10th NTES Conference: Nickel and arsenic compounds alter the epigenome of peripheral blood mononuclear cells

Abstract

The mechanisms that underlie metal carcinogenesis are the subject of intense investigation ; however, data from in vitro and in vivo studies are starting to piece together a story that implicates epigenetics as a key player. Data from our lab has shown that nickel compounds inhibit dioxygenase enzymes by displacing iron in the active site. Arsenic is hypothesized to inhibit these enzymes by diminishing ascorbate levels- an important co-factor for dioxygenases. Inhibition of histone demethylase dioxygenases can increase histone methylation levels, which also may affect gene expression. Recently, our lab conducted a series of investigations in human subjects exposed to high levels of nickel or arsenic compounds. Global levels of histone modifications in peripheral blood mononuclear cells (PBMCs) from exposed subjects were compared to low environmentally exposed controls. Results showed that nickel increased H3K4me3 and decreased H3K9me2 globally. Arsenic increased H3K9me2 and decreased H3K9ac globally. Other histone modifications affected by arsenic were sex-dependent. Nickel affected the expression of 2,756 genes in human PBMCs and many of the genes were involved in immune and carcinogenic pathways. This review will describe data from our lab that demonstrates for the first time that nickel and arsenic compounds affect global levels of histone modifications and gene expression in exposed human populations.

Regulation of the Epigenome by Vitamin C

“…For example, intracellular ascorbate concentration in hepatocytes is decreased in aged mice due to a lower expression of SVCT1, as compared to young controls (61). Certain environmental exposures such as arsenic compounds also can diminish ascorbate levels and alter the epigenome of peripheral blood mononuclear cells (4). …”

Genetic and epigenetic determinants of inter-individual variability in responses to toxicants

“…Arsenic, a ubiquitous environmental contaminant, disrupts the normal epigenome transforming the epigenetic landscape to reflect that of a cancer cell [55]. Exposure to metals like arsenic causes significant epigenetic modifications such as changes in global histone methylation levels [56]. After exposure to arsenic compounds, human lung carcinoma A549 cells showed an increase in global levels of H3K4me3 and H3K9me2 [57].…”

Oxidative Stress, Epigenetics, and Cancer Stem Cells in Arsenic Carcinogenesis and Prevention

“…Although arsenic has been considered as a poorer mutagen, increasing evidence suggests that arsenic is highly capable of promoting epigenetic alterations, including DNA methylation 9, 10 , histone methylation 11, 12 , histone phosphorylation/acetylation 13, 14 , and microRNA regulation 14, 15 , through some signaling mediators, e.g., ROS 16, 17 , Akt 15, 18, 19 , FilaminA 20 that are required for arsenic induced cell transformation. However, the mechanisms of how arsenic elicits those effects remain elusive.…”