Epigenetic Alterations due to Trichloroethylene

Abstract

Trichloroethylene (TCE) is a volatile, water soluble, chlorinated hydrocarbon used as an intermediate in chemical synthesis. Wider use in the past and inappropriate disposal has resulted in large amounts of TCE in soil and water pollution including in hundreds of Superfund hazardous waste sites. Most TCE in human exposure comes through inhalation and drinking water where the main sources are occupational as well as contaminated ground water and soil. As heritable modifications of DNA and chromatin, epigenetic changes can occur near the time of toxic exposure and remain for years, eventually contributing to overt disease such as cancer or autoimmunity. TCE could affect epigenetics through effects on metabolism, mitochondrial function, cellular signaling and formation of protein adducts. In this chapter, we mainly consider the epigenetic modifications of DNA and histone methylation and histone acetylation. TCE can be toxic to many different organ systems in humans and animal models. Epigenetic effects have been demonstrated in animal models of TCE induced cancer, autoimmunity, neuropathy and congenital heart defects. TCE causes DNA hypomethylation in rodent models of liver cancer and interventions that restore methylation can also prevent the cancer. We showed that TCE exposure in a mouse model of autoimmune hepatitis causes increased expression of endogenous retrovirus-like sequences, changed expression of DNA methyltransferases and global DNA hypomethylation in CD4+ cells. Findings in this mouse model are discussed in light of the long-established activation of endogenous retrovirus expression in autoimmune diseases. We also studied the effects of TCE on behavior, gene expression, metabolism and epigenetics in the plasma and brains of mice. TCE caused a more oxidized cellular environment, compromised methyl metabolism and lower DNA methylation. Parallel analyses in multiple tissues and the development of biomarkers of TCE exposure are just some of the approaches that will help us understand the long-term health risks of TCE. This should also assist the development of effective interventions to reverse the epigenetic effects of TCE exposure with the goal of preventing diseases such as cancer and autoimmunity.