Hypothesis: a unifying mechanism for nutrition and chemicals as lifelong modulators of DNA hypomethylation

Duk-Hee Lee, David R Jacobs Jr, Miquel Porta, Duk-Hee Lee, David R Jacobs Jr, Miquel Porta

Abstract

Background: Although both nutrition and chemicals are important environmental factors modulating epigenetic changes, they are commonly studied separately by researchers in different fields. However, these two environmental factors cannot be separated from each other in the real world because a number of chemical agents contaminate food chains.

Objective: We propose a unifying mechanism that can link epigenetic alterations in relation to DNA hypomethylation due to chemical agents and to nutrient deficiency or imbalance, emphasizing the importance of an integrative approach in the field of environmental epidemiology.

Discussion: Methyl groups from S-adenosylmethionine (SAM) are needed for DNA methylation. Diets low in sources of methyl groups can lead to global DNA hypomethylation by impairing synthesis of SAM. However, even without nutritional deficiency, enhanced need to synthesize glutathi-one (GSH) can impair synthesis of SAM and perturb DNA methylation, because the methylation cycle and the GSH synthesis pathways are biochemically linked. Exposure to environmental chemicals is a common situation in which the need for GSH synthesis is enhanced, because GSH is consumed to conjugate diverse chemicals. Given that GSH conjugation happens at any chemical dose, this hypothesis is relevant even at exposures below the high doses that cause toxicologic responses.

Conclusion: At present, general populations are exposed to a large number of chemicals, each at a very low dose. Thus, DNA hypomethylation due to chemical exposure may be common in modern societies and can synergistically interact with nutrition-induced DNA hypomethylation.

Keywords: DNA hypomethylation; chemicals; epigenetics; glutathione; nutrient; persistent organic pollutants.

Figures

Figure 1
Figure 1
A hypothetical unifying mechanism linking DNA hypomethylation due to chemicals and nutrient deficiency or imbalance. Vit, vitamin. DNA methylation pattern can be disturbed because of depletion of GSH when it is chronically consumed for conjugation of chemicals and their metabolites. Under usual circumstances, metabolism of homocysteine contributes to both the methionine and GSH synthesis pathways. In the presence of chemicals such as persistent organic pollutants that deplete GSH, contribution to the methionine pathway may be diminished because of greater need to synthesize GSH (numbered boxes on the right).

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