Effect of Long-Term Low-Dose Arsenic Exposure on DNA Methylation and Gene Expression in Human Liver Cells

Abstract

Millions of people around the world are exposed to elevated levels of arsenic through food or drinking water. Epidemiological studies have linked chronic arsenic exposure to an increased risk of several cancers, cardiovascular disease, central nervous system neuropathies, and genotoxic as well as immunotoxic effects. In addition to the induction of oxidative stress and inhibition of DNA repair processes, epigenetic effects, including altered DNA methylation patterns resulting in aberrant gene expression, may contribute to carcinogenicity. However, the underlying mechanisms by which chronic micromolar concentrations of arsenite affect the methylation status of DNA are not fully understood. In this study, human HepG2 hepatocarcinoma cells were treated with 0.5–10 μM sodium arsenite for 24 h, 10, or 20 days. During these periods, the effects on global DNA methylation, cell cycle phase distribution, and gene expression were investigated. While no impact on DNA methylation was seen after short-term exposure, global hypomethylation was observed at both long-term exposure periods, with concomitant induction of the DNA methyltransferase genes DNMT1 and DNMT3B, while DNMT3A was slightly down-regulated. Pronounced time- and concentration-dependent effects were also seen in the case of genes involved in DNA damage response and repair, inflammation, oxidative stress response, and metal homeostasis. These results suggest that chronic low-dose arsenite exposure can lead to global hypomethylation. As an underlying mechanism, the consistent down-regulation of DNA methyltransferase genes could be excluded; alternatively, interactions at the protein level could play an important role.

Contaminated Drinking Water and Its Effect on Cancer

“…For example, arsenic inhibits the activity of enzymes such as PARP and DNA ligase, which are crucial for DNA repair. 6 • Epigenetic Changes: Contaminants can cause changes in DNA methylation and histone modification, altering gene expression patterns in ways that can promote cancer. Epigenetic modifications induced by contaminants can lead to the activation of oncogenes or the silencing of tumor suppressor genes, thereby contributing to carcinogenesis.…”

“…Chromium(VI) and arsenic have been shown to form DNA adducts and induce DNA strand breaks, leading to genomic instability. , Inhibition of DNA Repair Processes: Some contaminants inhibit the activity of key DNA repair enzymes, preventing the repair of DNA damage and leading to mutation accumulation. For example, arsenic inhibits the activity of enzymes such as PARP and DNA ligase, which are crucial for DNA repair Epigenetic Changes: Contaminants can cause changes in DNA methylation and histone modification, altering gene expression patterns in ways that can promote cancer.…”

“…It inhibits DNA repair by targeting enzymes such as PARP and DNA ligase, leading to mutation accumulation. Additionally, arsenic causes epigenetic modifications, such as DNA methylation and histone changes, which can alter gene expression, activate oncogenes, or silence tumor suppressor genes, contributing to cancer development …”

“…Heavy metals like arsenic are known for their genotoxic effects, inducing DNA damage through oxidative stress, inhibition of DNA repair, and epigenetic changes. 6 Arsenic generates reactive oxygen species (ROS) that damage DNA by causing base modifications, strand breaks, and cross-linking. 7 It inhibits DNA repair by targeting enzymes such as PARP and DNA ligase, leading to mutation accumulation.…”

“…Additionally, arsenic causes epigenetic modifications, such as DNA methylation and histone changes, which can alter gene expression, activate oncogenes, or silence tumor suppressor genes, contributing to cancer development. 6 Chromium. Hexavalent chromium (Cr(VI)) penetrates cells and is reduced to Cr(III), producing intermediates that damage DNA and generate ROS, interfering with DNA repair and leading to mutations.…”