We know that endocrine disruptors are awful for us, but can you explain why they are harmful from an epigenetic perspective?
Endocrine disruptors are synthetic chemicals that mimic human hormones, especially estrogen. They come in many varieties and are becoming a ubiquitous component of the environment, an ecological and health disaster. Estrogen mimics are particularly harmful to male sexual development. In fishes, they can cause males to become females. In frogs, they arrest male sexual maturity; and in mammals like us they cause abnormal sperm development and infertility.
Imprinted genes, as described above, are especially vulnerable to endocrine disruptors and the effects can be transmitted across generations. In one important study on mice it was shown that the fungicide, vinclozolin, a strong endocrine disruptor, causes all kinds of problems, including sperm defects in the offspring of exposed female mice. What was most alarming though, was that the next three generations were also infertile, though they were never exposed to the vinclozolin. The effects of the chemicals to which we are exposed may not be limited to ourselves, but also our children, our children’s children, and even our children’s children’s children. That is a nightmarish form of epigenetic inheritance.
Epigenetic effects grow as cells (and we) age. And epigenetic processes have the potential to be reversed… So, does it follow that some aging processes could be epigenetically reversed?
Aging is a booming field of epigenetic research and has already yielded some startling results. Epigenetic processes influence aging in a number of ways. Perhaps most fundamentally, there is a gradual reduction of DNA repair with aging. Our DNA is constantly under threat from a variety of environmental factors, most notoriously, radiation. Random errors during cell division are also important. When we are young, the repair of damaged DNA is robust; as we age, not so much. The process of DNA repair is under epigenetic control and this epigenetic repair gradually wanes with age.
It is also well known that caps at the ends of chromosomes, called telomeres, shorten with each cell division until they reach a critical threshold, at which point the cell becomes senescent and can no longer divide. With aging, more and more cells reach this point, which is associated with cancer and a host of other ailments. Recent epigenetic research has revealed that this telomere shortening is under epigenetic control, with histones at the center of things.
But perhaps the most exciting area of aging epigenetics is the recent notion of an epigenetic clock, called Horvarth’s clock, after its discoverer. The gist of it is that there is a strong association between the amount of genome-wide methylation and mortality. A lot of the genome is methylated when we are young but methylation is reduced in a constant clock-like way as we age. Methylation, recall, tends to silence genes. With age, it appears, an increasing amount of genes that should be silenced are not, rendering us more susceptible to all manner of ailments. From reading the amount of methylation in the epigenome, scientists can actually predict an individual’s age with impressive accuracy.
Of course, there is now much epigenetic research directed toward reversing these age-related epigenetic processes. The most promising seems to be reversing the age-related reduction in genome-wide methylation. But since this was only recently discovered, this research is in its infancy. Potentially, at least, dietary interventions might prove useful, as some foods and supplements, such as folic acid, are known to promote methylation. Other epigenetic research is focused on reversing the age-related reduction in telomere size. The epigenetics of DNA repair has proven a tougher nut to crack, due to its complexity.
We’re also intrigued by the notion that as parents we can affect the epigenetic (and overall) health of our children, another topic you touch upon in Epigenetics. Can you tell us more?
Some epigenetic effects span not only lifetimes but generations. I have already described two examples: the effects of the endocrine disruptor, vinclozolin, on sexual development in mice; and the increased incidence of obesity, heart disease, and diabetes of those born to women who experienced the Dutch famine in utero. A number of other examples have been reported since the publication of my book. There, I discuss at length the transgenerational transmission of epigenetic alterations in the stress response of mice caused by poor maternal parenting. In humans there is evidence of altered stress response in neglected and abused (both maternal and paternal) children that tends to perpetuate neglect and abuse in both sexes over several generations.
But only a minority of transgenerational epigenetic effects represent true epigenetic inheritance. The effects of the Dutch Famine, for example, are not examples of epigenetic inheritance, just a transgenerational epigenetic effect. To count as true epigenetic inheritance, the epigenetic mark, or epimutation, must be passed along intact from one generation to the next. This is actually quite common in plants, fungi, and some animals, but not in mammals like us. There are examples of inherited epimutations in mice and some suggestive evidence for humans. One recent report suggested epigenetic inheritance of a predisposition to a certain form of colon cancer.
Until recently, many traits that “run in families” were assumed to be genetic. We now know that many stem from transgenerational epigenetic effects, if not true epigenetic inheritance.
Although the research on epigenetics that exists today is fascinating, it seems that we have a long way to go. What needs to happen in order for us to have more answers—time, resources, funding?
Currently the study of epigenetics has a lot of momentum. But resistance from old guard geneticists is also pronounced. Many complain of epigenetic hype. To be sure, there has been some unnecessary hype. Some websites devoted to epigenetics are garbage. But the fact is, epigenetics needs no hype. Our understanding of cancer, aging, and stress—to name three areas of active research—has already been greatly enhanced by knowledge gained from epigenetics. And then there is the mystery at the very heart of developmental biology: How does a ball of generic embryonic stem cells develop into an individual with more than 200 cell types, from blood cells to hair cells to neurons, all of which are genetically identical? What makes stem cells special is epigenetic. And what makes neurons different from blood cells is epigenetic as well.
Epigenetic research has passed beyond the infant stage but is well short of adolescence. As such, we can expect much, much more from epigenetic research in the not too distant future.