Review
A new paradigm in toxicology and teratology: Altering gene activity in the absence of DNA sequence variation

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Abstract

‘Epigenetics’ is a heritable phenomenon without change in primary DNA sequence. In recent years, this field has attracted much attention as more epigenetic controls of gene activities are being discovered. Such epigenetic controls ensue from an interplay of DNA methylation, histone modifications, and RNA-mediated pathways from non-coding RNAs, notably silencing RNA (siRNA) and microRNA (miRNA). Although epigenetic regulation is inherent to normal development and differentiation, this can be misdirected leading to a number of diseases including cancer. All the same, many of the processes can be reversed offering a hope for epigenetic therapies such as inhibitors of enzymes controlling epigenetic modifications, specifically DNA methyltransferases, histone deacetylases, and RNAi therapeutics. ‘In utero’ or early life exposures to dietary and environmental exposures can have a profound effect on our epigenetic code, the so-called ‘epigenome’, resulting in birth defects and diseases developed later in life. Indeed, examples are accumulating in which environmental exposures can be attributed to epigenetic causes, an encouraging edge towards greater understanding of the contribution of epigenetic influences of environmental exposures. Routine analysis of epigenetic modifications as part of the mechanisms of action of environmental contaminants is in order. There is, however, an explosion of research in the field of epigenetics and to keep abreast of these developments could be a challenge. In this paper, we provide an overview of epigenetic mechanisms focusing on recent reviews and studies to serve as an entry point into the realm of ‘environmental epigenetics’.

Introduction

Regulation of gene expression is a crucial process from early development to adulthood. It is not only important when a gene is turned ‘on’ or ‘off’, but variation in gene expressions can lead to phenotypic diversity. The factors that contribute exactly to the regulation of gene expression are still not fully understood, but emerging knowledge shows that this process is not only governed by the genetic make-up of an individual, but also by epigenetic factors. Indeed, growing evidence points to an additional epigenetic code, notably the ‘epigenome’. Nonetheless, the extent by which epigenetic heterogeneity at the level of cell type, tissue, and organ within an individual as well as among individuals plays a role still needs to be determined [1].

The term ‘epigenetics’, was introduced by the developmental biologist Conrad H. Waddington (1905–1975), in 1942 to describe interactions of genes and their environment [2], [3]. Epigenetics is now used to describe heritable changes in gene expression that are not coded in the DNA sequence, but an interplay of DNA methylation, histone modifications and expression of non-coding RNAs, in the regulation of gene expression patterns. Epigenetic regulation is not only important for generating diversity of cell types during mammalian development, but also in maintaining the stability and integrity of the expression profiles of different cell types. Although epigenetic processes are essential for development and differentiation, they can become misdirected leading to birth malformations and various human diseases, especially cancer. This review aims to provide an overview on epigenetic mechanisms on gene expression, their role in normal development and disease, and relevance of epigenetic phenomena in toxicology and teratology.

Section snippets

Epigenetic mechanisms: it is not all in the DNA

Gene regulation without sequence alterations is brought about by epigenetic mechanisms that involve DNA methylation, histone modifications, and RNA-associated pathways. These three epigenetic regulatory mechanisms are generally associated with the initiation and maintenance of silencing of gene expressions, and interact to each other to effect heritable silencing [4]. An upsurge of research activities is evident and more epigenetic mechanisms are newly discovered. For instance, the phenomena in

Epigenetic events in mammalian development (e.g. X-chromosome inactivation, genomic imprinting)

Epigenetic regulation of gene expression plays an important role in developmental processes such as X-chromosome inactivation and genomic imprinting during mammalian development [5], [58]. X-inactivation is a phenomenon where only one of the two X-chromosomes in female somatic cells is transcriptionally active; i.e. a process that converts an X-chromosome from an active euchromatin into transcriptionally silent and highly condensed heterochromatin through a series of events that include the

Epigenetics in diseases

Epigenetic regulation of gene expression can be misdirected leading to diseases, notably cancer [7], [18], [60], [62], [63]. One misregulation involves imprinted genes. As already discussed above, imprinted genes are a subset of genes that are expressed from only one of the parental alleles. Monoallelic expression ensures that the levels of the proteins encoded by imprinted genes, important factors of embryonic growth, placental growth or adult metabolism, are assured. Loss of imprinting (LOI)

Epigenetic therapies

Epigenetic alterations are, in principle, more readily reversible than genetic events. Thus, there is great potential in the development of ‘epigenetic therapies’, such as inhibitors of enzymes controlling epigenetic modifications, specifically DNA methyltransferases and histone deacetylases, which have shown promising antitumorigenic effects for some malignancies. (For reviews and list of these epigenetic drugs, see Refs. [4], [68]). Many agents have been discovered that alter methylation

The road ahead: future directions and challenges

‘In utero’ or early life exposures to environmental exposures can have a profound effect on the epigenome leading to birth defects and adult diseases. For instance, the teratogenic effects of valproic acid (VPA), a drug used in the treatment of epilepsy and bipolar disorder but causes spina bifida if taken during pregnancy, are likely mediated by the inhibition of histone deacetylases (HDACs) [70]. Indeed, there are already examples in which environmental and dietary exposures can be linked to

Acknowledgement

We acknowledge those results of original research which are here described, but only cited as part of a previous review.

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