Epigenetics in toxicology and drug development

Abstract

Abstract Epigenetic features are influenced by exogenous stimuli and constitute a link between physiological changes and genome modulation in a cell-specific manner. Because disruptions of epigenetic features are implicated in various complex traits, epigenetic mechanisms need to be integrated into toxicology, at least for two reasons. (1) The attraction of epigenetic therapy has created a boost in the development of newer (epigenetic) drugs with DNA and chromatin-modifying capabilities to revert epigenetic imbalances in complex human diseases. (2) Conversely, the exposure of humans to external stimuli, also including therapeutics and environmental factors, can trigger unwanted epigenetic modulation. The role of epigenetic changes in the pre-disease state (e.g., pre-diabetes or pre-Alzheimers’) is a valuable area of investigation as healthcare paradigms shift toward disease prevention. This chapter reviews the important role of epigenetics in toxicology, and provides information on several relevant aspects: (1) disease-associated epigenetic aberrations in cellular and molecular depth as potential adverse effects as well as therapeutic targets, (2) critical safety insight on environmental hazards, (3) the current knowledge gaps in the medical field, (4) epigenetic drugs in practice and in development, and (5) viable solutions for the exploration of novel endpoints and the integration of screening tools toward the prediction of adverse epigenetic modulation in human safety assessment.