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At least 649 records · Page 36Linked to original sources
PubMed2006

Metabolism of arsenic in Drosophila melanogaster and the genotoxicity of dimethylarsinic acid in the Drosophila wing spot test.

Inorganic arsenic is nongenotoxic in the Drosophila melanogaster wing somatic mutation and recombination test (SMART). Recent evidence in mammalian systems indicates that methylated metabolites of arsenic are more genotoxic than inorganic arsenic. Thus, we hypothesized that inorganic arsenic is nongenotoxic in Drosophila because they are unable to biotransform arsenic to methylated forms. In the present study, we fed trivalent and pentavalent inorganic arsenic to Drosophila larvae and adults and measured the production of methylated derivatives. No biomethylated arsenic species were found in the organisms or in the growth medium, which suggests that Drosophila are unable to biomethylate inorganic arsenic. Exposure of Drosophila to the methylated arsenic derivative dimethylarsinic acid (DMA(V)) resulted in incorporation of this organoarsenic compound without demethylation. In addition, we used the SMART wing spot assay, which measures loss of heterozygosity (LOH) resulting from gene mutation, chromosomal rearrangement, chromosome breakage, and chromosome loss, to evaluate the genotoxicity of DMA. DMA by itself induced significant increases in the frequency of total spots, small spots, and large single spots. These results are consistent with the important role of arsenic biomethylation as a determinant of the genotoxicity of arsenic compounds. The absence of biomethylation in Drosophila could explain the lack of genotoxicity for inorganic arsenic and the genotoxicity of methylated arsenic species in the SMART wing spot assay.

Animals↗
PubMed2004

Overexpression of phytochelatin synthase in Arabidopsis leads to enhanced arsenic tolerance and cadmium hypersensitivity.

Phytochelatin synthase (PCS) catalyzes the final step in the biosynthesis of phytochelatins, which are a family of cysteine-rich thiol-reactive peptides believed to play important roles in processing many thiol-reactive toxicants. A modified Arabidopsis thaliana PCS sequence (AtPCS1) was active in Escherichia coli. When AtPCS1 was overexpressed in Arabidopsis from a strong constitutive Arabidopsis actin regulatory sequence (A2), the A2::AtPCS1 plants were highly resistant to arsenic, accumulating 20-100 times more biomass on 250 and 300 microM arsenate than wild type (WT); however, they were hypersensitive to Cd(II). After exposure to cadmium and arsenic, the overall accumulation of thiol-peptides increased to 10-fold higher levels in the A2::AtPCS1 plants compared with WT, as determined by fluorescent HPLC. Whereas cadmium induced greater increases in traditional PCs (PC2, PC3, PC4), arsenic exposure resulted in the expression of many unknown thiol products. Unexpectedly, after arsenate or cadmium exposure, levels of the dipeptide substrate for PC synthesis, gamma-glutamyl cysteine (gamma-EC), were also dramatically increased. Despite these high thiol-peptide concentrations, there were no significant increases in concentrations of arsenic and cadmium in above-ground tissues in the AtPCS1 plants relative to WT plants. The potential for AtPCS1 overexpression to be useful in strategies for phytoremediating arsenic and to compound the negative effects of cadmium are discussed.

Aminoacyltransferases↗
PubMed2003

The efficacy of monoisoamyl ester of dimercaptosuccinic acid in chronic experimental arsenic poisoning in mice.

The therapeutic efficacy of monoisoamyl meso-2,3-dimercaptosuccinic acid (MiADMSA), a new monoester of 2,3-dimercaptosuccinic acid on arsenic induced oxidative stress in liver and kidneys, alterations in hematopoietic system and depletion of arsenic burden was assessed, in mice. Three different doses of MiADMSA (25, 50 or 100 mg/kg) for five consecutive days were administered in chronically arsenic exposed mice (10 ppm in drinking water for six months). Oral administration of MiADMSA particularly at a dose of 50 mg/kg, produced relatively more pronounced beneficial effects on the inhibited blood delta-aminolevulinic acid dehydratase (ALAD), biochemical variables indicative of hepatic and renal oxidative stress and depletion of arsenic concentration in blood, liver and kidneys, compared with intraperitoneal administration of the drug. The treatment with MiADMSA although, produced essential metals imbalance which could be a restrictive factor for the possible therapeutic use of this compound in chronic arsenic poisoning and thus require further exploration.

Administration, Oral↗
PubMed2002

Interactions by carcinogenic metal compounds with DNA repair processes: toxicological implications.

Even though compounds of nickel, arsenic, cobalt and cadmium are carcinogenic, their mutagenic potentials are rather weak. In contrast, they exert pronounced comutagenic effects, which may be explained by disturbances of different DNA repair systems. Thus, cobalt, arsenic, nickel and cadmium interfere with base and nucleotide excision repair, even though they affect different steps of the respective repair systems and act by different, not yet completely understood mechanisms. Potential target molecules for some metal ions are so-called zinc finger structures in DNA repair proteins, but each zinc finger protein exerts its own sensitivity towards toxic metal ions. Possible consequences of repair inhibitions are discussed in more detail for soluble and particulate nickel compounds, which have recently been shown to interfere with the repair of stable DNA adducts induced by benzo[a]pyrene (B[a]P). Since nickel compounds and polycyclic aromatic hydrocarbons such as B[a]P are frequently associated in the ambient air, in cigarette smoke and at many workplaces, an impaired removal of B[a]P-derived DNA adducts will lead to persistent DNA damage and thus increase the risk of mutations and tumor formation.

Animals↗
PubMed2001

Methylated trivalent arsenic species are genotoxic.

The reactivities of methyloxoarsine (MAs(III)) and iododimethylarsine (DMAs(III)), two methylated trivalent arsenicals, toward supercoiled phiX174 RFI DNA were assessed using a DNA nicking assay. The induction of DNA damage by these compounds in vitro in human peripheral lymphocytes was assessed using a single-cell gel (SCG, "comet") assay. Both methylated trivalent arsenicals were able to nick and/or completely degrade phiX174 DNA in vitro in 2 h incubations at 37 degrees C (pH 7.4) depending on concentration. MAs(III) was effective at nicking phiX174 DNA at 30 mM; however, at 150 microM DMAs(III), nicking could be observed. Exposure of phiX174 DNA to sodium arsenite (iAs(III); from 1 nM up to 300 mM), sodium arsenate (from 1 microM to 1 M), and the pentavalent arsenicals, monomethylarsonic acid (from 1 microM to 3 M) and dimethylarsinic acid (from 0.1 to 300 mM), did not nick or degrade phiX174 DNA under these conditions. In the SCG assay in human lymphocytes, methylated trivalent arsenicals were much more potent than any other arsenicals that were tested. On the basis of the slopes of the concentration-response curve for the tail moment in the SCG assay, MAs(III) and DMAs(III) were 77 and 386 times more potent than iAs(III), respectively. Because methylated trivalent arsenicals were the only arsenic compounds that were observed to damage naked DNA and required no exogenously added enzymatic or chemical activation systems, they are considered here to be direct-acting forms of arsenic that are genotoxic, though they are not, necessarily, the only genotoxic species of arsenic that could exist.

Arsenic↗
PubMed1996

Assessment of a possible genotoxic environmental risk in sheep bred on grounds with strongly elevated contents of mercury, arsenic and antimony.

A part of Northern Palatinate country (Germany) was formerly influenced by mercury mining. Today, in many cases agricultural and housing areas are placed onto or near to former dump grounds of rubble. In the soil of these areas the concentration of mercury, arsenic and antimony was found ranging from basic natural contents up to strongly elevated levels. In a biomonitoring project, sheep bred on grounds contaminated with mercury (range 1-435 mg Hg/kg dry matter), arsenic (range 17-147 mg As/kg dry matter) and antimony (range 2-15 mg Sb/kg dry matter) were taken as example on the uptake of these elements from the environment and for possible effects of this exposure. Significantly elevated mercury levels were found in wool of one collective of exposed sheep (0.107 mg/kg mean vs. 0.048 mg/kg mean, p < 0.001, U-test). Surprisingly, the arsenic content of wool taken from sheep bred in the urban referential area was approx. 10 times higher than that of the sheep bred on the grounds contaminated with arsenic (0.57 mg/kg mean vs. 0.051 mg/kg mean, p < 0.001, U-test). In general, element concentrations in the examined blood samples were low and the differences between the collectives were small: mercury was found in concentrations ranging from 0.9 microgram/l up to 2.0 micrograms/l (means), arsenic and antimony were generally found in concentrations below 1 microgram/l. Neither in the alkaline elution technique nor in the sister chromatid exchange (SCE) analysis significant increases in the rate of DNA-damaging effects between the different sheep collectives were detected. This indicates that the transfer rate of genotoxic compounds of mercury, arsenic or antimony from the environment is too low to register effects with AFE and SCE although the soil was highly contaminated.

Animals↗
PubMed2006

Bushfires and tank rainwater quality: a cause for concern?

In early 2003, after a prolonged drought period, extensive bushfires occurred in the east of Victoria affecting 1.5 million hectares of land. At the time, smoke and ash from bushfires, settling on roofs, contained pollutants that could potentially contaminate rainwater collected and stored in tanks for domestic use. The major concerns include polycyclic aromatic hydrocarbons (PAHs) from incomplete combustion of organic matter and arsenic from burnt copper chrome arsenate (CCA) treated wood. An increase in microbial contamination through altered nutrient levels was also hypothesised. A pilot study of 49 rainwater tank owners was undertaken in north-east Victoria. A rainwater tank sample was taken and analysed for a variety of parameters including organic compounds, microbiological indicators, metals, nutrients and physico-chemical parameters. A survey was administered concurrently. A number of results were outside the Australian Drinking Water Guideline (ADWG) values for metals and microbiological indicator organisms, but not for any tested organic compounds. PAHs and arsenic are unlikely to be elevated in rainwater tanks as a result of bushfires, but cadmium may be of concern.

Arsenic↗
PubMed2001

Total, organic, and inorganic arsenic in some commercial species of crustaceans from the Mediterranean Sea (Italy).

Total, organic, and inorganic arsenic were measured in the flesh of different crustacean species: Parapenaeus longirostris, Aristeus antennatus, Plesionika martia, and Nephrops norvegicus, species extensively commercialized and widely consumed as food. Among the different species of crustaceans, the highest mean value of total arsenic was detected in N. norvegicus (45.00 microg g(-1) dry wt), followed by P. martia (40.76 microg g(-1) dry wt), P. longirostris (34.00 microg g(-1) dry wt), and A. antennatus (15.45 microg g(-1) dry wt). In all the species examined, most of this element was present as organic compounds, while inorganic arsenic was only a very modest percentage (3.5 to 5.7%) of the total arsenic present. There is a substantial epidemiological evidence that inorganic arsenic may cause lung and skin cancer. For this reason, the Joint Expert Committee of the FAO-WHO recommended a maximum acceptable daily intake of inorganic arsenic for humans of 2 microg/kg of body weight. The estimated daily intake was below this limit; therefore, no direct hazard for human health due to the consumption of this seafood was found.

Animals↗
PubMed2000

Organic and inorganic arsenic and lead in fish from the South Adriatic Sea, Italy.

Total, organic and inorganic arsenic and lead were measured from the muscle of different kinds of fish: skate (Raje spp.), hake (Merluccius merluccius) and blue whiting (Micromesistius poutassou), caught in the South Adriatic Sea (South Italy) in the period June-August 1995. The highest levels of total arsenic were found in skate (Raje spp.) whose values ranged from 14.4 to 61.5 mg/kg ww, followed by blue whiting (M. poutassou) and hake (M. merluccius) that showed lower levels ranging from 8.5 to 21.5 mg/kg ww and from 5.9 to 16.1 mg/kg ww, respectively. In all the species examined most of this element was present as organic compounds while inorganic arsenic was only a very modest percentage (0.47-3.5%) of the total arsenic present. Lead in all species analysed was at small concentrations with mean values ranging from 0.12 to 0.15 mg/kg ww. According to the rules in force in Italy no samples showed concentrations of lead exceeding the peak value of 2 mg/kg.

Animals↗
PubMedDate not supplied

Molecular aspects of arsenic stress.

Arsenic produces a variety of stress responses in mammalian cells, including metabolic abnormalities accompanied by growth inhibition and eventually apoptosis. Morphological alterations in cells exposed to arsenic often suggest underlying disruption of cytoskeletal structural elements responsible for cellular integrity, shape, and locomotion. However, specifics of the ultrastructural changes produced by arsenic remain poorly understood. Various tissues and organs differ in their sensitivity to arsenic, with the liver and skin being the most studied. Characteristic skin pathology related to arsenic exposure ranges from hyperkeratotic lesions to squamous-cell carcinomas. However, molecular events in the arsenic-exposed skin still remain to be elucidated. Although mutagenicity of arsenic has not been unequivocally established, recent evidence supports the view that oncogenic mutations do occur, and that only selected enzymes related to DNA replication and repair are affected by arsenic. Sensitivity of the mitotic spindle to arsenic, particularly its organic compounds, underlies the well-documented chromosomal aberrations in arsenic-exposed populations. Arsenite-induced stress at the molecular level shares many features with the heat shock response. This includes the differential sensitivity of the stress signal pathway elements to the magnitude of the stress, stressor-specific activation of the response elements, and the protective role of the heat shock response. Oxidative stress, the central component of heat shock response, is typical of arsenic-related effects that are, in fact, regarded as the chemical paradigm of heat stress. Similar to heat stress, arsenite induces heat shock proteins (HSPs) of various sizes. The signal cascade triggered by arsenite-like heat stress induces the activity of the mitogen-activated protein (MAP) kinases, extracellular regulated kinase (ERK), c-jun terminal kinase (JNK), and p38. Through the JNK and p38 pathways, arsenite activates the immediate early genes c-fos, c-jun, and egr-1, usually activated by various growth factors, cytokines, differentiation signals, and DNA-damaging agents. Like other oxygen radical-producing stressors, arsenic induces nitric oxide production at the level of transcriptional activation along with induction of poly(ADP)-ribosylation, NAD depletion, DNA strand breaks, and formation of micronuclei. This review presents an overview of current research on molecular aspects of arsenic stress with an emphasis on the tissue-specific events in humans. It deals with current progress on the understanding of the signal transduction pathways and mechanisms underlying the sensitivity of various species, organs, and tissues to arsenic.

Animals↗
PubMed2003

Free radical stress in chronic lymphocytic leukemia cells and its role in cellular sensitivity to ROS-generating anticancer agents.

2-Methoxyestradiol (2-ME), a new anticancer agent currently in clinical trials, has been demonstrated to inhibit superoxide dismutase (SOD) and to induce apoptosis in leukemia cells through a free radical-mediated mechanism. Because the accumulation of superoxide (O(2)-) by inhibition of SOD depends on the cellular generation of O(2)-, we hypothesized that the endogenous production of superoxide may be a critical factor that affects the antileukemia activity of 2-ME. In the present study, we investigated the relationship between cellular O(2)- contents and the cytotoxic activity of 2-ME in primary leukemia cells from 50 patients with chronic lymphocytic leukemia (CLL). Quantitation of O(2)- revealed that the basal cellular O(2)- contents are heterogeneous among patients with CLL. The O(2)- levels were significantly higher in CLL cells from patients with prior chemotherapy. CLL cells with higher basal O(2)- contents were more sensitive to 2-ME in vitro than those with lower O(2)- contents. There was a significant correlation between the 2-ME-induced O(2)- increase and the loss of cell viability. Importantly, addition of arsenic trioxide, a compound capable of causing reactive oxygen species (ROS) generation, significantly enhanced the activity of 2-ME, even in the CLL cells that were resistant to 2-ME alone. These results suggest that the cellular generation of O(2)- plays an important role in the cytotoxic action of 2-ME and that it is possible to use exogenous ROS-producing agents such as arsenic trioxide in combination with 2-ME to enhance the antileukemia activity and to overcome drug resistance. Such a combination strategy may have potential clinical applications.

2-Methoxyestradiol↗