Introducing the epigene-environment framework

Your Environment: Friend or Foe?

A significant challenge in medical research is understanding why we fall ill. Why is it that some of us get certain diseases whilst others do not. Although we are genetically very different from each other (unless you count your identical twin), understanding the reasons behind variability in health does not just fall onto the obvious candidate – genetics; rather we have to consider another very important variable, the environment.

A report published in 2006 by the World Health Organisation states that 13 million deaths occur from environmental causes and up to 24% of these deaths are actually preventable [1]. A large number of these environmental factors are pollutants such as metals and hydrocarbons, whilst some exposures arise as a by-product of our agricultural efforts like the use of pesticides. To really understand how we fall ill from these environmental factors, we have to understand how we as biological entities respond to our environment.

We are equipped with a static toolkit – the genome

The environment is highly dynamic, from weather patterns, to the air that we breath and the availability of water. Whilst we are equipped with a static toolkit – the genome, we have to turn on and off certain genes depending on stresses imposed on us by the environment. A classical example is the heat shock response, which is involved in turning on genes and making proteins that help to protect your cells, from a variety of stresses from exposure to heavy metals, cytotoxic drugs and viral infections [2]. It’s pretty clever actually, it allows your cells to “brace themselves” through a tough time. However a really interesting point here, is how is this communicated?

This is where a nascent field of research is taking the limelight. Environmental epigenetics is being used to interrogate our relationship with the environment. What is epigenetics? It is the study of heritable changes in gene expression without changes in the DNA sequence. Through epigenetics, we are able to adjust the the expression of certain genes in response to an exogenous influence, i.e. the environment. This is achieved through a variety of mechanisms, broadly referred to as epigenetic modifications. Examples include adjusting the levels of methylation on DNA to silence genes and adding chemical groups to proteins called histones which act as a scaffold for your DNA. This allows the DNA to have varied accessibility to the molecular machines involved in expressing your genes and more importantly it allows for variation in the relative expression of certain genes at specific times in response environmental stimulus.

 

The traditional gene-environment model, is not enough.

Traditionally, health outcomes were considered to occur from gene-environment interactions. In this model, diseases resulted from interactions between an individual’s genetic make up and the environmental factors. Those studying genetics have stood by the concept that the expression of a particular physical characteristic (phenotype) is variable and dependent on the environment to which the individual is exposed to. In this example, some people may have a relatively low risk in developing a disease in response to environmental factors, whilst others are more likely, purely due to their genetic differences or polymorphisms [*]. It has now become apparent this this approach is too simplified.

Recent research published in Nature’s Heredity, has stated that we should add an epigene-environment approach. In the epigene-environment framework, the relative differences in an individual imposed by epigenetic mechanisms are also important and of similar weight to our genetic differences. In this example, epigenetic differences, so the way in which I express my genes in response to the environment compared to you, may also adjust our susceptibility to diseases [3]. It also means that in addition to our genetic make-up, our epigenetic make-up will have an impact on our health in response to environmental exposures.

This approach is growing momentum due to the increasing evidence of epigenetic changes that occur as a result of environmental factors. Particulate matter and air pollution is believed to adjust the levels of DNA methylation of the iNOS gene, leading to negative health outcomes. Furthermore, environmental stresses during pregnancy can lead to permanent changes in epigenetic modifications, leading to stresses in the newborn child, which has recently been shown by studying women that were pregnant during the 9/11 attacks [4]. This idea of inheriting an experience with an associated health outcome is particularly alarming. In mice exposed to air from a steel manufacturing plant, it has been shown that the DNA in their sperm is hypermethylated and this persists even after removal of the exposure, suggesting that such epigenetic abnormalities can be transmitted transgenerationally [5]. In addition to DNA methylation, aberrant histone modification has also been identified as a result of exposure to metals such as, nickel, chromium, lead and arsenic – the latter is found in abundance in the water table of developing countries, allowing for a chronic exposure. As histone modifications can regulate the levels of gene expression, environmental factors that impinge on this process can be destructive often leading to cancer and neurodegenerative disorders [6].

Although the epigene-environment framework described above has yet to to be formalised, there is growing evidence that epigentics may assist us in predicting the risks and susceptibility of an individual to develop disease.  The challenges now are to determine what the epigenetic alterations are and also to understand the physiological meaning of these events in the context of disease.

 

References:

1. Pruss-Ustun A, Corvalan C., (2006). Preventing disease through healthy environments. Towards an estimate of the environmental burden of disease. Geneva, World Health Organization (WHO).

2. Santoro, M., (2000). Heat shock factors and the control of the stress response. Biochemical Pharmacology, 59(1), pp.55–63.

3. Bollati, V. & Baccarelli, A., (2010). Environmental epigenetics. Heredity, 105(1), pp.105–112.

4. http://news.bbc.co.uk/1/hi/health/4508879.stm

5. Yauk C, Polyzos A, Rowan-Carroll A, Somers CM, Godschalk RW, Van Schooten FJ et al. (2008). Germ-line mutations, DNA damage, and global hypermethylation in mice exposed to particulate air pollution in an urban/industrial location. Proc Natl Acad Sci USA 105: 605–610.

6. Fragou, D. et al., 2011. Epigenetic mechanisms in metal toxicity. Toxicology Mechanisms and Methods, 21(4), pp.343–352.

*(to know more about polymorphisms please refer to the Call of Duty article)