Epigenetics and the Heritability of Toxicity

Epigenetics and the Heritability of Toxicity

Lucas Perrella

ENST 434 – Dr. Yonkos

November 13, 2015

Throughout life, humans and animals are exposed to many environmental factors and substances through the food they eat, the air they breathe as well as through their lifestyles such as tobacco smoke, the use of cosmetics, the use of drugs, and the list goes on. The list of potential exposures is vast and even if the doses are in small traces, the constant exposure can have detrimental effects on health. The effects of environmental impacts on the genetic code have been well documented but recent studies have suggested that these influences from the environment may cause damage on not only genetic information but also on epigenetic mechanisms. Epigenetic mechanisms include DNA methylation, Histone modifications, and miRNA activity. These mechanisms do not change the DNA sequence, they alter the way genes are expressed, silenced, and replicated. These findings that these exposures could cause indirect DNA alterations signified a major step forward in risk assessment and prevention. Many toxic agents have been inspected over the past few years to discover their roles in epigenetics which gave a new area of insight in toxicology. To discover that certain substances can alter the way our genes are expressed and replicated is a huge deal. Some toxic agents that have shown to, or are suspected to cause changes in epigenetic mechanisms include polycyclic aromatic hydrocarbons, microorganisms such as bacteria and viruses, radioactivity, tobacco smoke, and others (Weinhold, 2006). Nowadays, many illnesses can be traced, to varying degree, back to epigenetic alterations. Some of these illnesses include, but are not limited to, neurobehavioral, respiratory, and cardiovascular illnesses as well as almost all types of cancer (Epigenetics: The science of change). Contrasting mutations, epigenetic alterations are usually brought on by environmental influences, are able to be reversed, and they do not make changes to the DNA sequence (Pierce, 2012).

What is Epigenetics?

        According to Dictionary.com, Epigenetics is defined as “the study of the process by which genetic information is translated into the substance and behavior of an organism: specifically, the study of the way in which the expression of heritable traits is modified by environmental influences or other mechanisms without a change to the DNA sequence.” This branch of genetics aims to look at the various markers in which DNA is expressed or repressed without the alteration of the genetic code itself. These epigenetic modifications add another layer of information and understanding to the genome and to what was previously assumed as a static code that is only changed via mutations. Most phenotypic traits are encoded by the DNA sequences found in our nuclei however, alterations in the epigenome can affect how these traits are expressed or silenced. These alterations are often passed from one cell to another in cellular replications and sometimes through multiple generations of offspring (Pierce, 2012). The modifications the epigenome occur in the differentiation of cells so that the different cell types have different genes acting on them and these changes are then inherited by the daughter cells. Most alterations are deleted in germ cells although some changes can persist and be passed on to future generations. These transgenerational epigenetic mechanisms are still not fully understood but more research is being done (Institute of Science in Society). There have been many identified processes of epigenetics including DNA methylation (addition of methyl groups to Cytosine bases that are adjacent to Guanine bases), Histone modifications (methylation, acetylation, and deacetylation), and lastly miRNA activity. The epigenetic processes occur naturally and are important in organismal function (Weinhold, 2006). These mechanisms are essential to complex multicellular organismal function as differing epigenetic patterns will differentiate cell types and make sure that all parts of the genetic code are doing what it needs to do (Smirnova, 2012). If the processes begin to work improperly, detrimental health effects could ensue. Epigenetic processes can be manipulated and altered through external influences and these factors have been linked to various forms of cancers and other diseases. Recent research is showing that changes to the epigenetic mechanisms can be more dangerous than DNA mutations (Institute of Science in Society). This is the case because while DNA mutations are static and only remain in one spot, epigenetic changes can spread and affect other areas and genes. Genetic mutations are also relatively rare while epigenetic alterations are more common and affect a larger proportion of exposed cells. These changes, brought on by inherited and environmentally influenced factors, have been seen to play an early role in cancer development (Institute of Science in Society). Twin studies provide an excellent example of epigenetic variations due to environmental influences. One particular study used forty twin pairings ranging from ages 3 to 74 years old. With the younger twins, there was little variation in their epigenetic makeup. Their methylation and acetylation patterns were very similar and this could be attributed to their time together as well as similar lifestyles. However, with the older twins, they spent more time apart and lived different lifestyles which could be measured in their epigenome. The older twins experienced more variation in their epigenetic methylation and acetylation and this could be attributed to their differing lifestyles and exposure to different environmental influences (Smirnova, 2012).

Epigenetic Mechanisms

DNA Methylation

The most widely studied mechanism of epigenetics is hands down DNA methylation. This could largely be due to the technology that exists and is available to use for research. DNA methylation refers to the addition of methyl groups or their removal. Methylation occurs on Cytosine bases (C bases) in regions known as CpG islands. These CpG islands are large clusters of adjacent C and G (guanine) bases (Baccarelli, 2009). In normal cells, these islands are usually unmethylated and are found in promoter regions of tissue-specific genes and even tumor suppressor genes (Stefanska). When these CpG islands are methylated close to promoters or enhancers, the genes are silenced. Methylation in a recognition factor of transcription can make it so it can’t bind to DNA and thus transcription is silenced (Stefanska).  Hypermethylation of these CpG islands lead to an inhibition of expression by hindering transcription initiation. Hypermethylation was also found to lead to the silenced tumor suppressor genes, leading to cancer. Overall hyopmethylation is associated with reduced stability in the chromosome and has been found to alter genomic function (Baccarelli, 2009). Studies have shown that metals produce, through redox cycling, reactive oxygen species and these can impede on the normal functioning of the methylation mechanism and alter they methylation of the CpG islands (Baccarelli, 2009). These methylation patterns are deleted in the germ cell line in each subsequent generation and are then reformed in the formation of gametes. Sperm and eggs acquire different levels of methylation which will cause the alleles of the male and female to be expressed differentially, a phenomena known as genomic imprinting (Pierce, 2012).