Arsenic-induced DNA hypomethylation affects chromosomal instability in mammalian cells

Sciandrello, Giulia; Caradonna, Fabio; Mauro, Maurizio; Barbata, G

doi:10.1093/carcin/bgh029

Cited by 114 publications

(65 citation statements)

References 25 publications

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“…Effects observed just after treatment are aneuploidy and DNA methylation alterations (6). These findings are consistent with a non-mutagenic mode of action and are suggestive of indirect genotoxic mechanisms (7).…”

Section: Introductionsupporting

confidence: 75%

“…Briefly, 3x10 6 exponentially growing astrocytes, immediately after the arsenite treatment, were washed twice with Hank's salt solution, collected by trypsinization and then incubated in the dark with 25 μM CM-H 2 DCFDA for 1 h. Finally, they were analysed by flow cytometer (FACScan Becton Dickinson), using excitation sources and filters appropriate for fluorescein (FITC). Treated and untreated cells were evaluated.…”

Section: Ros Detectionmentioning

confidence: 99%

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Biological effects of inorganic arsenic on primary cultures of rat astrocytes

Catanzaro

Schiera²,

Sciandrello³

et al. 2010

Int J Mol Med

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Abstract. It is well established that inorganic arsenic induces neurotoxic effects and neurological defects in humans and laboratory animals. The cellular and molecular mechanisms of its actions, however, remain elusive. Herein we report the effects of arsenite (NaAsO 2 ) on primary cultures of rat astrocytes. Cells underwent induction of heat shock protein 70 only at the highest doses of inorganic arsenic (30 and 60 μM), suggesting a high threshold to respond to stress. We also investigated arsenic genotoxicity with the comet assay. Interestingly, although cells treated with 10 μM arsenite for 24 h maintained >70% viability, with respect to untreated cells, high DNA damage was already observed. Since arsenic is not known to be a direct-acting genotoxic agent, we investigated the possibility that its effects are due, in astrocytes as well, to ROS formation, as already described for other cell types. However, FACS analysis after CM-H 2 DCFDA staining did not evidence any significant increase of ROS production while, on the contrary, at the highest arsenite concentrations used, ROS production decreased. Concordantly, we found that, if most cells in the culture are still alive (i.e. up to 10 μM arsenite), they show a treatment-dependent increase in the concentration of SOD1. On the other hand, SOD2 concentration did not change. Finally, we found that astrocytes also synthesize PIPPin, an RNA-binding protein, the concentration of which was recently reported to change in response to stress induced by cadmium. Here we also report that, in cells exposed to high doses of arsenite, an anti-PIPPin antibody-positive faster migrating protein appears.

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Section: Introductionsupporting

confidence: 75%

Section: Ros Detectionmentioning

confidence: 99%

Biological effects of inorganic arsenic on primary cultures of rat astrocytes

Catanzaro

Schiera²,

Sciandrello³

et al. 2010

Int J Mol Med

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“…A Glaviano et al Mothersill et al, 1998) or hypermethylation (Sciandrello et al, 2004) or adduct formation. In theory, the persistent increase of dicentric chromosomes in the hTERTÀ cells could have arisen in three ways.…”

Section: Metal-induced Genomic Instabilitymentioning

confidence: 99%

Effects of hTERT on metal ion-induced genomic instability

et al. 2006

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There is currently a great interest in delayed chromosomal and other damaging effects of low-dose exposure to a variety of pollutants which appear collectively to act through induction of stress-response pathways related to oxidative stress and ageing. These have been studied mostly in the radiation field but evidence is accumulating that the mechanisms can also be triggered by chemicals, especially heavy metals. Humans are exposed to metals, including chromium (Cr) (VI) and vanadium (V) (V), from the environment, industry and surgical implants. Thus, the impact of low-dose stress responses may be larger than expected from individual toxicity projections. In this study, a short (24 h) exposure of human fibroblasts to low doses of Cr (VI) and V (V) caused both acute chromosome damage and genomic instability in the progeny of exposed cells for at least 30 days after exposure. Acutely, Cr (VI) caused chromatid breaks without aneuploidy while V (V) caused aneuploidy without chromatid breaks. The longerterm genomic instability was similar but depended on hTERT positivity. In telomerase-negative hTERTÀ cells, Cr (VI) and V (V) caused a long lasting and transmissible induction of dicentric chromosomes, nucleoplasmic bridges, micronuclei and aneuploidy. There was also a long term and transmissible reduction of clonogenic survival, with an increased b-galactosidase staining and apoptosis. This instability was not present in telomerasepositive hTERT þ cells. In contrast, in hTERT þ cells the metals caused a persistent induction of tetraploidy, which was not noted in hTERTÀ cells. The growth and survival of both metal-exposed hTERT þ and hTERTÀ cells differed if they were cultured at subconfluent levels or plated out as colonies. Genomic instability is considered to be a driving force towards cancer. This study suggests that the type of genomic instability in human cells may depend critically on whether they are telomerase-positive or -negative and that their sensitivities to metals could depend on whether they are clustered or diffuse.

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“…6 It has been shown that DNA methylation is important for maintaining centromeric chromatin stability and plays an important role in chromosomal segregation. 7,8 Polymorphisms of genes that encode enzymes involved in folate metabolism have been associated with the etiology of DS. [9][10][11][12] A polymorphism of the reduced folate carrier 1 (RFC1) gene consisting of an adenine-to-guanine substitution at position 80 (A80G) has been associated with altered concentrations of products derived from the folate metabolic pathway.…”

Section: Introductionmentioning

confidence: 99%

A80G polymorphism of reduced folate carrier 1 (RFC1) and C776G polymorphism of transcobalamin 2 (TC2) genes in Down's syndrome etiology

et al. 2008

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CONTEXT AND OBJECTIVE:There is evidence that polymorphisms of genes involved in folate metabolism may be associated with higher risk that mothers may bear a Down's syndrome (DS) child. This study therefore had the objective of investigating the A80G polymorphism of the reduced folate carrier 1 (RFC1) gene and the C776G polymorphism of the transcobalamin 2 (TC2) gene as maternal risk factors for DS among Brazilian women. DESIGN AND SETTING:Analytical cross-sectional study with control group, at Faculdade de Medicina de São José do Rio Preto (Famerp). METHODS:Sixty-seven mothers of DS individuals with free trisomy 21, and 113 control mothers, were studied. Molecular analysis of the polymorphisms was performed by means of the polymerase chain reaction with restriction fragment length polymorphism (PCR-RFLP), followed by electrophoresis on 2% agarose gel. RESULTS:The frequencies of the polymorphic alleles were 0.51 and 0.52 for RFC1 80G, and 0.34 and 0.34 for TC2 776G, in the case and control groups, respectively. Thus, there were no differences between the groups in relation to either the allele or the genotype frequency, for both polymorphisms (P = 0.696 for RFC1 A80G; P = 0.166 for TC2 C776G; P = 0.268 for combined genotypes). CONCLUSION:There was no evidence of any association between the RFC1 A80G and TC2 C776G polymorphisms and the maternal risk of DS in the sample evaluated.

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Arsenic-induced DNA hypomethylation affects chromosomal instability in mammalian cells

Cited by 114 publications

References 25 publications

Biological effects of inorganic arsenic on primary cultures of rat astrocytes

Biological effects of inorganic arsenic on primary cultures of rat astrocytes

Effects of hTERT on metal ion-induced genomic instability

A80G polymorphism of reduced folate carrier 1 (RFC1) and C776G polymorphism of transcobalamin 2 (TC2) genes in Down's syndrome etiology

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