a
specific disease.
Many human diseases have been associated with epigenetic
modifications due to environmental exposure. These include cancer, obesity,
diabetes, asthma, multiple sclerosis, mental illness and behavioural disorders
as well as premature ageing 1,2,3,4.
Humans are most vulnerable to epigenetic changes during the
development of the embryo in the womb, embryogenesis, where epigenetic
disruptions can be passed down through multiple generations 5. One
study on diethylstilbestrol (DES), an environmental oestrogen, found that DES induced
a genetic predisposition to a certain cancer and congenital birth defects that
was passed down two generations 6. Similarly, foetal exposures to
plasticizers such as bisphenol A, a chemical found commonly in plastic, contribute
to epigenetic changes, which lead to immune abnormalities. Maternal smoking
leads to increased pulmonary disease in adulthood including asthma; and certain
therapeutic drug exposure leads to vascular defects. These can all be
classified as epigenetic changes.
During the past decade, evidence has accumulated showing
that apart from genetic alterations (mutations), epigenetic alterations play a
major role in the initiation and progression of cancer 7. Human
cancers arise from a multi- step process characterised by tumour initiation and
progression 8 but only five
percent of cancers can be attributed to heredity. Genetics alone cannot
explain all of the properties of cancer. It is now understood that epigenetic
abnormalities and the turning off and on of certain genes play a major role in
tumour genesis—the development of and proliferation of tumours 9,10.
Cancer, which is caused by uncontrolled cellular growth, is
induced by mutations in the DNA, which can be initiated by errors in the DNA or
foreign chemicals called carcinogens. In addition to uncontrolled cellular
growth, a characteristic of cancer is inhibition of normal programmed cellular
death, called apoptosis. When the body’s DNA makes mistakes in a cell, the
mistakes are either fixed by additional DNA repair mechanisms or the cell is
destroyed to prevent further damage (apoptosis). Unfortunately, the genes that
are responsible for destroying rogue cells can be silenced (turned off) through
epigenetics and, as a result, mistakes in the DNA cannot be rectified before
they spread. The genes associated with cellular pathways that are prone to
cause cancer are called oncogenes. The silencing of tumour‑suppressing genes,
activation of oncogenes, and defects in DNA can be caused by epigenetic
mechanisms, which can affect several if not many of the steps in a cancer line 11.
We have literally removed the various roadblocks to
formation of cancer. Many of the genes that are inactivated by methylation in
carcinogenesis have classic tumour‑suppressor functions or play a critical role
in cell cycle control (repair of damage to DNA) apoptosis, differentiation,
angiogenesis, metastasis, growth factor response, drug resistance and detoxification
12. An incorrect change in the methylation of the DNA caused by
epigenetic carcinogens is the most common activation of cancer cell lines. Although
methylation changes occur to different genes depending on the type of cancer,
all cancers undergo changes in methylation, suggesting DNA methylation is a
major factor in tumour development and can be used as a genetic marker in
tumour development 13.
To put this in perspective, methylation in some areas of the
DNA, called CpG sites, in some tumour suppressor coding regions contributes to
as much as 50% of all inactivating mutations in some cancers and 25% of cancers
in general.
In contrast to genetic changes in cancer, epigenetic changes
are gradual in onset and are progressive. Their effects are dose-dependent and
are potentially reversible which increases the scope for the development of
epigenetic therapies for disease 14. These observations present new
opportunities in cancer risk modification and prevention using dietary and
lifestyle factors as well as treatment as you will see below. In this regard,
folate, a water-soluble B vitamin, has been a focus of intense interest because
of an inverse association between folate levels and the risk of several
malignancies (in particular, colorectal cancer) and because of its potential
ability to modulate DNA methylation. Through this process of supplementing with
folate, scientists have achieved a certain degree of reprogramming even in
adult cell DNA. The use of such inhibitors as folate has been shown to
reactivate expression of tumour‑suppressor genes that would otherwise be
silenced and a cancer would develop. Treatment for myelodysplastic syndrome, a
form of leukaemia, with epigenetic therapies is already approved for use in the
U.S. and there are a host of other treatments that continue to show promise 15.
Even more promising are the roles of diet and lifestyle. In a study of 30 men with low-risk prostate cancer who decided against conventional medical treatment such as surgery, radiation, chemotherapy or hormone therapy, three months of major lifestyle changes significantly lowered the level of prostate cancer. The changes included eating a diet rich in fruits, vegetables, whole grains and legumes and incorporating moderate exercise such as walking each day along with an hour of daily stress management 16.
Six of the control patients in this study underwent
conventional treatment due to an increase in prostate specific antigen (PSA)
levels or progression of disease measured by magnetic resonance imaging (MRI)
during the 3 months, while none of the lifestyle group did. PSA levels decreased four percent in
the experimental lifestyle group but increased by six percent in the control (no
change in lifestyle) group. Other markers such as the growth of prostate cancer
cells (LNCaP) were inhibited almost eight times more in blood serum from the
experimental group than blood serum from the control group (70% versus nine
percent). However, even more definitively, the changes in serum PSA and in
prostate cancer cell growth (LNCaP) were positively associated with the degree
of change in diet and lifestyle. That is, the more lifestyle changes the men
made, the greater the reduction in the prostate cancer markers. The lifestyle
group were literally reversing their cancer.
The researchers found even more profound changes when they
compared DNA from prostate biopsies taken before and after the lifestyle
changes. After only three months, the men had changes in expression of about
500 genes, including 48 that were turned on and 453 genes that were turned off.
The activity of disease-preventing genes increased while a number of
disease-promoting genes, including those involved in prostate cancer and breast
cancer, shut down. The lead researcher, Professor Dean Ornish, noted, “The
implications of our study are not limited to men with prostate cancer” 16.
In addition to the benefits in prostate diagnosis the men lost weight, lowered
their blood pressure and risk of heart attack and stroke and saw other health
improvements while reporting no negative side effects.
There is currently a great deal of interest in the promising
chemo-preventive actions of polyphenols, large organic molecules, such as
curcumin from curry, resveratrol found in grapes and berries and especially
Epigallocatechin-3-Gallate (EGCG) the major polyphenol in green tea 17.
EGCG in green tea has the ability to affect DNA epigenetics to fight cancer
beyond just its antioxidant potential. For example, treatment of human
oesophageal cancer cells with EGCG caused tumour suppressor genes, the genes
that stop cancers from growing, to be “turned on.” The activity of EGCG has
also been shown to possibly act to reduce cancer activity in prostate cancer
cells 17.
Other studies link obesity and malnutrition (low nutrient-dense
foods) in parents to hypertension in offspring and disease risk in offspring
later in life 18, specifically with regard to obesity and the onset of
diabetes later in life 19. Low-weight newborn babies are
biologically different than their bigger counterparts. Smaller infants have
fewer kidney nephrons, altered metabolism and are more insulin-resistant. These
differences show how dietary habits of the mother during pregnancy can alter
the expression of the genes of their offspring in such a way that they will
respond differently to the environment that follows after birth. Placental and
foetal growth is at its most vulnerable to maternal nutrition status in the
first trimester of pregnancy. Promotion of a healthy, nutritionally balanced womb
environment will not only ensure optimal foetal development but also reduce the
risk of chronic disease in adulthood 20. In support of this, it has
been found that folate levels in pregnant women affect DNA methylation in a
number of different gene promoter areas associated with infant health.
Some of the most well known studies linking epigenetics and
obesity have involved “agouti” mice. Over the past twenty years there have been
numerous studies indicating that impaired embryonic, foetal or infant nutrition
as a result of out processed western diet and environments can lead to greater
risk of obesity and metabolic compromise in later years 21. For
example, a short‑term dietary intervention in pregnant agouti mice, in the form
of supplements of folic acid, vitamin B 12, choline and betaine, have shown long‑lasting
beneficial influences on the health and appearance of the offspring for
multiple generations 22. By contrast, selectively bred diet‑induced
obesity dams (mothers) that were made obese during gestation and lactation had
more obese, insulin-resistant children who developed abnormalities of brain neurotransmitter
metabolism compared with offspring of lean diet‑induced obesity dams or dams
that were diet‑resistant 23. That is why there is so much emphasis
now on pregnant mothers supplementing, particularly with B vitamins. In a study
of sheep, metabolic and hormonal signals before birth increased the expression
of genes that regulate fat and the conversion of simple sugars into fatty acids
in the fat around the kidneys of sheep 24.
In one study, two types of rats were bred: one to develop
diet‑induced obesity and the other that was prone to be diet‑resistant. Researchers
found that the diet‑induced obesity rats would defend their increased body
weight when fed a high-fat diet (31%) whereas the diet‑resistant rats would
adjust their (high-fat) diet accordingly to maintain their lean physique. The
study also found that the diet‑induced obesity rats, even after long periods of
calorie restriction, would return to their higher weight once food was
available freely, even when on a five percent fat diet 25.
In other studies, researchers found that in a population
with a genetic predisposition toward obesity, the effects of maternal obesity
accumulated over successive generations to shift the population distribution
toward an increased adult body weight. Perhaps this is something we are heading
toward now in the human population…?
It is clear that epigenetic mechanisms may also drive
psychiatric and mental disorders. In particular what your mother eats during
pregnancy and you eat during childhood not only may influence your adult brain
function and its eventual decline as you age, but also may influence your
children’s cognitive potential and mental health 26. A foetus that endures
poor nutrition during gestation spares the growth of vital organs such as the
brain at the expense of tissues such as muscle; the pancreas adapts its
metabolism to the limited nutrition 27. Following on from this,
increasing evidence indicates that a disturbance in early neurodevelopment may
lead to a vulnerability to schizophrenia in adolescence or adulthood 28.
Twin studies have shown that people with schizophrenia and
bipolar disorder have changes in genetic activity caused by their respective environments.
The findings provide the strongest evidence yet that such gene changes might cause
these conditions. A study that scanned the genome of 22 pairs of identical
twins (one twin in each pair was diagnosed with schizophrenia or bipolar
disorder) found, as expected, that the twins had identical DNA. However, they
showed significant differences in epigenetic
markings and these changes were on genes that have been linked with
bipolar disorder and schizophrenia 29.
Regardless of which condition the twin had, the most
significant differences, with variations of up to 20% in the amount of methylation,
were in the promoter “switch” for a gene called ST6GALNAC1, which has been
linked with schizophrenia. The scans also revealed methylation differences in
Gpr24, a gene previously linked to bipolar disorder 29. In support
of this, other studies have found differences of up to 25% in methylation of
the same gene compared with controls.
Growing evidence suggests how we age is very much epigenetic-related.
Some of the strongest, decade-old evidence shows progressive changes in DNA
methylation in tissues in the ageing colon, stomach, oesophagus, liver, kidney
and bladder adding increased importance to the role of diet and lifestyle in
how we age.
Despite the role of our parents’ diet and lifestyles on our
future and the future of our own offspring, research shows we can change this
outcome by nutrition and lifestyle changes. We are largely in control of our
own destiny. From epigenetics, we are learning that it is not all in the genes.
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