Epigenetics and the Heritability of Toxicity

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Histone Modification

DNA is rarely in the double helix form that has become popular today. Usually, the DNA is tightly packed as chromatin and wrapped around eight globular proteins called histones. There are two of each of H2A, H2B, H3, and H4 Histones in which DNA is wrapped around. This forms the nucleosome. From this, N-terminal tails of these core histones stick out and interact with negatively charged DNA phosphate groups which ultimately results in compaction of chromatin (Stefanska). H3 and H4 histones, with their tails, can be acetylated, methylated, ubiquinated, phosphorylated, and can undergo many other transformations that ultimately effect gene expression (Baccarelli, 2009). These modifications have also been termed the “histone code” since they play a role in encoding information that determines how genes will come to be expressed. The two main processes associated with histone modifications are methylation of histones and acetylation of histones. Methylation is simply adding methyl groups to the histone tails which either bring about repression of transcription activation. For example, adding three methyl groups to Lysine 4 in the tail of H3 is often found in transcriptionally active promoters (Pierce, 2012). Like methylation, histone acetylation involves adding acetyl groups to histone proteins which ultimately initiates transcription. These acetyl groups destabilize the structure of the chromatin which lets transcription act. Acetyl groups are added via enzymes referred to as acetyltransferases and are removed by deacetylases which restrict transcription. Histone acetylase (also known as HAT) adds acetyl groups to the histones which causes loosening of DNA, which is associated with activated genes. Histone deacetylase (also known as HDAC) takes away an acetyl group which allows methylation to occur, which is associated with gene silencing (Pierce,2012). When a toxic agent affects the modifications of histones, these changes may indirectly affect DNA methylation and thus they genes and phenotypes expressed. Studies have shown that nickel reduces histone acetylation in yeas and mammalian cells (Baccarelli, 2009).

miRNA

The relationship between small noncoding RNAs and epigenetic processes result in the regulation of genetic information and, as a result, could play a large role in the cellular response to toxic agents. Due to this, exposure to toxicants that affect epigenetic mechanisms can lead to transcriptional and translational issues. Small noncoding RNAs play a crucial role in the regulation of gene expression through the use of epigenetics. Examples of how ncRNAs play a role include X-chromosome inactivation, heterocrhomatin formation, genomic imprinting, and gene silencing (Smirnova, 2012). Studies over the past few years have shown that miRNAs (micro RNAs, a noncoding RNA) might regulate over thirty percent of the protein-coding gene’s expression in humans. The miRNAs are a part of many regulatory processes such as cell proliferation, apoptosis, differentiation, and environmental stressor responses (Smirnova, 2012). miRNAs also have demonstrated that they play a large role in many disease processes including tumorigenesis. Small ncRNAs can be associated with inheritance of epigenetic information through paramutations. Paramutations are interactions between two alleles at a single location where one of the alleles causes an inheritable alteration of the other. This in itself can shed light on transgenerational toxicology. Tissue-specific expression patterns of miRNAs indicate that the miRNA expression could possibly be altered in response to xenobiotics which can open many doors in toxicological research as toxicological biomarkers (Smirnova, 2012).

Epigenetics and Toxicity

Epigenetics has shown there is much more that can be damaged than DNA sequences. Environmental influences can greatly affect the epigenome in detrimental ways and current studies are beginning to shed light on this. For example, methylmercury is a known neurotoxic chemical that is found in high levels in seafood. Exposure during developmental stages have been shown to suppress Brain Derived Neurtrophic Factor (BDNF) gene expression which predisposed the mice to depression (Baccarelli, 2009). Evidence also suggests that xenobiotic exposure during crucial developmental stages could promote lasting heritable changes to epigenetic mechanisms. Nickel, another example, also has well known carcinogenic effects and exposure to the element interacts with DNA methylation and also histone modification. Lung cell exposure resulted in a reduction in acetylation of all the histones (Smirnova, 2012). DNA methylation has also been found to be affected by arsenic exposure and leads to hypomethylation. The arsenic interferes with a compound known as SAM that cells use as methyl donators in methylation reactions and processes. Arsenic also plays a role in histone modification by inhibiting HDACs thus causing the histones to be acetylated (Smirnova, 2012).

Heritability of Toxicity

The changes made to the epigenome through these various mechanisms have always thought to be taking place in somatic cells (not gametes) and thus could not be passed on to offspring, or non-heritable. Recent studies have begun to show that environmental agents could produce heritable epigenetic transformations that get passed down the lineage (Stern). The reproduction process is complicated and complex with many steps along the way. Toxins have been investigated in their impact on reproductive systems but not until recent has there been an emphasis on reproductive toxicity (Ewing, 1987). Epigenetic modifications have been thought to get deleted during the formation of gametes however, a 2005 report suggested that these epigenetic changes could potentially get passed down to at least four generations (Weinhold, 2006). Michael Skinner, a molecular biologist at Washington State University, and his colleagues exposed pregnant rats to high amounts of methoxychlor and vinclozolin. They found lowered sperm production and higher rates of male fertility in the male offspring. There was evidence of altered DNA methylation in two genes of the rat pups. As the experiment went on, ninety percent of males in up to 4 generations all experienced this altered DNA methylation even without exposure to the chemicals (Weinhold, 2006). These results are startling because they propose that, during a specific developmental state, exposing germ cells to environmental factors could lead to epigenetic changes that can be passed along (Hou, 2012). Another study out of Wayne State University found that mothers that had high levels of lead in their blood affect not only their children, but

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