Hypothesis Environmental regulation of 5-hydroxymethyl-cytosine by oxidative stress

Many environmental toxins, such as heavy metals, air particles and ozone, induce oxidative stress and decrease the levels of NADH and NADPH, cofactors that drive anabolic biochemical reactions and provide reducing capacity to combat oxidative stress. Recently, it was found that the Ten-eleven translocation (TET) protein family members, which oxidize 5-methyl-cytosine (5-mC) to 5-hydroxymethyl-cytosine (5-hmC) in the DNA, were found to be activated under high oxygen conditions by alpha ketoglutarate (alpha-KG), a cofactor produced by aerobic metabolism in the citric acid cycle. TET, Jumonji-family histone demethylases and prolylhydroxylase, a repressor of HIF1 alpha under high oxygen conditions, all require alpha-KG as a cofactor for their activation. HIF1 alpha and TET proteins, which appear to have opposing functions, impact several aspects of human life, including cell growth regulation, embryonic stem cell maintenance, cell differentiation and tumorigenesis. The role of metabolism on the regulation of global DNA methylation and chromatin organization has recently gained greater attention from the biomedical research community. This article will discuss the possible role of TET activation and the regulation of 5-hmC and 5-mC levels in response to environmental stress. We will also discuss how 5-hmC and 5-mC levels at the promoters of specific genes might be a useful biomarker for exposure to environmental toxins.