Impact of Diet on Epigenetic Markings
One of the most compelling accounts of the effects of diet on gene expression dates back to 1944, the year of the Dutch famine. From November 1944 to April 1945, when the Germans occupied the Netherlands, daily rationing of food permitted a mere 500-1000 calories per person per day. Because of strict health record keep- ing and a well-defined period of rationing, data from this historical period of time was available for scientific review. There were three groups for this study:
1. People who were born or conceived during the famine (311
of them). 2. Their same-sex siblings who were born before or conceived after the famine (311 of them).
3. Unrelated people as controls (349 of them).
Studies on the people conceived during the famine showed they had impaired glucose tolerance, hypercholesterolemia, raised blood pressure and higher rates of both cancer and obesity in adult- hood. In effect, those children born or conceived during the famine became extremely efficient at storing calories because of the lack of food at the time. However, once food was readily available, these individuals continued to readily store the calories to the point of obesity with resultant cardiovascular, cancerous, and metabolic derangements.
Another well known example is that of the Agouti mouse. In
Figure 3, the two mice pictured are actually genetically identical, yet they have markedly differ- ent physical appearances. The difference results from nutrition and its ef- fects on the agouti gene. Agouti mice are use- ful for epigenetic studies because they have a ge- netically modifiable gene that makes them obese and yellow which can be turned off by methylation. Mice with the agouti gene
Figure 3. Agouti mice
turned off are genetically identical to their yellow obese kin, but are skinny and brown, because of methylation of the agouti gene. The mother of the skinny brown mouse ate food that was sup- plemented with folate, vitamin B12, choline, and betaine (all chemi- cals that supply methyl groups to DNA) for two weeks before mating, through 3 weeks of pregnancy, and lactation. Once the mice were weaned they ate the same food until they were 21 days old – when the picture was taken. Similar effects are noted when mother mice are fed a diet supplemented with bisphenol A (BPA, a chemical used in the manufacture of plastics and resins which is known to modify gene expression negatively). The effect can be abolished by maternal dietary supplementation with folate, B12, choline or betaine. Clearly, diet can profoundly alter epigenetic patterns in animals. While the causal relationship between diet and cancer development is more challenging to demonstrate, numerous studies have clearly shown a positive correlation between consumption of certain foods and the inhibition of several different forms of cancer. Bioactive food components from garlic, broccoli, and resveratrol in wine, have been shown to alter epigenetic processes for cellular function. These in- clude control of cell proliferation, increased apoptosis (programmed cell death which is lost in cancer cells), and reduction in inflamma-
14 Natural Nutmeg October 2012
tion. Catechins, the most abundant of bioactive compounds in green tea, can inhibit breast, ovarian, prostate, gastric, esophageal, skin, colorectal, and pancreatic cancers. Curcumin, the main component of turmeric, has anti-inflammatory, anti-oxidant, and anti-cancer effects. Its greatest effects can be seen on leukemia, cervical, and pancreatic cancers. A summary of epigenetic diet compounds, food sources, and possible cancer type impacted is given in Figure 4.
Impact of Physical Activity on Epigenetic Markings
Physical inactivity is strongly associated with increased risk of colorectal cancer. There is a growing body of evidence that suggests epigenetic modifications may impact exercise-induced changes in gene expression. The expression of some genes has been altered in the colon tissue of animals engaging in varying levels of physical activity. These findings are in part mediated by changes in epigenetic patterns. The epigenetic changes observed generally involve methy- lation and other alterations as well. Furthermore, histone modifica- tion was observed in human muscle biopsy tissue following exercise, providing evidence that epigenetic effects may be important in mediating skeletal muscle adaptations to exercise.
Impact of Stress on Epigenetic Markings
One of the most extraordinary examples of environmental influences on gene expression comes from studies that examined the effects of maternal grooming on offspring in rats. There is natural variation that exists in both licking and grooming as well as nursing in rats. Rat pups born to mothers that exhibit high levels of grooming and nursing are less fearful as adults and show reduced response to stress. These differences appear to be related to epigenetic modi- fications of the glucocorticoid receptor (GR) in the hippocampus area of the brain. Rat pups that were raised by mothers who licked and groomed them had low levels of methylation. Pups raised by mothers who ignored them had high levels of methylation, which can develop within 2 hours of the pups being neglected. Interest- ingly, rat pups treated with a chemical that reverses the epigenetic modification ultimately had increased GR expression. The treatment eliminated differences in stress response, suggesting a direct correla- tion between the induced epigenetic changes and control of adult rat behavior.
Subsequently, these results prompted a study in humans to determine the relationship between prenatal exposure to maternal mood and methylation of the human GR gene. Methylation of the human GR gene in newborns was sensitive to prenatal maternal mood, suggesting that epigenetic mechanisms may be important in mediating the influence of stress in a very broad sense. Recent studies have been initiated to determine the epigenetic influences on chronic stress as it impacts the development of chronic or mood anxiety disorders. Clearly, future studies will be necessary to further define the complex interplay between stress and gene expression.
The Future and (of) Epigenetics
The ability of diet, exercise, stress and other lifestyle factors to act epigenetically in cancer cells (Figure 5) has important implica- tions for determining not only susceptibility to cancer and rate of tumor development but also cancer prevention. While observational studies help establish associations between environmental exposures and cancer risk, intervention studies are necessary to establish clear causality. Furthermore, significant challenges remain in translating
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