Epigenetic toxicity of trichloroethylene: A single-molecule perspective

Yi Cui, Samrat Roy Choudhury, Joseph Irudayaraj

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)641-650
Number of pages10
JournalToxicology Research
Volume5
Issue number2
DOIs
StatePublished - Jan 1 2016
Externally publishedYes

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Trichloroethylene
Epigenomics
Toxicity
Molecules
Heterochromatin
DNA
Oligomers
Hazardous Waste
5-Methylcytosine
Industrial Waste
Metabolomics
Immune System Diseases
Medical problems
Aberrations
MicroRNAs
Dimers
Toxicology
Cysteine
Neoplasms
Cardiovascular Diseases

ASJC Scopus subject areas

  • Toxicology
  • Health, Toxicology and Mutagenesis

Cite this

Epigenetic toxicity of trichloroethylene : A single-molecule perspective. / Cui, Yi; Choudhury, Samrat Roy; Irudayaraj, Joseph.

In: Toxicology Research, Vol. 5, No. 2, 01.01.2016, p. 641-650.

Research output: Contribution to journalArticle

Cui, Yi ; Choudhury, Samrat Roy ; Irudayaraj, Joseph. / Epigenetic toxicity of trichloroethylene : A single-molecule perspective. In: Toxicology Research. 2016 ; Vol. 5, No. 2. pp. 641-650.
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