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PMID: 17970581 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, N.I.H., Intramural Review

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

Chemical research in toxicology ·Vol. 21 ·No. 1 ·2008-01-00 ·Pages 28-44

Salnikow K, Zhitkovich A

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.

MeSH Terms
Animals Arsenic/toxicity Carcinogens/toxicity Chromium/toxicity Cocarcinogenesis DNA/genetics Humans Metals/toxicity Neoplasms/chemically induced,genetics Nickel/toxicity
Chemicals
Carcinogens Metals Chromium Nickel DNA Arsenic
Authors & Affiliations
2 authors, click to expand affiliations / ORCID
Salnikow Konstantin
National Cancer Institute, Frederick, MD 21702, USA.
Zhitkovich Anatoly
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Article Info
Journal
Chemical research in toxicology
Abbr.
Chem Res Toxicol
ISSN
0893-228X
DOI
10.1021/tx700198a
Published
2008-01-00
Epub
2007-00-30
Pages
28-44
Language
English
Region
United States
NLM ID
8807448
PMCID
PMC2602826
Subset
IM
Grants
NIEHS NIH HHS · R01 ES008786-11 · United States
NIEHS NIH HHS · ES008786 · United States
NIEHS NIH HHS · R01 ES008786 · United States
NIEHS NIH HHS · P42 ES013660-030004 · United States
NIEHS NIH HHS · ES012915 · United States
Intramural NIH HHS · United States
NIEHS NIH HHS · R01 ES012915-04 · United States
NIEHS NIH HHS · R01 ES012915 · United States
NIEHS NIH HHS · P42 ES013660 · United States
External Links
PubMed source DOI: 10.1021/tx700198a PMC Full Text View journal details
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