Genetic and epigenetic determinants of 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.
References (100)
- et al.
MicroRNA expression in the livers of inbred mice
Mutat Res
(2011) - et al.
Hepatic epigenetic phenotype predetermines individual susceptibility to hepatic steatosis in mice fed a lipogenic methyl-deficient diet
J Hepatol
(2009) - et al.
Striking immune phenotypes in gene-targeted mice are driven by a copy-number variant originating from a commercially available C57BL/6 strain
Cell Rep
(2016) - et al.
Population variation and genetic control of modular chromatin architecture in humans
Cell
(2015) - et al.
Genetic control of chromatin states in humans involves local and distal chromosomal interactions
Cell
(2015) - et al.
Hallmarks of cancer: the next generation
Cell
(2011) - et al.
Epigenetics and chemical safety assessment
Mutat Res
(2010) - et al.
10th NTES conference: nickel and arsenic compounds alter the epigenome of peripheral blood mononuclear cells
J Trace Elem Med Biol
(2015) - et al.
Effects of nickel, chromate, and arsenite on histone 3 lysine methylation
Toxicol Appl Pharmacol
(2009) - et al.
Interactions between DNA damage, repair, and transcription
Mutat Res
(2012)
Role of epigenetic aberrations in the development and progression of human hepatocellular carcinoma
Cancer Lett
ATM-dependent chromatin changes silence transcription in cis to DNA double-strand breaks
Cell
Epigenetic alterations induced by genotoxic occupational and environmental human chemical carcinogens: a systematic literature review
Mutat Res Rev Mutat Res
Long term low-dose arsenic exposure induces loss of DNA methylation
Biochem Biophys Res Commun
Effects of cadmium on DNA-(Cytosine-5) methyltransferase activity and DNA methylation status during cadmium-induced cellular transformation
Exp Cell Res
High-resolution mapping and characterization of open chromatin across the genome
Cell
The chromatin structure of specific genes: I. Evidence for higher order domains of defined DNA sequence
Cell
DNA sequence bias during Tn5 transposition
J Mol Biol
Science and decisions: advancing risk assessment
Genomewide association studies–illuminating biologic pathways
N Engl J Med
Cancer pharmacogenomics: strategies and challenges
Nat Rev Genet
Towards precision medicine
Nat Rev Genet
Review of the gene-environment interaction literature in cancer: what do we know?
Genet Epidemiol
Toxicogenetics: population-based testing of drug and chemical safety in mouse models
Pharmacogenomics
A sequence-based variation map of 8.27 million SNPs in inbred mouse strains
Nature
Ten years of the collaborative cross
Genetics
Addressing human variability in next-generation human health risk assessments of environmental chemicals
Environ Health Perspect
Characterization of variability in toxicokinetics and toxicodynamics of tetrachloroethylene using the collaborative cross mouse population
Environ Health Perspect
Collaborative cross mouse population enables refinements to characterization of the variability in toxicokinetics of trichloroethylene and provides genetic evidence for the role of PPAR pathway in its oxidative metabolism
Toxicol Sci
Interstrain differences in liver injury and one-carbon metabolism in alcohol-fed mice
Hepatology
Epigenetic mechanisms of mouse interstrain variability in genotoxicity of the environmental toxicant 1,3-butadiene
Toxicol Sci
Interstrain differences in the liver effects of trichloroethylene in a multistrain panel of inbred mice
Toxicol Sci
Sex-specific gene expression in the BXD mouse liver
Physiol Genomics
Replication and narrowing of gene expression quantitative trait loci using inbred mice
Mamm Genome
Mouse population-guided resequencing reveals that variants in CD44 contribute to acetaminophen-induced liver injury in humans
Genome Res
Genome-level analysis of genetic regulation of liver gene expression networks
Hepatology
Physiologically-based pharmacokinetic (PBPK) modeling of inter-strain variability in trichloroethylene metabolism in the mouse
Environ Health Perspect
Genetic analysis of complex traits in the emerging collaborative cross
Genome Res
Using the emerging collaborative cross to probe the immune system
Genes Immun
Diversity outbred mice identify population-based exposure thresholds and genetic factors that influence benzene-induced genotoxicity
Environ Health Perspect
A mouse diversity panel approach reveals the potential for clinical kidney injury due to DB289 not predicted by classical rodent models
Toxicol Sci
Identification of structural variation in mouse genomes
Front Genet
Genomic copy number and expression variation within the C57BL/6J inbred mouse strain
Genome Res
Precision medicine, genomics and drug discovery
Hum Mol Genet
A user's guide to the encyclopedia of DNA elements (ENCODE)
PLoS Biol
A comparative encyclopedia of DNA elements in the mouse genome
Nature
Integrative analysis of 111 reference human epigenomes
Nature
Protein-DNA binding in high-resolution
Crit Rev Biochem Mol Biol
ATAC-seq: a method for assaying chromatin accessibility genome-wide
Curr Protoc Mol Biol
The genotype-tissue expression (GTEx) project
Nat Genet
Cited by (11)
Types of cellular responses to chemical toxicants
2023, Essentials of Pharmatoxicology in Drug Research: Toxicity and Toxicodynamics: Volume 1Using liver models generated from human-induced pluripotent stem cells (iPSCs) for evaluating chemical-induced modifications and disease across liver developmental stages
2022, Toxicology in VitroCitation Excerpt :With continued progress and success, the use of iPSC-derived hepatocytes as a surrogate target cell for general chemical screening would save time and valuable resources by predicting toxicity in the liver and other potential target cells as the toxicology community aims to shift away from in vivo research. Diversity among the human population results in inter-individual toxicity and disease susceptibility associated with chemical exposures (Arzuk et al., 2018; Lewis et al., 2017). The establishment of in vitro methods to evaluate inter-individual variability (i.e., genetic & environmental) of toxicity is thus important to accurately evaluate risk, identify vulnerable populations, and characterize effective therapeutic interventions.
Chromatin accessibility as a strategy to detect changes associated with development, disease, and exposure and susceptibility to chemical toxins
2018, Toxicoepigenetics: Core Principles and ApplicationsChallenges in designing and executing clinical trials in a dish studies
2018, Journal of Pharmacological and Toxicological MethodsCitation Excerpt :Epigenetic regulation of gene expression refers to heritable factors that are functionally relevant genomic modifications, but that do not involve changes in DNA sequence. For many of these, an exposure at any point in a person's life can lead to permanent alterations in a person's DNA, and result in modified drug responses (Egger, Liang, Aparicio, & Jones, 2004; Simmons, 2008; Lewis, Crawford, Furey, & Rusyn, 2017). Because the effects can be cumulative, by definition, the presence of such factors increase throughout a person's lifetime.
Intra- And Inter-Species Variability in Urinary N7-(1-Hydroxy-3-buten-2-yl)guanine Adducts following Inhalation Exposure to 1,3-Butadiene
2021, Chemical Research in Toxicology