Genetic and Epigenetic Mechanisms in Metal Carcinogenesis and Cocarcinogenesis: Nickel, Arsenic, and Chromium

Abstract

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.

Global and gene‐specific promoter methylation changes are related to anti‐B[a]PDE‐DNA adduct levels and influence micronuclei levels in polycyclic aromatic hydrocarbon‐exposed individuals

“…On the other hand, it is known that some metals, in addition to genetic damage via both oxidative and nonoxidative mechanisms (DNA adducts), can also cause significant changes in DNA methylation (for a review see Ref. 37). Therefore, we cannot exclude that the presence of some metals in coke emissions, or rather reactive oxygen species, produced through PAH 38 or metal 36 metabolism, can contribute along with PAH exposure (for which we have supplied a measure of internal dose and biologically effective dose, i.e., the specific promutagenic anti-B[a]PDE-DNA) in modifying DNA methylation.…”

Epigenetics in the Human Brain

“…Given the above, one cannot exclude that at least some of the epigenetic alterations reported in diseased postmortem brain are not necessarily stable imprints that exist for very long periods of time, and instead, could potentially reflect a mechanism that operated on a much shorter time scale before death, perhaps lasting only a few days or even less. The rapidly growling list of conditions acutely affecting the regulation of chromatin structure and function in brain includes ischemia (Endres et al, 2000), and exposure to environmental toxins (Bollati et al, 2007;Desaulniers et al, 2005;Salnikow and Zhitkovich, 2008), nicotine (Satta et al, 2008), alcohol (Marutha Ravindran and Ticku, 2004), psychostimulants (LaPlant et al, 2010;Numachi et al, 2007;Numachi et al, 2004), antipsychotic drugs (Cheng et al, 2008;Dong et al, 2008;Li et al, 2004;Mill et al, 2008;Shimabukuro et al, 2006) and mood stabilizers such as lithium (Kwon and Houpt, 2010) and valproate (Bredy et al, 2007;Dong et al, 2008).…”

Arsenic Toxicity to Saccharomyces cerevisiae Is a Consequence of Inhibition of the TORC1 Kinase Combined with a Chronic Stress Response

“…Exposure to arsenic evokes a broad spectrum of cellular reactions in Saccharomyces cerevisiae Haugen et al, 2004;Jin, 2008;Thorsen et al, 2007) and in higher eukaryotes (Salnikow and Zhitkovich, 2008). A number of mechanisms exist for detoxification, probably because arsenic has always been widespread in the environment.…”

“…In more recent times EhrlichЈs discovery of the antisyphilitic drug arsphenamine (also known as salvarsan) by systematic chemical modification of arsenic derivatives marked the beginning of modern pharmaceutical research. Arsenic trioxide (ATO) is used today in cancer treatment (Evens et al, 2004;Lu et al, 2007;Wang and Chen, 2008).Exposure to arsenic evokes a broad spectrum of cellular reactions in Saccharomyces cerevisiae Haugen et al, 2004;Jin, 2008;Thorsen et al, 2007) and in higher eukaryotes (Salnikow and Zhitkovich, 2008). A number of mechanisms exist for detoxification, probably because arsenic has always been widespread in the environment.…”