title: 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.
authors.affiliation: Toxicology & Environmental Research and Consulting (TERC), The Dow Chemical Company, Midland, MI 48674, USA. RRasoulpour@Dow.com
authors.forename: Reza J
authors.initials: RJ
authors.lastname: Rasoulpour
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: LeBaron
authors.forename: Robert G
authors.initials: RG
authors.lastname: Ellis-Hutchings
authors.forename: Joanna
authors.initials: J
authors.lastname: Klapacz
authors.forename: B Bhaskar
authors.initials: BB
authors.lastname: Gollapudi
mesh_terms: D000826:Animal Testing Alternatives; D000818:Animals; D019175:DNA Methylation / Q000187:drug effects / Q000235:genetics; D064420:Drug-Related Side Effects and Adverse Reactions / Q000139:chemically induced* / Q000235:genetics; D052244:Endocrine Disruptors / Q000633:toxicity; D044127:Epigenesis, Genetic / Q000187:drug effects*; D005819:Genetic Markers; D018392:Genomic Imprinting / Q000187:drug effects / Q000235:genetics; D006657:Histones / Q000235:genetics; D006801:Humans; D018570:Risk Assessment; D018675:Toxicity Tests; D014116:Toxicology / Q000379:methods*
chemical_list: D052244:Endocrine Disruptors; D005819:Genetic Markers; D006657:Histones