The Need for Regulations Regarding Nutritional Supplements with Epigenetic Effects

Epigenetics is the way in which proteins and RNA interact with DNA to affect the expression of the DNA. The proteins and RNA interact in such a way as to turn small lengths of DNA, called genes, either on or off. This process is called methylation. Via methylation, genes can be expressed more (meaning that the genes act as templates for the production of proteins) or the genes can cease being expressed at all (meaning that, even though genes for the coding of particular proteins exist, those genes will not be read and so the proteins will not be made). Thus, while a person might have a gene for a particular characteristic, that person will not necessarily exhibit that characteristic because the gene for that characteristic could have been turned off. This is how identical twins can appear so different despite the fact that they have identical DNA.

There are two crucial things to note about the science of epigenetics.

First, epigenetic changes are heritable. If a gene is turned off in the germ (egg or sperm) cells of a parent, the same gene will be turned off in the somatic (non reproductive) cells of the offspring (as well as the germ cells of the offspring). A prime example of this is what resulted from the prescription of the synthetic estrogen compound diethylstilbestrol (DES) to prevent miscarriages in pregnant women in the mid-20th century. Despite being lesser known than the horrific Thalidomide compound, DES was (in one way) worse. Specifically, it was not only associated with an increased risk for vaginal and breast cancers in daughters, but also an increased risk of ovarian cancer in maternal granddaughters. That is, it altered the epigenetics of the germ cells of the user and the altered epigenetics were then inherited by the offspring and the offspring's offspring, affecting generations to come.

Second, the nutrients we ingest, via the foods we eat, affect our epigenetics. One of the clearest examples of this is in the case of the honeybee. Honeybee colonies comprise of worker bees and queen bees. Worker bees live for approximately 20 days, and spend this time constructing honeycomb, feeding larvae, and foraging for nectar and pollen. They never produce offspring. In contrast, queen bees live for many years. They are fed and preened by worker bees, so that they are free to focus on their sole task: to lay up to 2,000 eggs a day. With such differences in lifespans and behavior patterns, it is surprising to discover that worker bees and queen bees are in fact genetically identical. The differences are solely a consequence of the queen bees being fed royal jelly, which methylates their DNA differently to the methylation of the DNA of worker bees. This in turn causes their DNA to be expressed differently than the DNA of the worker bees, resulting in lifespans and behaviors that are starkly different.

Before all the readers go out and buy royal jelly, it should be noted that it will not necessarily have such a profound effect on the methylation of human DNA. But there are some nutrients that will.

See the table below, for a list of some of the most important nutrients for humans from an epigenetic standpoint. Generally, in the right amounts, these nutrients have a positive effect by regulating gene expression in such a way as to protect against cancer and delay aging. However, in excess, these same nutrients can make too many epigenetic changes, thereby no longer helping but instead hindering the health of the individual. It is a classic case of “too much of a good thing”. In the right hand column, I have outlined some of the deleterious consequences resulting from the excess consumption of nutrients that have an epigenetic effect.

Nutrient	Food Origin	Epigenetic Role	Health Effect of Excess
Methionine	Sesame seeds, brazil nuts, fish, peppers, spinach	SAM-e synthesis (SAM-e then transfers a methyl group to the DNA, causing methylation)	One study has shown that excess methionine may exacerbate the symptoms of schizophrenia, as it leads to epigenetic changes that cause the dysfunction of GABAergic neurons.
Folic Acid	Leafy vegetables, sunflower seeds, baker's yeast, liver	Methionine synthesis (methionine is then converted into SAM-e, which transfers a methyl group to DNA, causing methylation)	Too much prenatal folic acid is associated with increased allergies and asthma in the offspring, likely due to epigenetic changes to the mother's oocyte (egg) cells.
Vitamin B12	Meat, liver, shellfish, milk (supplements are necessary for vegans)	Methionine synthesis (methionine is then converted into SAM-e, which transfers a methyl group to the DNA, causing methylation)	In one study, researchers found high vitamin B12 levels in patients suffering from prostate cancer, and their conclusion was that epigenetic changes caused by cobalamin (vitamin B12) stimulate prostate cancer development.
Vitamin B6	Meats, whole grain products, vegetables, nuts	Methionine synthesis (methionine is then converted into SAM-e, which transfers a methyl group to the DNA, causing methylation)	One child was born with pyridoxine (vitamin B6) dependency after the mother received large amounts of vitamin B6 during pregnancy, which altered the epigenetics of her oocyte cells. The child suffered from seizures and progressive mental retardation if not administered vitamin B6 daily.
SAM-e	Popular dietary supplement pill; unstable in food (produced in the body by metabolism of methionine)	Enzymes transfer methyl groups from SAM-e directly to the DNA	In mouse studies, excess SAM-e resulted in fatty livers, fibrosis and hepatocelular carcinomas. This is likely due to the epigenetic effect of SAM-e.
Choline	Egg yolks, liver, soy, cooked beef, chicken, veal and turkey (brocolli is a good source for vegans)	Methyl donor to SAM-e	Choline has been linked to down regulation of certain genes. These epigenetic changes have been associated with pre-eclampsia in pregnancy.
Betaine	Wheat, spinach, shellfish, and sugar beets	Breaks down the toxic byproducts of SAM-e synthesis	Excess betaine causes epigenetic changes that result in higher LDL (bad cholesterol) concentrations.
Resveratrol	Red wine	Removes acetyl groups from histones (condensing DNA structure and turning the genes “off” so proteins are not made)	Resveratrol causes epigenetic changes to many genes, causing blood thinning (which can be problematic for people already on blood thinners such as warfarin).
Genistein	Soy, soy products (it is also in coffee, for those who try to avoid soy)	Increased methylation of DNA via an unknown mechanism	As with DES (discussed above) and BPA's (in plastics) excess pre and post natal exposure to genistein is associated with epigenetic changes that result in weight gain in offspring.
Sulforaphane	Broccoli	Adds acetyl groups to histones, which turns “on” anti-cancer genes	Excess sulfurophane blocks a critical liver enzyme (possibly due to epigenetic changes) that functions as a bottleneck for breaking down common prescription drugs.
Butyrate	A compound produced in the intestine when dietary fiber is fermented	Adds acetyl groups to histones, which turns “on” 'protective' genes, increasing lifespan	Excessive butyrate may affect gene expression (i.e. cause epigenetic changes) so as to induce severe intestinal epithelial cell apoptosis and disrupt the intestinal barrier.
Diallyl sulphide (DADS)	Garlic	Adds acetyl groups to histones, which turns “on” anti-cancer genes	Excess DADS may affect gene expression (i.e. cause epigenetic changes) so as to trigger vomiting, irritate the oral mucosa, and cause severe burning sensations in the esophagus and stomach.

As stated above, when consumed in appropriate amounts, these nutrients create a state of “epigenetic health”, whereupon the right genes are expressed in the right amounts to achieve optimum health. However, as you will note from the right hand column, the same nutrients that cause positive epigenetic effects in natural doses, can cause deleterious epigenetic effects when consumed in excess amounts. The major determinant of whether an appropriate versus an excessive dosage is received is the means via which the nutrients are delivered. As is clear from the table, these nutrients are all either available from dietary sources or are created by the body. Generally, it is difficult to consume excess nutrients via dietary sources. However, it is common for people who believe their diet to be lacking, to take nutritional supplements. It is these nutritional supplements that lead to a risk of excess dosages and consequent deleterious epigenetic changes.

Thus, nutritional supplements should be treated with the respect they deserve, given the profound and long lasting consequences such supplements can have. However, currently, little respect is paid.

Nutritional supplements do not need to be approved by the FDA before they are released into the marketplace. Moreover, nutritional supplements are available for purchase from grocery stores, without prescription. And yet, nutritional supplements have intergenerational effects. Whereas, most allopathic drugs (i.e. those without epigenetic effects, which might, at most, affect the next generation if taken during pregnancy) must pass rigorous testing to receive FDA approval and are only available upon prescription.

Furthermore, when nutritional supplements are prescribed, they are generally prescribed by a naturopath. In New York State, naturopaths do not need to be registered. In contrast, allopathic doctors must be registered. And yet, the naturopaths are the ones responsible for prescribing nutritional supplements that have epigenetic effects. These affects will be inherited and therefore impact several generations of people. Thus, the consequences are far more severe and long lasting than for many allopathic drugs (aside from the emerging milliuea of epigenetic drugs) that are prescribed by allopathic doctors.

I propose the following solutions based on evaluation of foreign and domestic US laws:

1) REQUIRED FDA APPROVAL OF NUTRITIONAL SUPPLEMENTS WITH EPIGENETIC EFFECTS

The European Union's Food Supplements Directive of 2002 requires that nutritional supplements be demonstrated to be safe, both in dosages and in purity. In contrast, under the United States' Dietary Supplement Health and Education Act of 1994 (DSHEA), manufacturers do not need to register their products with the FDA nor get FDA approval before producing or selling nutritional supplements. It is simply left up to the manufacturer to ensure that a nutrititional supplement is safe before it is marketed. The FDA can then take action against any unsafe nutritional supplement after it reaches the market. Clearly, at this point, it is too late. The DSHEA should be amended to require FDA approval of nutritional supplements with known epigenetic effects. In particular, this approval process should dictate that the dosages of the nutritional supplements accord closely with accepted RDI's (i.e. it should no longer be possible to purchase nutritional supplements with epigenetic effects with dosages of 3000 times the recommended daily intake).

2) REQUIREMENT FOR PRESCRIPTIONS FOR NUTRITIONAL SUPPLEMENTS WITH EPIGENETIC EFFECTS

SAM-e is a prescription only drug in Italy, Spain and Germany. These countries have recognized the profound and lasting effects that this supplement can have on epigenetics. The US should follow suit, making SAM-e available by prescription only, along with the other nutritional supplements that are known to impact epigenetics. Obviously, there is a risk associated with this approach as many people will be too lazy, time or cash poor, or doctor averse, to get a prescription. Thus, they will simply not access the supplements they need (and become deficient, which will cause a whole host of other epigenetic changes with deleterious effects). However, it is up to the US government to factor in this risk and draft the amendments in such a way as to minimize the risk. For example, perhaps in addition to doctors and naturopaths being granted the power to prescribe nutritional supplements, pharmacists might also be granted the power to prescribe. As these pharmacists are stationed at every Walgreens and Duane Reade, they are accessible to the public and pose a minimal psychological, time or financial barrier to people who wish to access the supplements they need.

3) REGISTRATION SYSTEM FOR NATUROPATHS

Currently, 16 States, the District of Columbia, and the United States territories of Puerto Rico and the US Virgin Islands have licensing laws for naturopaths. In these locations, naturopaths are required to graduate from an accredited four year naturopathy program and pass an extensive board examination in order to receive a license. New York State, and the remaining US States, should adopt similar requirements.

CONCLUSION

The lack of regulation of nutritional supplements and nutritional supplement prescribers, reflects a lack of understanding of the true power and consequences of nutritional supplementation. Nutritional supplements, particularly those with epigenetic effects, should be respected for what they really are and the impact that they can have, not just for the user, but for generations to come.

Until the government realizes the power and consequences of nutritional supplementation, and steps up to properly regulate the prescribers, implement prescription requirements, mandate warning labeling and require FDA approval of nutritional supplements, in order to protect consumers, it is up to us to protect ourselves. Before you buy the next nutritional supplement with 300% the RDI of folate for example, think twice about how that might affect you, and your children, and your children's children...