The increasing utilization of heavy metals in modern industries leads to an increase in the environmental burden. Nickel represents a good example of a metal whose use is widening in modern technologies. As the result of accelerated consumption of nickel-containing products nickel compounds are released to the environment at all stages of production and utilization. Their accumulation in the environment may represent a serious hazard to human health. Among the known health related effects of nickel are skin allergies, lung fibrosis, variable degrees of kidney and cardiovascular system poisoning and stimulation of neoplastic transformation. The mechanism of the latter effect is not known and is the subject of detailed investigation. This review provides an analysis of the current state in the field.

Nickel essentiality, toxicity, and carcinogenicity.

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.

Nickel-induced toxicity and carcinogenicity, with an emphasis on the generation and role of reactive oxygen species is reviewed. Nickel is a known haematotoxic, immunotoxic, neurotoxic, genotoxic, reproductive toxic, pulmonary toxic, nephrotoxic , hepatotoxic and carcinogenic agent. This article presents a selective review on nickel and effect of its acute, subchronic and chronic doses on certain metabolically active tissues in human as well as animals. Nickel exposure causes formation of free radicals in various tissues in both human and animals which lead to various modifications to DNA bases, enhanced lipid peroxidation, and altered calcium and sulphydryl homeostasis. The primary route for nickel toxicity is depletion of glutathione and bonding to sulphydryl groups of proteins. Nickel homeostasis, nickel-induced activation of signaling pathways and the protective role of enzymatic and non-enzymatic antioxidants against nickel toxicity and carcinogenicity are also discussed.

Nickel, its adverse health effects & oxidative stress.

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.

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

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Toxicological profile for nickel

NiCl2 was examined for mutagenic activity in a number of Salmonella tester strains. Conditions were established where there was substantial uptake of the metal into the bacterial cells. However, even when the metal ion was apparently taken up, as determined by metal association with cells, there was a lack of mutagenic activity. These results suggest that nickel is unable to induce basepair or frameshift mutations in Salmonella tester strains and are discussed in relationship to the low binding affinity of Ni(II) for DNA.

Neal W. Biggart

Papers

Assessment of the uptake and mutagenicity of nickel chloride in salmonella tester strains.