The need for epigenotoxicity testing

While the genome codes for all proteins an organism can express, only certain sets of proteins are expressed in defined cell types. A cell's phenotype is influenced by the life-stage, exposure to signal molecules, as well as the exposome, i.e., external influences including physical stressors or chemicals from food, the environment or microorganisms. The interplay between genetics and these exposures is termed gene x environment interaction (GxE). Epigenetics contributes to GxE by modifying the accessibility of genes and thus their ability to be translated to proteins. Epigenetic mechanisms include DNA methylation, histone modifications, non-coding RNAs, and changes in local DNA packaging. As genetics and the exposome often jointly contribute to disease, understanding epigenetics may enable a better understanding of many human pathologies. Often, epigenetics will retain the memory of exposure, which changes an organism's susceptibility to subsequent, other exposures. This concept may allow new insights into mixture toxicity, especially when the exposures do not take place at the same time. Knowledge on epigenetic processes provides a basis for novel drugs that modify cell phenotypes (e.g., in cancer or neurodegenerative disease). Here, we provide an overview of the role of epigenetics in toxicology, and we call for a systematic assessment of epigenetic changes as part of investigative, and possibly regulatory, toxicity assessments. We propose tools and strategies for using human-relevant models, biomarkers, and AI to better predict who may be at risk. Ultimately, adding epigenetics to toxicology will help us create safer products and protect vulnerable individuals and future generations.