Elsevier

Current Opinion in Toxicology

Volume 6, October 2017, Pages 50-59
Current Opinion in Toxicology

Genetic and epigenetic determinants of inter-individual variability in responses to toxicants

https://doi.org/10.1016/j.cotox.2017.08.006Get rights and content

Highlights

  • Genetic variability is a major driver for susceptibility to disease.

  • Recent studies identified epigenetic variability factors linked to genetic variants.

  • Environmental agents may cause toxicity through epigenetic mechanisms.

  • Environmental effects on the epigenome in the context of genetic variability is a budding research area.

  • Studies of Gene × Environment × Epigenome can provide important mechanistic clues in toxicology.

Abstract

It is well established that genetic variability has a major impact on susceptibility to common diseases, responses to drugs and toxicants, and influences disease-related outcomes. The appreciation that epigenetic marks also vary across the population is growing with more data becoming available from studies in humans and model organisms. In addition, the links between genetic variability, toxicity outcomes and epigenetics are being actively explored. Recent studies demonstrate that gene-by-environment interactions involve both chromatin states and transcriptional regulation, and that epigenetics provides important mechanistic clues to connect expression-related quantitative trait loci (QTL) and disease outcomes. However, studies of Gene × Environment × Epigenetics further extend the complexity of the experimental designs and create a challenge for selecting the most informative epigenetic readouts that can be feasibly performed to interrogate multiple individuals, exposures, tissue types and toxicity phenotypes. We propose that among the many possible epigenetic experimental methodologies, assessment of chromatin accessibility coupled with total RNA levels provides a cost-effective and comprehensive option to sufficiently characterize the complexity of epigenetic and regulatory activity in the context of understanding the inter-individual variability in responses to toxicants.

Section snippets

Genetic variability

Estimation of the degree of inter-individual variability in the population is a required step in assessing the human health hazard posed by environmental chemicals. Indeed, the National Academies report Science and Decisions [1] called for the need to better “account for differences among humans in cancer susceptibility other than from possible early-life susceptibility.” Recent advances in the ability to conduct genome-wide association studies (GWAS) that identify quantitative trait loci (QTL)

Linkages between genetic, transcriptional, and epigenetic variability

Comprehensive maps of human and mouse regulatory DNA were recently published by the ENCODE (Encyclopedia of DNA Elements) Consortium [30], mouse ENCODE [31], and the Roadmap Epigenomics Project [32]. These studies comprehensively characterized the location and relationships between chromatin accessibility, histone modifications, chromatin looping, transcription, DNA methylation and the occupancy of sequence-specific factors. The wide spectrum of different cultured cell lines and tissues that

Environmental agents cause toxicity through epigenetic mechanisms

Epigenetic reprogramming has been proposed as an integral part of the “genome instability” enabling characteristic of cancer cells [46] and it is well established that chemical carcinogens may affect the cellular epigenetic state [47]. Changes in DNA methylation, histone/chromatin remodeling, and altered expression of miRNAs represent the most frequently reported toxicant-induced alterations of the epigenome [48]. Because of the potential impact of these epigenotoxic effects on gene expression

Environmental effects on the epigenome in the context of genetic variability

There is now overwhelming evidence that connects genetic variability and epigenetic marks and that chemical exposures can exert toxicity through epigenetic mechanisms; yet less is known about how the effects on the epigenome may vary in the population. Intriguing novel insights into linkages between genotoxic and epigenetic mechanisms of carcinogenesis, and the role of genetic variability among individuals have been provided by studies of a classical genotoxic carcinogen 1,3-butadiene. It is a

Opinion: Studies of Gene × Environment × Epigenome in genetically diverse populations can provide a mechanistic explanation for expression and QTL effects

Studies of Gene × Environment × Epigenome seek to uncover not only relationships between environment exposures and gene expression levels, but also to determine the epigenetic gene regulatory mechanisms altered by these exposures that contribute to the observed expression changes (Fig. 1). These studies further extend the complexity of the experimental designs and require choosing the most informative epigenetic readouts to interrogate multiple individuals, exposures, tissue types and toxicity

Author declaration

We wish to confirm that there are no known conflicts of interest associated with this publication and there has been no significant financial support for this work that could have influenced its outcome.

We confirm that the manuscript has been read and approved by all named authors and that there are no other persons who satisfied the criteria for authorship but are not listed. We further confirm that the order of authors listed in the manuscript has been approved by all of us.

We confirm that we

Conflict of interest

The authors declare no conflict of interest.

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