Carcinogenic metals and the epigenome: understanding the effect of nickel, arsenic, and chromium

Carcinogenic metals, such as nickel, arsenic, and chromium, are widespread environmental and occupational pollutants. Chronic exposure to these metals has been connected with increased risks of numerous cancers and as well as non-carcinogenic health outcomes, including cardiovascular disease, neurologic deficits, neuro-developmental deficits in childhood, and hypertension. However, currently the specific molecular targets for metal toxicity and carcinogenicity are not fully understood. Here, we propose that the iron- and 2-oxoglutarate-dependent dioxygenase family enzymes, as well as, other histone modifying enzymes are important intracellular targets that mediate the toxicity and carcinogenicity of nickel, and maybe potential targets in chromium and arsenic induced carcinogenesis. Our data demonstrate that all three metals are capable of inducing post-translational histone modifications and affecting the enzymes that modulate them (i.e. the iron- and 2-oxoglutarate-dependent dioxygenase family, including HIF-prolyl hydroxylase PHD2, histone demethylase JHDM2A/JMJD1A, and DNA repair enzymes ABH3 and ABH2, and histone methyltransferases, G9a). Given the effects that these metals can exert on the epigenome, future studies of their involvement in histone modifying enzymes dynamics would deepen our understanding on their respective toxicities and carcinogenicities.     

Exposure to nickel, chromium, or cadmium causes distinct changes in the gene expression patterns of a rat liver derived cell line

Many heavy metals, including nickel (Ni), cadmium (Cd), and chromium (Cr) are toxic industrial chemicals with an exposure risk in both occupational and environmental settings that may cause harmful outcomes. While these substances are known to produce adverse health effects leading to disease or health problems, the detailed mechanisms remain unclear. To elucidate the processes involved in the toxicity of nickel, cadmium, and chromium at the molecular level and to perform a comparative analysis, H4-II-E-C3 rat liver-derived cell lines were treated with soluble salts of each metal using concentrations derived from viability assays, and gene expression patterns were determined with DNA microarrays. We identified both common and unique biological responses to exposure to the three metals. Nickel, cadmium, chromium all induced oxidative stress with both similar and unique genes and pathways responding to this stress. Although all three metals are known to be genotoxic, evidence for DNA damage in our study only exists in response to chromium. Nickel induced a hypoxic response as well as inducing genes involved in chromatin structure, perhaps by replacing iron in key proteins. Cadmium distinctly perturbed genes related to endoplasmic reticulum stress and invoked the unfolded protein response leading to apoptosis. With these studies, we have completed the first gene expression comparative analysis of nickel, cadmium, and chromium in H4-II-E-C3 cells.     

Oxidative stress and apoptosis in metal ion-induced carcinogenesis

Epidemiological evidence suggests that exposure to certain metals causes carcinogenesis. The mechanisms of metal-induced carcinogenesis have been pursued in chemical, biochemical, cellular, and animal models. Significant evidence has accumulated that oxidative stress may be a common pathway in cellular responses to exposure to different metals. For example, in the last few years evidence in support of a correlation between the generation of reactive oxygen species, DNA damage, tumor promotion, and arsenic exposure has strengthened. This article summarizes the current literature on metal-mediated oxidative stress, apoptosis, and their relation to metal-mediated carcinogenesis, concentrating on arsenic and chromium.     

The effect of exposure to carcinogenic metals on histone tail modifications and gene expression in human subjects

The precise mechanisms by which nickel and arsenic compounds exert their carcinogenic properties are not completely understood. In recent years, alterations of epigenetic mechanisms have been implicated in the carcinogenesis of compounds of these two metals. In vitro exposure to certain nickel or arsenic compounds induces changes in both DNA methylation patterns, as well as, in the levels of posttranslational modifications of histone tails. Changes in DNA methylation patterns have been reported in human subjects exposed to arsenic. Here we review our recent reports on the alterations in global levels of posttranslational histone modifications in peripheral blood mononuclear cells (PBMCs) of subjects with occupational exposure to nickel and subjects exposed to arsenic in their drinking water. Occupational exposure to nickel was associated with an increase in H3K4me3 and decrease in H3K9me2. A global increase in H3K9me2 and decrease in H3K9ac was found in subjects exposed to arsenic. Additionally, exposure to arsenic resulted in opposite changes in a number of histone modifications in males when compared with females in the arsenic population. The results of these two studies suggest that exposure to nickel or arsenic compounds, and possibly other carcinogenic metal compounds, can induce changes in global levels of posttranslational histone modifications in peripheral blood mononuclear cells.     

The role of metals in site-specific DNA damage with reference to carcinogenesis

We reviewed the mechanism of oxidative DNA damage with reference to metal carcinogenesis and metal-mediated chemical carcinogenesis. On the basis of the finding that chromium (VI) induced oxidative DNA damage in the presence of hydrogen peroxide (H2O2), we proposed the hypothesis that endogenous reactive oxygen species play a role in metal carcinogenesis. Since then, we have reported that various metal compounds, such as cobalt, nickel, and ferric nitrilotriacetate, directly cause site-specific DNA damage in the presence of H2O2. We also found that carcinogenic metals could cause DNA damage through indirect mechanisms. Certain nickel compounds induced oxidative DNA damage in rat lungs through inflammation. Endogenous metals, copper and iron, catalyzed ROS generation from various organic carcinogens, resulting in oxidative DNA damage. Polynuclear compounds, such as 4-aminobiphenyl and heterocyclic amines, appear to induce cancer mainly through DNA adduct formation, although their N-hydroxy and nitroso metabolites can also cause oxidative DNA damage. On the other hand, mononuclear compounds, such as benzene metabolites, caffeic acid, and o-toluidine, should express their carcionogenicity through oxidative DNA damage. Metabolites of certain carcinogens efficiently caused oxidative DNA damage by forming NADH-dependent redox cycles. These findings suggest that metal-mediated oxidative DNA damage plays important roles in chemical carcinogenesis.     

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

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 2756 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.     

Determination of Heavy Metals in Fish and Vegetables in Bangladesh and Health Implications

Concentrations of six heavy metals (chromium, nickel, copper, arsenic, cadmium, and lead) in fish and vegetables were estimated to evaluate contamination levels and health risks for Bangladeshi adults. The analyzed metals varied between different species of fish and vegetables. Metals like Ni, Cd, and Pb in fish species were higher than the respective maximum allowable concentrations (MAC), whereas As, Cd, and Pb in some species of vegetables exceeded the MAC. Health risks associated with these metal intakes were evaluated in terms of dietary intake and target hazard quotients (THQs). The THQ values for individual metals were below 1 (except As for some species), suggesting that people would not experience significant health hazards if they ingest a single metal from one species of fish and/or vegetable. However, total metal THQ (TTHQ) signifies the potential non-carcinogenic health hazard to the highly exposed consumers in Bangladesh. Also, the estimation showed that the carcinogenic risk (TR) of arsenic and lead were within the acceptable range for fish but exceeded the accepted risk level for vegetables. From the health point of view, this study showed that the inhabitants who consume contaminated fish and vegetables are exposed chronically to metal pollution with carcinogenic and non-carcinogenic consequences.     

Molecular mechanisms of arsenic carcinogenesis

Arsenic is a metalloid compound that is widely distributed in the environment. Human exposure of this compound has been associated with increased cancer incidence. Although the exact mechanisms remain to be investigated, numerous carcinogenic pathways have been proposed. Potential carcinogenic actions for arsenic include oxidative stress, genotoxic damage, DNA repair inhibition, epigenetic events, and activation of certain signal transduction pathways leading to abberrant gene expression. In this article, we summarize current knowledge on the molecular mechanisms of arsenic carcinogenesis with an emphasis on ROS and signal transduction pathways.     

Cell apoptosis induced by carcinogenic metals

Well-documented evidence suggests that environmental and occupational exposure of toxic metals or metal-containing compounds can cause a number of human diseases, including inflammation and cancer, through DNA damage, protein modifications, or lipid peroxidation. This mini-review addresses the mechanisms of cell death induced by some carcinogenic metals, including arsenic (III), chromium (VI) and vanadium (V). A possible contribution of reactive oxygen species to metal-induced cell death is also discussed.     

The cellular redox state as a modulator in cadmium and copper responses in Arabidopsis thaliana seedlings

The cellular redox state is an important determinant of metal phytotoxicity. In this study we investigated the influence of cadmium (Cd) and copper (Cu) stress on the cellular redox balance in relation to oxidative signalling and damage in Arabidopsis thaliana. Both metals were easily taken up by the roots, but the translocation to the aboveground parts was restricted to Cd stress. In the roots, Cu directly induced an oxidative burst, whereas enzymatic ROS (reactive oxygen species) production via NADPH oxidases seems important in oxidative stress caused by Cd. Furthermore, in the roots, the glutathione metabolism plays a crucial role in controlling the gene regulation of the antioxidative defence mechanism under Cd stress. Metal-specific alterations were also noticed with regard to the microRNA regulation of CuZnSOD gene expression in both roots and leaves. The appearance of lipid peroxidation is dual: it can be an indication of oxidative damage as well as an indication of oxidative signalling as lipoxygenases are induced after metal exposure and are initial enzymes in oxylipin biosynthesis.In conclusion, the metal-induced cellular redox imbalance is strongly dependent on the chemical properties of the metal and the plant organ considered. The stress intensity determines its involvement in downstream responses in relation to oxidative damage or signalling.