01.10.2012 Natural Health

Epigenetics and Disease

Epigenetics suggests we are not captive to our genes. Report by Peter Dingle PhD

(Read Part 1 "Beating our Genes" in our September issue 19.7)

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 wellbeing, 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 plasticisers 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 5% 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 US 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 three months, while none of the lifestyle group did. PSA levels decreased 4% in the experimental lifestyle group but increased by 6% 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 9%). 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 from 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 best known studies linking epigenetics and obesity have involved "agouti" mice. Over the past 20 years there have been numerous studies indicating that impaired embryonic, foetal or infant nutrition as a result of our 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, has shown long lasting beneficial influences on the health and appearance of the offspring for multiple generations (22). In contrast, selectively bred diet-induced obesity dams (mothers) that were made obese during gestation and lactation had more obese, insulin-resistant offspring that 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 5% 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 (http://www.newscientist.com/article/mg20827853.500-genes-marked-by-stress-make-grandchildren-mentally-ill.html) 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 (http://www.newscientist.com/article/mg19926641.500-rewriting-darwin-the-new-nongenetic-inheritance.html) 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.
DISCLAIMER

Dr Peter Dingle is a researcher, educator and public health advocate. He has a PhD in the field of environmental toxicology and is not a medical doctor.

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"http://hmg.oxfordjournals.org/search?author1=Emma+L.+Dempster&sortspec=date&submit=Submit" Dempster,
"http://hmg.oxfordjournals.org/search?author1=Ruth+Pidsley&sortspec=date&submit=Submit" Pidsley et al 2011

Peter Dingle

Dr Peter Dingle (PhD) has spent the past 30 years as a researcher, educator, author and advocate for a common sense approach to health and wellbeing. He has a PhD in the field of environmental toxicology and is not a medical doctor. He is Australia’s leading motivational health speaker and has 14 books in publication.

http://www.drdingle.com/

https://www.facebook.com/DrPeterDingle/

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