Hypothesis: environmental regulation of 5-hydroxymethylcytosine 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-methylcytosine (5-mC) to 5-hydroxymethylcytosine (5-hmC) in the DNA, is activated under high oxygen conditions by alpha ketoglutarate (α-KG), a cofactor produced by aerobic metabolism in the citric acid cycle. TET, Jumonji-family histone demethylases, and prolyl hydroxylase, a repressor of HIF1α under high oxygen conditions, all require alpha ketoglutarate (α-KG) as cofactors for their activation. The impact of the HIF1α and TET proteins, which appear to have opposing functions, reaches several aspects of human life-including cell growth regulation, embryonic stem cell maintenance, cell differentiation, and tumorigenesis. The role of metabolism on regulating global DNA methylation and chromatin organization is recently demanding 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.