Epigenetic screening in product safety assessment: are we there yet?

Abstract

There has been a growing concern that epigenetic events, that is, heritable changes in gene expression superimposed on DNA nucleotide sequences, may be involved in chemically and/or nutritionally mediated adverse health outcomes, such as reproductive toxicity and cancer. This concern has been driven by an increasing number of studies reporting toxicant-induced alterations to the epigenome in the form of changes in DNA methylation, histone/chromatin remodeling, and altered expression of non-coding RNAs. These three major mechanisms of epigenetic modifications may have coordinated, independent, or potentially antagonistic influences on gene expression. Complicating this understanding is the incomplete understanding of the normal state and dynamic variation of the epigenome, which differs widely between cells, tissues, developmental state, age, strain, and species. This review serves as a framework to outline characteristics composing an ideal epigenetic screen(s) for hazard identification in product safety assessment. In order to implement such a screen, first there needs to be a better understanding of adaptive versus adverse changes in the epigenome, which includes identification of robust and reproducible causal links between epigenetic changes and adverse apical end points, and second development of improved reporter assay tools to monitor such changes. An ideal screen would be in vitro-based, medium- to high-throughput, and assess all three branches of epigenome control (i.e. methylation, histone modifications, non-coding RNAs), although also being quantitative, objective, portable (i.e. lab to lab), and relevant to humans.

Keywords::

• Epigenetics
• risk assessment
• chemical safety
• regulatory testing

Acknowledgement

The authors thank Joyce Wachner for agouti colony maintenance, Sonya Lidke and Rachel Golden for assistance in preparing figures, and Dr. Darrell Boverhof for editing and technical review of the manuscript.

Declaration of interest

The authors report no conflicts of interest. The authors are responsible for the content and writing of the article

Notes

¹The term “apical end point” literally means at or toward the tip, that is, farthest away from the base/body. In the spirit of the term, an apical end point in toxicology means a measurable end point, that is, an end point farthest away from the exposure. Apical end points are the traditional toxicological end points, such as behavioral changes, reproductive and developmental abnormalities, histopathological changes, death, and so on. Knowledge of the apical end points does not guarantee an understanding of the underlying mechanisms of toxicity or toxicity pathways.

²Metastable epialleles show variable expression between cells and between individuals in spite of the absence of genetic heterogeneity. Such variable expression is driven by their differential epigenetic states such as methylated versus unmethylated states. The term “metastable” refers to the labile nature of the epigenetic state, reflected in the variegated expression pattern of the allele; and the term “epiallele” refers to the potential of these alleles in maintaining their differential epigenetic states and expression patterns transgenerationally.