Epigenetics and environmental chemicals

Abstract

Purpose of review: Epigenetics investigates heritable changes in gene expression occurring without changes in DNA sequence. Several epigenetic mechanisms, including DNA methylation, histone modifications, and microRNA expression, can change genome function under exogenous influence. Here, we review current evidence indicating that epigenetic alterations mediate toxicity from environmental chemicals.

Recent findings: In-vitro, animal, and human investigations have identified several classes of environmental chemicals that modify epigenetic marks, including metals (cadmium, arsenic, nickel, chromium, and methylmercury), peroxisome proliferators (trichloroethylene, dichloroacetic acid, and TCA), air pollutants (particulate matter, black carbon, and benzene), and endocrine-disrupting/reproductive toxicants (diethylstilbestrol, bisphenol A, persistent organic pollutants, and dioxin). Most studies conducted so far have been centered on DNA methylation, whereas only a few investigations have studied environmental chemicals in relation to histone modifications and microRNA.

Summary: For several exposures, it has been proved that chemicals can alter epigenetic marks, and that the same or similar epigenetic alterations can be found in patients with the disease of concern or in diseased tissues. Future prospective investigations are needed to determine whether exposed individuals develop epigenetic alterations over time and, in turn, which such alterations increase the risk of disease. Also, further research is needed to determine whether environmental epigenetic changes are transmitted transgenerationally.

Figure 1. Potential mechanisms linking environmental exposures to epigenetic effects

Environmental chemicals may modify multiple biological processes that affect epigenetic mechanisms, including DNA methylation, histone codes, and miRNA expression. These changes may, in turn, modify chromatin organization and condensation, gene expression, and affect disease risk.

Figure 2. Example of possible mechanisms of gene-regulation by histone modifications

Modifications under histone methylases (HMTs), histone acetyltransferases (HATs) and histone deacetylases (HDACs) control alter gene expression. Modifications may generate a structure that contains bromo- and chromo-domains allowing the recruitment of ATP-dependent chromatin remodelling factors to open the chromatin. Effects of histone modifications on gene expression is dependent on the specific position of the chemical modification on the histone subunit.

Figure 3. miRNA Processing and Activity

miRNAs are initially transcribed by RNA Polymerase II and expressed as a part of primary miRNAs (pri-miRNAs). The miRNA portion of the pri-miRNA transcript likely forms a hairpin with signals for dsRNA-specific nuclease cleavage. The dsRNA-specific ribonuclease Drosha digests the pri-miRNA in the nucleus to release hairpin that is called pre-miRNA (approximately 70 nt). Exportin-5 exports pre-miRNAs from the nucleus to the cytoplasm, where Dicer cleaves the pre-miRNA approximately 19 bp from the Drosha cut giving a mature miRNA. Each mature miRNA is complementary to a part of one or more messenger RNAs (mRNAs). The annealing of the miRNA to the mRNA(s) inhibits protein translation.