Review
Epigenetic transgenerational actions of environmental factors in disease etiology

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The ability of environmental factors to promote a phenotype or disease state not only in the individual exposed but also in subsequent progeny for successive generations is termed transgenerational inheritance. The majority of environmental factors such as nutrition or toxicants such as endocrine disruptors do not promote genetic mutations or alterations in DNA sequence. However, these factors do have the capacity to alter the epigenome. Epimutations in the germline that become permanently programmed can allow transmission of epigenetic transgenerational phenotypes. This review provides an overview of the epigenetics and biology of how environmental factors can promote transgenerational phenotypes and disease.

Section snippets

Environmental factors and disease

Epidemiology research suggests significant environmental effects on disease. Each geographic region around the world generally has a distinct disease frequency. For example, some regions have high rates of prostate disease and low rates of stomach disease (North America), whereas others have low rates of prostate disease and high rates of stomach disease (eastern Asia) 3, 4. If a person is moved early in life from one region to the other, they often develop the new region's disease frequencies.

Epigenetics

Although the history and definition of epigenetics has evolved (Box 1), the majority of the molecular elements of epigenetic regulatory processes have only been recently elucidated [1]. The first epigenetic molecular factor identified was DNA methylation in the 1970s [22] (Table 2). Significant focus was put on DNA methylation with the analysis of X chromosome inactivation and imprinted genes in the late 1980s and early 1990s [23]. The next epigenetic element identified was histone

Epigenetics and environmental factors

Initial observations of how the environment can influence epigenetics and phenotype were shown in plants [44]. In animals, many examples associate environmental influences to epigenetic changes. Epigenetic influences have been observed with environmental compounds, nutritional factors 45, 46 such as methyl donors (e.g. folate) 47, 48, inorganic contaminants such as arsenic 20, 21, airborne polycyclic aromatic hydrocarbons [49], drugs such as cocaine [50], endocrine disruptors such as BPA 14, 51

Epigenetic transgenerational phenomena

Because the germline is required for transmitting genetic information between generations, a permanent epigenetic modification in it can result in transgenerational phenomena (Box 2). Epigenetic programming of the germline occurs during the migration of the primordial germ cells in the embryo. The migrating primordial germ cells in the genital ridge undergo an erasure of methylation of the DNA during migration and colonize the early bipotential gonad before gonadal sex determination 77, 78.

Concluding remarks

Epigenetic transgenerational phenomena generally require the involvement of the germline to allow the transmission of an epigenetic abnormality down several generations. The ability of environmental factors or toxicants to alter the epigenome will be common in somatic tissues, but is less common for the germline because of the limited developmental period it is sensitive to reprogramming. In the event of an altered germline epigenome becoming permanently programmed, an epigenetic

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