Nickel (II) enhances benzo[a]pyrene diol epoxide-induced mutagenesis through inhibition of nucleotide excision repair in human cells: a possible mechanism for nickel (II)-induced carcinogenesis (original) (raw)
Related papers
Reviews on Environmental Health, 2011
Nickel, a naturally occurring element that exists in various mineral forms, is mainly found in soil and sediment, and its mobilization is influenced by the physicochemical properties of the soil. Industrial sources of nickel include metallurgical processes such as electroplating, alloy production, stainless steel, and nickel-cadmium batteries. Nickel industries, oil-and coal-burning power plants, and trash incinerators have been implicated in its release into the environment. In humans, nickel toxicity is influenced by the route of exposure, dose, and solubility of the nickel compound. Lung inhalation is the major route of exposure for nickel-induced toxicity. Nickel may also be ingested or absorbed through the skin. The primary target organs are the kidneys and lungs. Other organs such as the liver, spleen, heart and testes may also be affected to a lesser extent. Although the most common health effect is an allergic reaction, research has also demonstrated that nickel is carcinogenic to humans. The focus of the present review is on recent research concerning the molecular mechanisms of nickel-induced genotoxicity and carcinogenicity. We first present a background on the occurrence of nickel in the environment, human exposure, and human health effects.
Carcinogenesis, 2002
Nickel compounds are well-known human carcinogens, but the underlying mechanisms are still not fully understood. Even though only weakly mutagenic, nickel chloride has been shown previously to impair the repair of UV-induced DNA damage as well as oxidative DNA damage. However, the carcinogenic potential depends largely on solubility, with poorly water-soluble nickel subsulfide and nickel oxide being strong carcinogens. Within the present study we investigated the effects of particulate black NiO and soluble NiCl 2 on the induction and removal of stable DNA adducts formed by benzo[a]pyrene (B[a]P) measured by a highly sensitive high performance liquid chromatography (HPLC)/fluorescence assay. With respect to adduct formation, NiO but not NiCl 2 reduced the generation of DNA lesions by~30%. Regarding their repair, in the absence of nickel compounds, most lesions were removed within 24 h; nevertheless, between 20 and 35% of induced adducts remained even 48 h after treatment. NiCl 2 and NiO reduced the removal of adducts in a dose-dependent manner. Thus, 100 µM NiCl 2 led to~80% residual repair capacity; after 500 µM the repair was reduced to~36%. Also, even at the completely non-cytotoxic concentration of 0.5 µg/cm 2 black NiO, lesion removal was reduced to~35% of control and to 15% at 2.0 µg/cm 2 . Furthermore, both nickel compounds increased the benzo[a]pyrene-7,8-diol 9,10epoxide (BPDE)-induced cytotoxicity. Taken together, our results indicate that the nucleotide excision repair pathway is affected in general by water-soluble and particulate nickel compounds and provide further evidence that DNA repair inhibition may be one predominant mechanism in nickel-induced carcinogenicity.
Oxidative DNA damage in cultured cells and rat lungs by carcinogenic nickel compounds
Free Radical Biology and Medicine, 2001
DNA damage in cultured cells and in lungs of rats induced by nickel compounds was investigated to clarify the mechanism of nickel carcinogenesis. DNA strand breaks in cultured cells exposed to nickel compounds were measured by using a pulsed field gel electrophoresis technique. Among nickel compounds (Ni 3 S 2 , NiO (black), NiO (green), and NiSO 4 ), only Ni 3 S 2 , which is highly carcinogenic, induced lesions of both double-and single-stranded DNA in cultured human cells (Raji and HeLa cells). Treatment of cultured HeLa cells with Ni 3 S 2 (10 g/ml) induced a 1.5-fold increase in 8-hydroxy-2Ј-deoxyguanosine (8-OH-dG) compared with control, whereas NiO (black), NiO (green), and NiSO 4 did not enhance the generation of 8-OH-dG. Intratracheal instillation of Ni 3 S 2 , NiO(black), and NiO(green) to Wistar rats increased 8-OH-dG in the lungs significantly. NiSO 4 induced a smaller but significant increase in 8-OH-dG. Histological studies showed that all the nickel compounds used induced inflammation in lungs of the rats. Nitric oxide (NO) generation in phagocytic cells induced by Ni 3 S 2 , NiO(black), and NiO(green) was examined using macrophage cell line RAW 264.7 cells. NO generation in RAW 264.7 cells stimulated with lipopolysaccharide was enhanced by all nickel particles. Two mechanisms for nickel-induced oxidative DNA damage have been proposed as follows: all the nickel compounds used induced indirect damage through inflammation, and Ni 3 S 2 also showed direct oxidative DNA damage through H 2 O 2 formation. This double action may explain relatively high carcinogenic risk of Ni 3 S 2 .
Carcinogenesis, 1997
radical attack, has been observed after treatment of isolated 1 To whom correspondence should be addressed calf thymus DNA with nickel(II) and H 2 O 2 (6) and of isolated Compounds of nickel(II) and cadmium(II) are carcinogenic human chromatin with nickel(II) in the absence or presence to humans and to experimental animals. One frequently of H 2 O 2 (7). The formation of 7,8-dihydro-8-oxoguanine discussed mechanism involved in tumor formation is an (8-hydroxyguanine*) was further enhanced when nickel(II) increase in reactive oxygen species by both metals with the was complexed to heterochromatic proteins (8). An increase subsequent generation of oxidative DNA damage. In the in oxidative DNA damage by nickel(II) has also been detected present study we used human HeLa cells to investigate the in experimental animals. An elevated level of 8-hydroxypotential of nickel(II) and cadmium(II) to induce DNA guanine was induced in rat kidney cells after a single i.p. lesions typical for oxygen free radicals in intact cells and injection of nickel acetate (9), and the extent was considerably the effect on their repair. As indicators of oxidative DNA higher after the administration of nickel(II)-histidine (10). damage, we determined the frequencies of DNA strand Nevertheless, data supporting the induction of oxidative DNA breaks and of lesions recognized by the bacterial formdamage in mammalian cells in culture are still missing.
Toxicological interactions between nickel and radiation on chromosome damage and repair
Environmental Health Perspectives, 1994
Carcinogenic nickel compounds are usually found to be weak mutagens; therefore these compounds may not exert their carcinogenic activity through conventional genotoxic mechanisms. On the other hand, the activities of many nickel compounds have not been adequately investigated. We evaluated the genotoxic activities of nickel acetate using conventional chromosome aberration and sister chromatid exchange assays and found that there was no increase of chromosome aberrations or sister chromatid exchanges, although the highest dose (1000 pM) caused mitotic inhibition. In addition,. we investigated its effect on DNA repair using our challenge assay. In this assay, lymphocytes were exposed to 0.1 to 100 pM nickel acetate for 1 hr during the GO phase of the cell cycle. The cells were washed free of the chemical and, 1.5 hr later, were irradiated with two doses of y-rays (75 cGy per dose separated by 60 min). A significant dose-dependent increase of chromosome translocations was observed (p<0.05). The increase is more than expected based on additive effects from exposure to nickel or trays individually. In contrast to the increase of chromosome translocations, there was no increase in chromosome deletions, although there was a nickel dose-dependent reduction of mitotic indices. Our data suggest that pretreatment with nickel interferes with the repair of radiation-induced DNA damage and potentially cause mistakes in DNA repair. Furthermore, we suggest that nickel-induced abnormal DNA repair may be a mechanism for its carcinogenic properties. The DNA repair problems that we observed after exposure to low doses of nickel may be viewed as a type of adaptive response. Contrary to some investigators who showed that adaptive responses may be beneficial, our data indicated that some responses may cause more problems than expected.
Mutation Research/DNA Repair, 1989
With regard to contradictory results concerning the mutagenicity of nickel compounds in short-term assays, especially in bacterial test systems, Chinese hamster V79 cells were used to measure mutagenicity, comutagenicity and the induction of sister-chromatid exchanges (SCEs) by NiC12. We confirmed the induction of mutations at the HGPRT locus as well as SCEs. In addition, NiC12 shows a pronounced comutagenic effect towards UV. When using confluent cultures or resting cells due to serum deprivation, where more time is given for repair processes, the comutagenic effect is higher compared to logarithmically growing cells (10 and 4 times, respectively, compared to twice). Hence, we attribute this enhancement in mutagenicity to inhibition of DNA repair. Also the increase in induced SCEs after combined treatment with UV and NiC12 supports this thesis. Furthermore, NiC12 enhances the cyto-toxicity of cis-DDP about 12-fold. Since no comutagenic effect is observed in combination with MMS, we suggest that the inhibition of DNA repair by Ni(II) applies to all DNA changes that are repaired by the 'long-patch' excision repair system. This inhibition may occur via replacement of other divalent metal ions essential in repair and regulation processes.
Nickel impairs the repair of UV- and MNNG-damaged DNA
Cellular & molecular biology letters, 2004
Nickel(II) is reported to be genotoxic, but the mechanisms underlying its genotoxicity are largely unknown. It can interfere with DNA repair and this may contribute to its genotoxicity. We studied the effect of nickel chloride on the repair of DNA damaged by UV radiation or N-methyl-N-nitro-N-nitrosoguanidine (MNNG) in human lymphocytes using the alkaline comet assay. Nickel(II) at 1 microM caused an accumulation of DNA breaks during repair incubation, which could follow from the inhibition of the polymerization/ligation step of UV-damaged DNA repair. On the other hand, nickel(II) inhibited the formation of transient DNA breaks brought by the repair process after incubation with MNNG at 5 microM, which might follow from interference with the recognition/incision step of excision repair. Additionally, nickel at 1 microM inhibited the activity of formamidopyrimidine-DNA glycosylase (Fpg) and 3-methyladenine-DNA glycosylase II (Alk A), enzymes involved in DNA excision repair. A decreas...
Gene (HPRT) and Chromosomal (MN) Mutations of Nickel Metal Powder in V79 Chinese Hamster cells
Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis, 2020
Nickel metal is a naturally occurring element used in many industrial and consumer applications. Human epidemiological data and animal cancer bioassays indicate that nickel metal is not likely to be a human carcinogen. Yet, nickel metal is classified as a suspected human carcinogen (CLP) and possibly carcinogenic to humans (IARC). There are no reliable studies on the potential for nickel metal to induce gene and micronucleus (MN) mutations. To fill these datagaps and increase our understanding of the mechanisms underlying the lack of nickel metal carcinogenicity, gene and micronucleus mutation studies were conducted with nickel metal powder (N36F) in V79 Chinese Hamster cells following OECD 476 and 487 guidelines, respectively, under GLP. Gene mutation at the hprt locus was tested, with and without metabolic activation, after 4-h treatment with 0.05-2.5 mM nickel metal powder. Cytokinesis-block MN frequency following exposure to 0.25-1.5 mM nickel metal was tested after 4-h treatment, with and without metabolic activation, followed by a 24-h treatment without metabolic activation. In the gene mutation assay, there were modest increases in hprt mutants observed at some test concentrations, not exceeding 2.2-fold, which were either within the historical control values and/or showed no concentration-response trend. The positive controls showed increases of at least 7-fold. Likewise, no increases in the MN frequency exceeding 1.5-fold were observed with nickel metal, with no concentration-response trends. Taking these results together, it can be concluded that nickel metal is non-mutagenic and does not cause gene nor chromosomal mutations.
Nickel(II) interferes with the incision step in nucleotide excision repair in mammalian cells
Cancer Research, 1994
Nickel compounds are carcinogenic to humans and experimental aol mals. However, the mechanisms leading to tumor formation are stiH not understood since the mutagenic potential is rather weak. In contrast, nickel(ll) enhances the cytotoxicity and genotoxicity in combination with several other DNA-damaging agents. To elucidate possible interactions with DNA re@ processes, the effect of nlckel(ll) on the nucleotide excision repair pathway has been investigated after UV irradiation in HeLa cells. NlckeI(ll) blocks the removal of cyclobutane pyrimidine dimers. as determined by T4 endonuclease V-sensitive sites. When the alkaline unwinding technique was applied, significantly less transient DNA strand breaks after UV irradiation were detected in the presence of nickel(ll) compared to UV alone, suggesting an Inhibition of the Incision step of nucleotide excision repair. Once incisions are made, the ligation of repair patches is delayed as well in nickel-treated cells, as observed by the alkaline unwinding and nucieoid sedimentation techniques. This Inhibi lion of DNA re@ is partly reversible by the addition of magnesium(ll), indicating that the competition between NI2@and @4g2@ may provide an Important mechanism for the disturbance of DNA-protein interactions