The Disappearing Male is a Canadian Broadcasting Corporation documentary about the health threat posed by environmental chemicals to the male reproductive system.
The last few decades have seen steady and dramatic increases in the incidence of boys and young men suffering from genital deformities, low sperm count, sperm abnormalities and testicular cancer. At the same time, boys are now far more at risk of suffering from ADHD, autism, Tourette’s syndrome, cerebral palsy, and dyslexia.
The Disappearing Male takes a close and disturbing look at what many doctors and researchers now suspect are responsible for many of these problems: a class of common chemicals that are ubiquitous in our world.
Found in everything from shampoo, sunglasses, meat and dairy products, carpet, cosmetics and baby bottles, they are called “hormone mimicking” or “endocrine disrupting” chemicals and they may be starting to damage the most basic building blocks of human development.
To understand the importance of the new science of epigenetics for health, we have to visit cell development and the cellular processes which, if they go wrong, lead to cancer.
Understanding these processes could help us better anticipate and prevent possible health hazards from environmental chemicals, develop better models for risk assessment, and even lead to novel treatments for cancer.
Epigenetics and development
One single fertilised cell, in order to become a human, has to differentiate itself into about 200 cell types. Every single cell, however, contains the same complete set of around 25,000 genes. This means different genes have to be turned on and off at certain times in order for a cell to develop into and function as, for example, a skin cell rather than a liver cell.
This regulation of when genes are turned on and off is governed by epigenetic processes. Rather than mutations, which are changes to the genetic code, epigenetic changes affect genes themselves, like software in relation to DNA hardware.
During development, epigenetic regulation is one factor responsible for determining the course of development of a cell, setting it on the path to becoming a skin cell rather than a liver cell, or a brain cell instead of a muscle cell.
Sometimes, however, external influences can result in genes being silenced or activated at the wrong times. In effect, this can confuse the developmental instructions being acted on by a cell, subtly taking it away from its natural developmental pathway and down an altered route, with a range of potential knock-on effects.
The effects of these alterations have been studied in humans, in relation to parental dietary changes and effect on adult health, finding that the children of starving mothers are more likely to give birth to underweight babies and parental diet can affect longevity of grandchildren, such as in this Dutch and this Swedish study.
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How are genes switched on and off? Two of the most well-known types of alterations which affect gene expression are DNA methylation and histone modification.
DNA methylation: Here, a methyl (-CH3) chemical group is added to the DNA base cytosine. This change can prevent the affected gene from being expressed because the cellular processes which read genes and transform them into proteins are blocked by the methyl group.
Histone modification: Histones are proteins which pack DNA into tightly-bundled chromosomes, so the two-metre-long molecule can fit into the cell nucleus.
In order for genes in the chromosome to be expressed, the histone proteins have to temporarily unpack the DNA so cellular processes can read it.
This unpacking process is regulated by the addition of methyl, acetyl or phosphorous groups to the histones; if these groups are added or removed at the wrong time, then genes can be expressed at the wrong time for healthy development.
In animals, revealing research has been done into the effects which exposure to chemicals can have on epigenetic processes. One particularly famous example of the effects of chemically-induced epigenetic change is the feeding of pregnant mice on a diet rich in substances known to change gene expression by adding methyl groups to DNA.
In this case, the mouse offspring were not expressing the genes which would have made them yellow (agouti) rather than brown: the diet had switched the agouti genes off.
Mice which were not fed the DNA-methylating diet ended up with fully-activated agouti genes, which meant they were yellow in colour and they even became obese; one of the effects of leaving active the genes which make the mice yellow is to also prevent them from being able to tell when they are full, so the yellow mice eat their way to obesity.
The relationship between epigenetic changes and cancer
In general, cancer is understood by scientists to be a genetic disease, where mutated genes are thought to initiate transformation of normal cells into malignant cells. These cells show uncontrolled growth and the ability to invade other tissues and spread to other locations in the body.
The dominant theory is that a mutation initiates cancer by affecting a gene involved in the regulation of cell division, cell survival and/or DNA repair processes. This disables the safeguards preventing uncontrolled growth, allowing the cells to endlessly multiply and become destructive and invasive.
The genes involved in regulation of cell division and cell survival are known as tumour suppressor genes and cell proliferation regulator genes (also known as “protooncogenes”). Damage to suppressor genes is well-recorded in early-onset breast cancers, while mutations in the protooncogenes turns them into cancer-causing genes.
Epigenetic research, however, is starting to reveal another layer of complexity to the process: while cancer cells show mutations in protooncogenes, in addition these genes almost always display epigenetic changes in addition to the mutations.
The concern is that epigenetic changes are switching off tumour suppression genes, thereby initiating or causing progression in malignant transformation of the cell. Malignant growth could also be initiated by the epigenetic switching-on of oncogenes.
A particularly infamous example of cancer-causing interference in epigenetic processes is the drug diethylstilbestrol (DES), a synthetic oestrogen often prescribed to pregnant women until around 1971.
DES was prohibited for this use when it was discovered that it elevated the risk of rare vaginal cancers in the daughters of women who took the drug. The theory is that in utero exposure to DES turns on persistent over-expression of certain protooncogenes.
Are there more potentially cancer-causing chemicals than we thought?
In an attempt to limit the number of cases of cancer caused by chemicals, risk assessments are carried out to determine a chemical’s ability to cause mutations, and its use is then restricted accordingly.
The underlying assumption in carrying out risk assessments is that cancer is caused by genotoxins and mutagens altering the DNA sequence, resulting in uncontrolled cell replication.
Epigenetics, however, is making this assumption look false: the evidence coming from new studies is strongly suggesting that some substances are toxic because of their epigenetic effects, not because they directly damage the DNA sequence itself.
For example, the environmental contaminants cadmium, nickel, chromium and arsenic are known carcinogens that induce epigenetic alterations.
Chemicals such as vinclozan (a fungicide), methoxychlor (an insecticide), bisphenol A (found in food containers), benzene (in air pollution), diethylstilbestrol (a synthetic oestrogen) and persistent organic pollutants (particularly dioxin) have been shown to cause epigenetic alterations by increasing or decreasing DNA methylation.
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How is DNA methylation implicated in cancer? DNA methylation is carried out by enzymes called DNA methyltransferases (DNMTs). It is thought that levels of these enzymes are altered in cancer cells.
Global hypomethylation has been shown in ‘all’ tumours and is called a striking feature of neoplasia in a review of epigenetics and cancer (Feinberg at al. 2006). Over-expression of DNMTs has been linked to specific cancers.
It is also known that deregulation of histone modifications is implicated in cancer. Alteration of the DNA packaging process by histones resulting from changes in the levels of methylation, acetylation or phosphorylation can lead to unpacking of the DNA at the wrong time.
Consequently, the DNA can be accessed, transcribed and the gene expressed at the wrong moment.
This knowledge is not yet making its way into assessing potential for harm in risk assessment, which still assumes chemicals cause cancer by mutating genes, even though exposure to chemicals which have epigenetic effects is common and could be influencing incidence rates of cancer.
Since suspected carcinogens are currently only risk-assessed and categorised by their capacity to alter the DNA sequence, and not their capacity to change whether or not a gene is expressed, then some chemicals which may have a role in causing cancer could well be slipping through the regulatory net.
What does all this mean for cancer prevention?
Although epigenetics, as a new field, shows us there is a lot we don’t really know about carcinogenesis, it has already opened up several important avenues for implementing a conservative approach to preventing harm to health from the environment.
For one thing, there is good reliable evidence that epigenetic changes occur early in the cancer initiation and progression stages. The fact epigenetic alteration is reversible gives us targets for novel cancer treatments and possibly, as the example of the agouti mice shows, chemoprevention.
We also know that chemical exposures can cause epigenetic alterations, and that epigenetic changes during the development stages have serious implications later in life. These changes could initiate a cancer in utero, while exposure to something later in life could cause the progression of malignant transformation. Elimination of these chemical exposures could help reduce incidence rates of a number of cancers.
Given that cancer is easier to prevent than to treat, epigenetics also gives us helpful targets for primary prevention. This is where improvements in risk assessment and chemical regulation aimed at limiting exposure to environmental contaminants with known epigenetic effects (one candidate being bisphenol-A) is of critical importance.
Anway MD, Cupp AS, Uzumcu M, Skinner MK. Epigenetic transgenerational actions of endocrine disruptors and male fertility. Science. 2005; 308(5727): 1466–1469.
Baccarelli A, Bollati V. Epigenetics and environmental chemicals. Current Opinion in Pediatrics, 2009; 21:243–251.
Edwards TM, Peterson Myers J. Environmental Exposures and Gene Regulation in Disease Etiology. Environ Health Perspect. 2007; 115(9): 1264–1270.
Feinberg AP, Ohlsson R, Henikoff S. The epigenetic progenitor origin of human cancer. Nature Reviews Genetics. 2006; 7: 21-33.
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