Free radicals, metals and antioxidants in oxidative stress-induced cancer

Heavy metals are naturally occurring elements that have a high atomic weight and a density at least five times greater than that of water. Their multiple industrial, domestic, agricultural, medical, and technological applications have led to their wide distribution in the environment, raising concerns over their potential effects on human health and the environment. Their toxicity depends on several factors including the dose, route of exposure, and chemical species, as well as the age, gender, genetics, and nutritional status of exposed individuals. Because of their high degree of toxicity, arsenic, cadmium, chromium, lead, and mercury rank among the priority metals that are of public health significance. These metallic elements are considered systemic toxicants that are known to induce multiple organ damage, even at lower levels of exposure. They are also classified as human carcinogens (known or probable) according to the US Environmental Protection Agency and the International Agency for Research on Cancer. This review provides an analysis of their environmental occurrence, production and use, potential for human exposure, and molecular mechanisms of toxicity, genotoxicity, and carcinogenicity.

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Heavy metal toxicity and the environment.

Heavy metal toxicity has proven to be a major threat and there are several health risks associated with it. The toxic effects of these metals, even though they do not have any biological role, remain present in some or the other form harmful for the human body and its proper functioning. They sometimes act as a pseudo element of the body while at certain times they may even interfere with metabolic processes. Few metals, such as aluminium, can be removed through elimination activities, while some metals get accumulated in the body and food chain, exhibiting a chronic nature. Various public health measures have been undertaken to control, prevent and treat metal toxicity occurring at various levels, such as occupational exposure, accidents and environmental factors. Metal toxicity depends upon the absorbed dose, the route of exposure and duration of exposure, i.e. acute or chronic. This can lead to various disorders and can also result in excessive damage due to oxidative stress induced by free radical formation. This review gives details about some heavy metals and their toxicity mechanisms, along with their health effects.

https://sciendo.com/pdf/10.2478/intox-2014-0009

Toxicity, mechanism and health effects of some heavy metals

Metal contamination issues are becoming increasingly common in India and elsewhere, with many documented cases of metal toxicity in mining industries, foundries, smelters, coal-burning power plants and agriculture. Heavy metals, such as cadmium, copper, lead, chromium and mercury are major environmental pollutants, particularly in areas with high anthropogenic pressure. Heavy metal accumulation in soils is of concern in agricultural production due to the adverse effects on food safety and marketability, crop growth due to phytotoxicity, and environmental health of soil organisms. The influence of plants and their metabolic activities affects the geological and biological redistribution of heavy metals through pollution of the air, water and soil. This article details the range of heavy metals, their occurrence and toxicity for plants. Metal toxicity has high impact and relevance to plants and consequently it affects the ecosystem, where the plants form an integral component. Plants growing in metal-polluted sites exhibit altered metabolism, growth reduction, lower biomass production and metal accumulation. Various physiological and biochemical processes in plants are affected by metals. The contemporary investigations into toxicity and tolerance in metal-stressed plants are prompted by the growing metal pollution in the environment. A few metals, including copper, manganese, cobalt, zinc and chromium are, however, essential to plant metabolism in trace amounts. It is only when metals are present in bioavailable forms and at excessive levels, they have the potential to become toxic to plants. This review focuses mainly on zinc, cadmium, copper, mercury, chromium, lead, arsenic, cobalt, nickel, manganese and iron.

Heavy metals, occurrence and toxicity for plants: a review

Advances in metal-induced oxidative stress and human disease

Chronic exposure to nickel(II), chromium(VI), or inorganic arsenic (iAs) has long been known to increase cancer incidence among affected individuals. Recent epidemiological studies have found that carcinogenic risks associated with chromate and iAs exposures were substantially higher than previously thought, which led to major revisions of the federal standards regulating ambient and drinking water levels. Genotoxic effects of Cr(VI) and iAs are strongly influenced by their intracellular metabolism, which creates several reactive intermediates and byproducts. Toxic metals are capable of potent and surprisingly selective activation of stress-signaling pathways, which are known to contribute to the development of human cancers. Depending on the metal, ascorbate (vitamin C) has been found to act either as a strong enhancer or suppressor of toxic responses in human cells. In addition to genetic damage via both oxidative and nonoxidative (DNA adducts) mechanisms, metals can also cause significant changes in DNA methylation and histone modifications, leading to epigenetic silencing or reactivation of gene expression. In vitro genotoxicity experiments and recent animal carcinogenicity studies provided strong support for the idea that metals can act as cocarcinogens in combination with nonmetal carcinogens. Cocarcinogenic and comutagenic effects of metals are likely to stem from their ability to interfere with DNA repair processes. Overall, metal carcinogenesis appears to require the formation of specific metal complexes, chromosomal damage, and activation of signal transduction pathways promoting survival and expansion of genetically/epigenetically altered cells.

http://pubs.acs.org/doi/pdf/10.1021/tx700198a

Genetic and epigenetic mechanisms in metal carcinogenesis and cocarcinogenesis: nickel, arsenic, and chromium.

Drinking water supplies in many geographic areas contain chromium in the +3 and +6 oxidation states. Public health concerns are centered on the presence of hexavalent Cr that is classified as a known human carcinogen via inhalation. Cr(VI) has high environmental mobility and can originate from anthropogenic and natural sources. Acidic environments with high organic content promote the reduction of Cr(VI) to nontoxic Cr(III). The opposite process of Cr(VI) formation from Cr(III) also occurs, particularly in the presence of common minerals containing Mn(IV) oxides. Limited epidemiological evidence for Cr(VI) ingestion is suggestive of elevated risks for stomach cancers. Exposure of animals to Cr(VI) in drinking water induced tumors in the alimentary tract, with linear and supralinear responses in the mouse small intestine. Chromate, the predominant form of Cr(VI) at neutral pH, is taken up by all cells through sulfate channels and is activated nonenzymatically by ubiquitously present ascorbate and small thi...

Chromium in drinking water: sources, metabolism, and cancer risks.

Importance of chromium-DNA adducts in mutagenicity and toxicity of chromium(VI).

A transgenic gpt+ Chinese hamster cell line (G12) was found to be susceptible to carcinogenic nickel-induced inactivation of gpt expression without mutagenesis or deletion of the transgene. Many nickel-induced 6-thioguanine-resistant variants spontaneously reverted to actively express gpt, as indicated by both reversion assays and direct enzyme measurements. Since reversion was enhanced in many of the nickel-induced variant cell lines following 24-h treatment with the demethylating agent 5-azacytidine, the involvement of DNA methylation in silencing gpt expression was suspected. This was confirmed by demonstrations of increased DNA methylation, as well as by evidence indicating condensed chromatin and heterochromatinization of the gpt integration site in 6-thioguanine-resistant cells. Upon reversion to active gpt expression, DNA methylation and condensation are lost. We propose that DNA condensation and methylation result in heterochromatinization of the gpt sequence with subsequent inheritance of the now silenced gene. This mechanism is supported by direct evidence showing that acute nickel treatment of cultured cells, and of isolated nuclei in vitro, can indeed facilitate gpt sequence-specific chromatin condensation. Epigenetic mechanisms have been implicated in the actions of some nonmutagenic carcinogens, and DNA methylation changes are now known to be important in carcinogenesis. This paper further supports the emerging theory that nickel is a human carcinogen that can alter gene expression by enhanced DNA methylation and compaction, rather than by mutagenic mechanisms.

Anatoly Zhitkovich

Papers

Genetic and epigenetic mechanisms in metal carcinogenesis and cocarcinogenesis: nickel, arsenic, and chromium.

Chromium in drinking water: sources, metabolism, and cancer risks.

Importance of chromium-DNA adducts in mutagenicity and toxicity of chromium(VI).

Carcinogenic nickel silences gene expression by chromatin condensation and DNA methylation: a new model for epigenetic carcinogens.

Depletion of Intracellular Ascorbate by the Carcinogenic Metals Nickel and Cobalt Results in the Induction of Hypoxic Stress