DNA hydroxymethylation: Implications for toxicology and epigenetic epidemiology

5-Hydroxymethylcytosine (5-hmC), much like its relative 5-methylcytosine, plays crucial roles in early development and disease pathogenesis. In certain contexts, 5-hmC appears to be a stable epigenetic mark, rather than serving simply as a transient marker of demethylation. As our understanding of the multifaceted role of 5-hmC in the genome expands, so has the interest in the occurrence of changes in 5-hmC upon exposure to environmental toxicants and in disease states. In this review, we introduce the chemistry of DNA hydroxymethylation, the role of ten-eleven translocation (TET)-mediated DNA hydroxymethylation in gene regulation, the techniques for 5-hmC measurement, and the interaction between environmental exposures and the changes in 5-hmC in both in vitro and in vivo models. We also discuss the current challenges in understanding the responses of this unique “signature” of the epigenome to environmental stressors.