Mechanisms of carcinogenicity are discussed for metals and their compounds, classified as carcinogenic to humans or considered to be carcinogenic to humans: arsenic, antimony, beryllium, cadmium, chromium, cobalt, lead, nickel and vanadium. Physicochemical properties govern uptake, intracellular distribution and binding of metal compounds. Interactions with proteins (e.g., with zinc finger structures) appear to be more relevant for metal carcinogenicity than binding to DNA. In general, metal genotoxicity is caused by indirect mechanisms. In spite of diverse physicochemical properties of metal compounds, three predominant mechanisms emerge: (1) interference with cellular redox regulation and induction of oxidative stress, which may cause oxidative DNA damage or trigger signaling cascades leading to stimulation of cell growth; (2) inhibition of major DNA repair systems resulting in genomic instability and accumulation of critical mutations; (3) deregulation of cell proliferation by induction of signaling pathways or inactivation of growth controls such as tumor suppressor genes. In addition, specific metal compounds exhibit unique mechanisms such as interruption of cell-cell adhesion by cadmium, direct DNA binding of trivalent chromium, and interaction of vanadate with phosphate binding sites of protein phosphatases.

Carcinogenic metal compounds : recent insight into molecular and cellular mechanisms

Arsenic Exposure and Toxicology: A Historical Perspective

Purpose of review Epigenetics investigates heritable changes in gene expression occurring without changes in DNA sequence. Several epigenetic mechanisms, including DNA methylation, histone modifications, and microRNA expression, can change genome function under exogenous influence. Here, we review current evidence indicating that epigenetic alterations mediate toxicity from environmental chemicals. Recent findings In-vitro, animal, and human investigations have identified several classes of environmental chemicals that modify epigenetic marks, including metals (cadmium, arsenic, nickel, chromium, and methylmercury), peroxisome proliferators (trichloroethylene, dichloroacetic acid, and TCA), air pollutants (particulate matter, black carbon, and benzene), and endocrine-disrupting/reproductive toxicants (diethylstilbestrol, bisphenol A, persistent organic pollutants, and dioxin). Most studies conducted so far have been centered on DNA methylation, whereas only a few investigations have studied environmental chemicals in relation to histone modifications and microRNA. Summary For several exposures, it has been proved that chemicals can alter epigenetic marks, and that the same or similar epigenetic alterations can be found in patients with the disease of concern or in diseased tissues. Future prospective investigations are needed to determine whether exposed individuals develop epigenetic alterations over time and, in turn, which such alterations increase the risk of disease. Also, further research is needed to determine whether environmental epigenetic changes are transmitted transgenerationally.

Epigenetics and environmental chemicals.

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.

Titanium dioxide (TiO2) nanoparticles are manufactured worldwide in large quantities for use in a wide range of applications including pigment and cosmetic manufacturing. Although TiO2 is chemically inert, TiO2 nanoparticles can cause negative health effects, such as respiratory tract cancer in rats. However, the mechanisms involved in TiO2-induced genotoxicity and carcinogenicity have not been clearly defined and are poorly studied in vivo. The present study investigates TiO2 nanoparticles–induced genotoxicity, oxidative DNA damage, and inflammation in a mice model. We treated wild-type mice with TiO2 nanoparticles in drinking water and determined the extent of DNA damage using the comet assay, the micronuclei assay, and the γ-H2AX immunostaining assay and by measuring 8-hydroxy-2′-deoxyguanosine levels and, as a genetic instability endpoint, DNA deletions. We also determined mRNA levels of inflammatory cytokines in the peripheral blood. Our results show that TiO2 nanoparticles induced 8-hydroxy-2′-deoxyguanosine, γ-H2AX foci, micronuclei, and DNA deletions. The formation of γ-H2AX foci, indicative of DNA double-strand breaks, was the most sensitive parameter. Inflammation was also present as characterized by a moderate inflammatory response. Together, these results describe the first comprehensive study of TiO2 nanoparticles–induced genotoxicity in vivo in mice possibly caused by a secondary genotoxic mechanism associated with inflammation and/or oxidative stress. Given the growing use of TiO2 nanoparticles, these findings raise concern about potential health hazards associated with TiO2 nanoparticles exposure. [Cancer Res

https://cancerres.aacrjournals.org/content/canres/69/22/8784.full.pdf

Titanium dioxide nanoparticles induce DNA damage and genetic instability in vivo in mice.

DNA hypermethylation of promoter of gene p53 and p16 in arsenic-exposed people with and without malignancy.

Chronic arsenic toxicity (arsenicosis) as a result of drinking arsenic-contaminated groundwater is a major environmental health hazard throughout the world, including India. A lot of research on health effects, including genotoxic effect of chronic arsenic toxicity in humans, have been carried out in West Bengal during the last 2 decades. A review of literature including information available from West Bengal has been made to characterize the problem. Scientific journals, monographs, and proceedings of conferences with regard to human health effects, including genotoxicity, of chronic arsenic toxicity have been reviewed. Pigmentation and keratosis are the specific skin diseases characteristic of chronic arsenic toxicity. However, in West Bengal, it was found to produce various systemic manifestations, such as chronic lung disease, characterized by chronic bronchitis, chronic obstructive and/or restrictive pulmonary disease, and bronchiectasis; liver diseases, such as non cirrhotic portal fibrosis; polyneuropathy; peripheral vascular disease; hypertension; nonpitting edema of feet/hands; conjunctival congestion; weakness; and anemia. High concentrations of arsenic, greater than or equal to 200 μg/L, during pregnancy were found to be associated with a sixfold increased risk for stillbirth. Cancers of skin, lung, and urinary bladder are the important cancers associated with this toxicity. Of the various genotoxic effects of arsenic in humans, chromosomal aberration and increased frequency of micronuclei in different cell types have been found to be significant. Various probable mechanisms have been incriminated to cause DNA damage because of chronic arsenic toxicity. The results of the study in West Bengal suggest that deficiency in DNA repair capacity, perturbation of methylation of promoter region of p53 and p16 genes, and genomic methylation alteration may be involved in arsenic-induced disease manifestation in humans. P53 polymorphism has been found to be associated with increased occurrence of arsenic-induced keratosis. Of the various genes involved in the regulation of arsenic metabolism, single-nucleotide polymorphisms of purine nucleoside phosphorylase, in one study, showed increased occurrence of arsenicosis.

https://onlinelibrary.wiley.com/doi/epdf/10.1016/j.kjms.2011.05.003

Chronic arsenic toxicity: Studies in West Bengal, India

Gene-specific hypermethylation has previously been detected in Arsenic exposed persons. To monitor the level of whole genome methylation in persons exposed to different levels of Arsenic via drinking water, DNA was extracted from peripheral blood mononuclear cells of 64 persons. Uptake of methyl group from (3)H labeled S-Adenosyl Methionine after incubation of DNA with SssI methylase was measured. Results showed statistically significant (P = 0.0004) decrease in uptake of (3)H methyl group in the persons exposed to 250-500 microg/L arsenic, indicating genomic hypermethylation.

Arsenic exposure induces genomic hypermethylation.

The objective of the paper was to study the association of polymorphisms of phases I and II xenobiotic metabolizing enzyme genes cytochrome P450 (CYP-4501A1*2A, *2B, *2C and *4 alleles, CYP-4502D6*4 allele), glutathione-S-transferase (GSTM1 and GSTT1 null genotypes) and N-acetyl transferase 2 (NAT2*6B and *7A alleles) with the incidence of acute myeloid leukemia (AML) in an eastern Indian population. Polymerase chain reaction and restriction fragment length polymorphism of genomic DNA from peripheral blood cells were used to detect CYP-450 and NAT2 gene polymorphisms in 110 AML patients and 144 racially and geographically matched normal controls. Polymerase chain reaction was also applied to detect GST gene polymorphisms in both groups. A statistically significant difference between the AML group and the normal group was observed in the case of glutathione-S-transferase M1 null (odds ratio 3.25, 95% confidence interval 1.9-5.58, P<0.001) and N-acetyl transferase 2*6B (odds ratio 3.04, 95% confidence interval 1.79-5.16, P<0.001) genotypes. Combined deficiency of N-acetyl transferase 2 and glutathione-S-transferase M1 genes produced an odds ratio of 11.91 (95% confidence interval 4.06-34.96, P<0.001). The effect of N-acetyl transferase 2*6B (P<0.001) is significant only at ages <or=40. In the population studied, persons with glutathione-S-transferase M1 null genotype and N-acetyl transferase 2*6B allele are at increased risk of developing AML, and the risk is considerably enhanced in persons with both glutathione-S-transferase M1 and N-acetyl transferase 2 deficiency.

Association of cytochrome P450, glutathione S-transferase and N-acetyl transferase 2 gene polymorphisms with incidence of acute myeloid leukemia.

324 alleles of the β-globin gene from unrelated thalassaemia patients native to the eastern region of India (mainly from the state of West Bengal) were analysed for β-globin gene mutations by the ampl

Uma B. Dasgupta

Papers

DNA hypermethylation of promoter of gene p53 and p16 in arsenic-exposed people with and without malignancy.

Chronic arsenic toxicity: Studies in West Bengal, India

Arsenic exposure induces genomic hypermethylation.

Association of cytochrome P450, glutathione S-transferase and N-acetyl transferase 2 gene polymorphisms with incidence of acute myeloid leukemia.

Major beta-globin gene mutations in eastern India and their associated haplotypes.