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.