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Issue 2, 2016
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Epigenetic toxicity of trichloroethylene: a single-molecule perspective

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Abstract

The volatile, water soluble trichloroethylene (TCE) is a hazardous industrial waste and could lead to various health problems, including cancer, neuropathy, cardiovascular defects, and immune diseases. Toxicological studies using in vitro and in vivo models have been conducted to understand the biological impacts of TCE at the genetic, transcriptomic, metabolomic, and signaling levels. The epigenetic aberrations induced by TCE have also been reported in a number of model organisms, while a detailed mechanistic elucidation is lacking. In this study we uncover an unreported mechanism accounting for the epigenetic toxicity due to TCE exposure by monitoring the single-molecule dynamics of DNA methyltransferase 3a (Dnmt3a) in living cells. TCE-induced global DNA hypomethylation could be partly attributed to the disrupted Dnmt3a–DNA association. By analyzing the components of detached Dnmt3a, we found that the Dnmt3a oligomers (e.g., dimer, trimer, and high-order oligomers) dissociated from heterochromatin in a dose-dependent manner upon exposure. Thereafter the diminished DNA-binding affinity of Dnmt3a resulted in a significant decrease in 5-methylcytosine (5mC) under both acute high-dosage and chronic low-dosage TCE exposure. The resulting DNA demethylation might also be contributed by the elevated expression of ten-eleven-translocation (Tet) enzymes and a reformed cysteine cycle. Besides the global effect, we further identified that a group of heterochromatin-located, cancer-related microRNAs (miRNAs) experienced promoter demethylation upon TCE exposure.

Graphical abstract: Epigenetic toxicity of trichloroethylene: a single-molecule perspective

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Publication details

The article was received on 30 Nov 2015, accepted on 25 Jan 2016, published on 27 Jan 2016 and first published online on 27 Jan 2016


Article type: Paper
DOI: 10.1039/C5TX00454C
Citation: Toxicol. Res., 2016,5, 641-650
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    Epigenetic toxicity of trichloroethylene: a single-molecule perspective

    Y. Cui, S. R. Choudhury and J. Irudayaraj, Toxicol. Res., 2016, 5, 641
    DOI: 10.1039/C5TX00454C

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