Overview of possible mechanisms of action for environmental chemicals on DNA methylation based on reviews of experimental studies
]. Metals, POPs, and PAH increase reactive oxygen species (ROS) formation. Under chronic consumption of glutathione (GSH) for conjugation with ROS, chemicals, and their metabolites, homocysteine is employed into GSH rather than methionine synthesis pathways, leading to a reduced synthesis of S-adenosylmethionine (SAM, a substrate for DNA methyltransferases (DNMT) which catalyzes the addition of the methyl group onto the 5-carbon cytosine (5C) to become 5-methylcytosine (5mC)). SAM depletion, thus, potentially inhibits DNA methylation and results in subsequent DNA hypomethylation . Exposures to specific environmental chemicals such as short-term cadmium, PAH, lead, and mercury exposures can directly reduce the enzymatic activity and concentrations of DNMT . In addition, oxidative stress is proposed to stimulate the alpha-ketoglutarate (α-KG) production from isocitrate. α-KG activates ten-eleven translocation (TET) proteins that catalyze the oxidation of 5mC to 5-hydroxymethylcytosine (5hmC), 5-formlycytosine (5fC), and 5-carboxycytosine (5caC) in the presence of cofactors, iron and oxygen. 5hmC, 5fC, and 5caC could act as an intermediate in both passive and active DNA demethylation pathways [3,135] involving DNA repair enzymes like AID, APOEC, and TDG. Overall, it facilitates DNA hypomethylation. Conversely, it has been suggested that long-term cadmium exposure induces compensatory DNMT overexpression  that could lead to increased DNA methylation. On the other hand, environmental chemicals can modulate the enzymes involved in covalent modifications (acetylation (Ac), methylation (Me)), phosphorylation (P) and ubiquitination (Ub)) at the histone tails that can interact with the DNA methylation or demethylation machinery. Lead has been related with transcription-active histone modifications (associated to DNA hypomethylation), while methylmercury and nickel have been related with transcription-repressive histone modifications (associated to DNA hypermethylation) [5,136]. Finally, while other environmental toxicants have been related to DNA hypomethylation (BPA, PFCs) and hypermethylation (tungsten, antimony) in epidemiologic studies, their mechanism of action in epigenetic regulation of gene transcription is unknown.