ADHD and phthalates.

Prenatal (before birth) exposure to a group of chemicals called phthalates has been linked with ADHD like symptoms in a study published on the Environmental Health Perspectives website on January 28, 2010. Phthalates are a group of chemicals often added to plastics to give them their plastic-flexible like qualities, as well as in paints, lubricants and detergents (yep the ones in your supermarket). They are also found in some personal car products such as nail polish, liquid soap, shampoos, perfume and eye shadow. They are pretty well everywhere in our homes.

The study found that mothers with higher levels of the phtalates in their blood reported poorer behaviour in their children (ages 4-9 years), including typical ADHD symptoms. However, ADHD is not the only problem associated with phthaltes. Phthaltes have been linked in both animal experiments and human research with sexual organ and sexual behaviour dysfunction to name a just a few of the problems they can create.

Phthaltes are considered endocrine disruptors because, at incredibly low levels, they interfere with hormones such as estrogen in the body. The most vulnerable stage of these chemicals to have an impact is on the developing foetus in pregnant mothers.

In another study in the Journal of Paediatrics, February 2010, the use of baby personal care products such as lotions, shampoos and powder was associated with higher levels of phthalates in the babies blood.

The message is to become aware of the chemicals in your home and reduce the exposure to everyone but particularly to mums to-be. You can find a lot more on toxic chemical exposure in my book “Is Your Home Making You Sick”

It’s Not All in the Genes: The Science of EPIGENETICS

In 1953, James D. Watson and Francis Crick proposed the concept of the double helix as the structure of DNA. With this finding, the fields of genetics and biology experienced a monumental shift: seemingly, scientists had finally discovered why we are who we are. The quest began to isolate DNA and map the entire human genome. However, after spending billions and maybe even a trillion dollars unravelling the human genome, researchers have come to the realisation that it is not all in the genes. In recent years, a new idea has come to the forefront of genetics and is the focus of thousands of studies: epigenetics.

Genetic determinism—that is, the notion that “it’s all in the genes,” that everything is determined by our DNA and that we are victims of our hereditary—has been programmed into us since our first high school science lessons. This concept is disseminated by the media and even further propagated in medical school. If one gets a disease, it is deemed “genetic.” However, only a very few diseases—such as Huntington’s chorea, beta thalassemia and cystic fibrosis—can be blamed entirely on one faulty gene. These single-gene diseases affect less than two percent of the population ¹. It is estimated that only five percent of diseases are a direct result of gene mutations; the rest are a result of environmental (about which I have written extensively and coined a term, “the DEAL—Diet, Environment, Attitude and Lifestyle”) influences ². It is now theorised that Alzheimer’s disease, cancers, cardiovascular disease, asthma, autoimmune diseases such as lupus and conditions such as schizophrenia are linked to epigenetic triggers ³. The vast majority of diseases that afflict us today are a result of complex interactions between genes and the environment. Classic genetics alone cannot explain the diversity of disease characteristics in society.

It is true that genes may have an association with a disease, but this does not prove causation. The genes may be related to a disease but are not directing or causing it. Long ago, biologist Jean-Baptiste Lamarck was ridiculed because of his evolutionary ideas when he proposed that the environment, including our diet, can influence our genes. Now science has caught up with Lamarck’s hypothesis. Even Darwin recognized environmental factors outside the hereditary material but that has largely been ignored until now.

Perhaps we need to look at our genes differently. In his book, The Greatest Show on Earth, Richard Dawkins (2009) suggests that our DNA is not a blueprint like that used to build a house, but is in fact a broad recipe from which certain outcomes arise. Tissues and bodily structures are not formed according to set plans or blueprints contained in our DNA, but self-assemble responding to environmental [local] conditions and the laws of chemistry.

Epigenetics provides the missing link between the environment and the development of disease. It goes beyond many of the subtle changes in DNA that explain only a fraction of the diseases humans develop. For the first time since DNA was discovered, epigenetics has encouraged scientists to move from genetic determinism to studying how the environment can shape our lives. Previously, it was believed that DNA would determine the makeup of the person—his or her predisposition to disease, hair colour, metabolic rate, etc. However, not only is “nurture” becoming more significant than “nature,” but also there is a transgenerational property to epigenetics: genes can be turned on and off, and those changes can be passed on for generations ⁴.

It appears that genes are not our destiny. It is environmental signals that activate the expression of the gene. Environmental factors are capable of causing epigenetic changes in DNA that can potentially alter gene expression and result in genetic diseases, including cancer and behavioural disorders. Environmental influences including nutrition, behaviour, stress, chemicals, radiation and emotions can change how the genes are expressed and can silence or activate a gene without altering the genetic code in any way. These are changes in gene expression that occur without a change in DNA sequence.

Known or suspected culprits behind negative epigenetic changes include agents such as heavy metals, pesticides, plastic compounds including BPA, diesel exhaust, tobacco smoke, polycyclic aromatic hydrocarbons, hormones, radioactivity, viruses, bacteria and deficiencies in basic nutrients. Each nutrient, each interaction, each experience can therefore manifest itself through biochemical changes, which may have effects at birth or 40 years down the track. These epigenetic changes often occur at foetal or embryonic levels, but they set the stage for an adult’s susceptibility to a host of diseases and behavioural responses. There are certain periods of an organism’s life during which it is more susceptible to methylation and epigenetic changes—including gestation, neonatal growth, puberty and old age—but the period in which an organism is most likely affected by methylation is during the formation of the embryo ⁵.

Detractors have largely ignored epigenetics, and in fact harshly criticised early studies, including one in which researchers used supplements to offset the results of a particular gene in mice. Researchers fed pregnant mice, all of which had an abnormal “agouti” gene, methyl-rich supplements, folic acid, B12, betaine and choline and, as a result, changed the binding characteristics of the regulatory chromosomal proteins. Agouti mice have yellow coats and are extremely obese, which predisposes them to cardiovascular disease, diabetes and cancer ^6,7. The pregnant mice that were given the supplements produced standard lean, healthy offspring that lived longer and weighed half that of the yellow agouti mice, even though they still had the agouti gene. These observations suggest, at least in this special case, that maternal dietary supplementation may positively affect health and longevity of offspring.

The research also shows that the epigenetic effects might go on for a number of generations; a disease you are suffering today could be a result of your great-grandmother being exposed to an environmental toxin during pregnancy. Researchers exposed pregnant rats to environmental toxins during the period that the sex of their offspring was being determined. The compounds—vinclozolin, a fungicide commonly used in vineyards, and methoxychlor. Pregnant rats exposed to these chemicals produced male offspring with low sperm counts and low fertility. Those males were still able to produce offspring, however even when they were mated with females that had not been exposed to the toxins, their male offspring had the same problems of low sperm counts and low fertility. The effect persisted through all four generations tested, with more than 90% of the male offspring in each generation affected with no additional pesticide exposures ⁸. The findings provide a new paradigm for disease etiology and basic mechanisms in toxicology and evolution not previously appreciated.

One study found that over-eating during the SGP (slow growth period of the teen years) by male grandparents led to a higher rate of diabetes and cardiovascular disease in their grandchildren ⁹. All the results indicated that these potential epigenetic traits were passed down through the male gene line ¹⁰. In a later study ¹¹, researchers also induced these alterations through maternal ingestion of genistein, the major phytoestrogen in soy, at doses comparable to those a human might receive from a high-soy diet, and found that they may also cause health problems, via additive or synergistic effects on DNA methylation, when it interacts with other substances such as folic acid. Through these and subsequent studies, it has been revealed that both the mother’s and father’s diets and environment during pregnancy and childhood, respectively, are of paramount importance to the epigenome and development of the offspring ¹².

Studies have found that epigenetic effects occur not just in the womb, but also over the full course of a human life span. In a study of 40 pairs of identical twins, ranging in age from three to 74, twins were epigenetically indistinguishable during the early years of life, while older monozygous (identical) twins exhibited remarkable differences in their overall content and genomic distribution of 5-methylcytosine DNA and histone acetylation, affecting their gene-expression portrait. That is, younger twin pairs and those who shared similar lifestyles and spent more years together had very similar DNA methylation and histone acetylation patterns. But older twins, especially those who had different lifestyles and had spent fewer years of their lives together, had markedly different patterns in many different tissues, such as lymphocytes, epithelial mouth cells, intra-abdominal fat and selected muscles ¹³. As one example, the researchers found four times as many differentially expressed genes between a pair of 50-year-old twins compared to three-year-old twins, and the 50-year-old twins with more DNA hypomethylation and histone hyperacetylation (the epigenetic changes usually associated with transcriptional activity) had the higher number of over-expressed genes. The degree of epigenetic change therefore was directly linked with the degree of change in genetic function ¹³.

Numerous studies have linked epigenetic factors to cancers of almost all types, genetic disorders and paediatric syndromes as well as contributing factors in autoimmune diseases, cognitive dysfunction, reproductive, autoimmune, respiratory disease, neurobehavioral illnesses, mental retardation and aging ^14,15. The expression and activity of enzymes that regulate these epigenetic modifications have been reported to be abnormal in the airways of patients with respiratory disease ¹⁵.

While epigenetic changes can lead to an increase in diseases it now puts us in control. Not only can we avoid so many diseases that were once thought of as in our genes but research is showing by changing our diet and lifestyle we can also reverse many of these conditions.

References

1.     Lipton 2005

2.     Willet 2002

3.     Esteller 2008

4.     Anway et al. 2005

5.     Dolinoy et al. 2007

6.     Wolff et al. 1998

7.     Waterland and Jirtle 2003

8.     Skinner et al. 2005

9.     Kaati et al. 2002

10.  Kaati et al. 2007

11.  Jirtle, April 2006,

12.  Morgan et al. 2008

13.  Fraga et al 2005

14.  Weinhold 2005

15.  Adcock et al. 2006

Epigenetics and Disease

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.

References

1.     Bollatti and Baccarelli 2010;

2.     Dolinoy et al. 2007;

3.     Isles and Wilkinson 2008;

4.     Weidmann et al. 2007

5.     Attig et al. 2010

6.     Newbol 2004

7.     Nystrom and Mutanen 2009

8.     Dworkin, Huang and Toland 2009

9.     Esteller 2008;

10.  Shikhar, Kelly and Jones 2010

11.  Herceg 2007

12.  Kim 2006

13.  Banerjee 2009

14.  Adcock et al. 2006

15.  Issa 2006

16.  Ornish et al. 2008

17.  Link, Balaguer and Goel 2010

18.  Friaz et al. 2011

19.  Ryan 2011

20.  Wu et al. 2004

21.  Gluekman and Hanson 2008

22.  Freeman 2009

23.  Levin et al. 2005

24.  Muhlhausler et al. 2007

25.  Levin 2008

26.  Williams 2008

27.  Jones PB, Rantakallio P, Hartikainen AL, Isohanni M, Sipila P

28.  Brown and Susser 2008

29.  Dempster, Pidsley et al 2011