Arsenic induces oxidative DNA damage in mammalian cells

Although arsenic is a well-established human carcinogen, the underlying carcinogenic mechanism(s) is not known. Using the human-hamster hybrid (A(L)) cell mutagenic assay that is sensitive in detecting mutagens that induce predominately multilocus deletions, we showed previously that arsenite is indeed a potent gene and chromosomal mutagen and that oxyradicals may be involved in the mutagenic process. In the present study, the effects of free radical scavenging enzymes on the cytotoxic and mutagenic potential of arsenic were examined using the AL cells. Concurrent treatment of cells with either superoxide dismutase or catalase reduced both the cytotoxicity and mutagenicity of arsenite by an average of 2-3 fold, respectively. Using immunoperoxidase staining with a monoclonal antibody specific for 8-hydroxy-2'-deoxyguanosine (8-OHdG), we demonstrated that arsenic induced oxidative DNA damage in A(L) cells. This induction was significantly reduced in the presence of the antioxidant enzymes. Furthermore, reducing the intracellular levels of non-protein sulfhydryls (mainly glutathione) using buthionine S-R-Sulfoximine increased the total mutant yield by more than 3-fold as well as the proportion of mutants with multilocus deletions. Taken together, our data provide clear evidence that reactive oxygen species play an important causal role in the genotoxicity of arsenic in mammalian cells.     

Mechanism of comutagenesis of sodium arsenite withn-methyl-n-nitrosourea

Arsenic compounds are known carcinogens. Although many carcinogens are also mutagens, we have previously shown that sodium arsenite is not mutagenic at either the Na⁺/K⁺ ATPase orhprt locus in Chinese hamster V79 cells. It can, however, enhance UV-mutagenesis. We now confirm the nonmutagenicity of sodium arsenite in line G12, a pSV2gpt-transformed V79 (hprt ⁻) cell line, which is able to detect multilocus deletions in addition to point mutations and small deletions. The lack of arsenic mutagenicity has led to studies emphasizing its comutagenicity. Sodium arsenite at relatively nontoxic concentrations (5 μM for 24 h or 10 μM for 3 h) is comutagenic withN-methyl-N-nitrosourea (MMU) at thehprt locus in V79 cells. Using a nick translation assay, which measures DNA strand breaks by incorporating radioactive deoxyribonucleoside monophosphate at their 3′OH ends in permeabilized cells, we found that much more incorporation was seen in cells treated with MNU (4 mM, 15 min) followed by 3-h incubation with 10 μM sodium arsenite compared with cells exposed to the same MNU treatment followed by 3-h incubation without sodium arsenite. This result shows that in the presence of arsenite, strand breaks resulting from MNU or its repair accumulate over a 3-h period. We suggest that the repair of MNU-induced DNA lesions may be inhibited by arsenite either by affecting the incorporation of dNMPs into the MNU-damaged DNA template or by interfering with the ligation step.     

Toxicity, transformation and accumulation of inorganic arsenic species in a microalga Scenedesmus sp. isolated from soil

Arsenic speciation and cycling in the natural environment are highly impacted via biological processes. Since arsenic is ubiquitous in the environment, microorganisms have developed resistance mechanisms and detoxification pathways to overcome the arsenic toxicity. This study has evaluated the toxicity, transformation and accumulation of arsenic in a soil microalga Scenedesmus sp. The alga showed high tolerance to arsenite. The 72-h 50 % growth inhibitory concentrations (IC₅₀ values) of the alga exposed to arsenite and arsenate in low-phosphate growth medium were 196.5 and 20.6 mg? L^?1, respectively. When treated with up to 7.5 mg? L^?1 arsenite, Scenedesmus sp. oxidised all arsenite to arsenate in solution. However, only 50 % of the total arsenic remained in the solution while the rest was accumulated in the cells. Thus, this alga has accumulated arsenic as much as 606 and 761 μg? g^?1 dry weight when exposed to 750 μg? L^?1 arsenite and arsenate, respectively, for 8 days. To our knowledge, this is the first report of biotransformation of arsenic by a soil alga. The ability of this alga to oxidise arsenite and accumulate arsenic could be used in bioremediation of arsenic from contaminated water and soil.     

Characterization of As(III) oxidizing <Emphasis Type="Italic">Achromobacter</Emphasis> sp. strain N2: effects on arsenic toxicity and translocation in rice

Achromobacter sp. strain N2 was isolated from a pyrite-cinder-contaminated soil and presented plant growth promoting traits (ACC deaminase activity, production of indole-3-acetic and jasmonic acids, siderophores secretion, and phosphate solubilization) and arsenic transformation abilities. Achromobacter sp. strain N2 was resistant to different metals and metalloids, including arsenate (100 mM) and arsenite (5 mM). The strain was resistant to ionic stressors (i.e., arsenate and NaCl), whereas bacterial growth was impaired by osmotic stress. Strain N2 was able to oxidize 1.0 mmol L^?1 of arsenite to arsenate in 72 h. This evidence was supported by the retrieval of an arsenite oxidase AioA gene highly homologous to arsenite oxidases of Achromobacter and Alcaligenes species. Rice seeds of Oryza sativa (var. Loto) were bio-primed with ACCD-induced and non-induced cells in order to evaluate the effect of inoculation on rice seedlings growth and arsenic uptake. The bacterization with ACCD-induced cells significantly improved seed germination and seedling heights if compared with the seeds inoculated with non-induced cells and non-primed seeds. Enhanced arsenic uptake was evidenced in the presence of ACCD-induced cells, suggesting a role of ACCD activity on the mitigation of the toxicity of arsenic accumulated by the plant. This kind of responses should be taken into account when proposing PGP strains for improving plant growth in arsenic-rich soils.     

Mutagenic activities of aflatoxin B 1 and G 1 in Neurospora crassa

Summary The mutagenicity and mutagenic specificity of aflatoxin B₁ and G₁ were studied with the adenine-3 (ad-3) test system of Neurospora crassa. Aflatoxin B₁ and G₁ failed to show mutagenicity in resting conidia, but both agents were mutagenic in growing vegetative cultures. The frequencies of ad-3 mutants induced by aflatoxin B₁ and G₁ (40g/ml) were 70.7x10^-6 survivors and 9.6x10^-6 survivors, respectively. Since aflatoxin B₁ gave a 177-fold increase over the spontaneous mutation frequency it is a rather potent mutagen, whereas aflatoxin G₁ gave only a 24-fold increase and so is only moderately mutagenic.Genetic analyses of ad-3 mutants induced by aflatoxin B₁ and G₁ indicate that both agents induce a low frequency of multilocus deletions. The spectra of point mutations at the ad-3A and ad-3B loci induced by aflatoxin B₁ and G₁ are not distinguishable from each other. Hence both agents probably induce the same relative frequencies of genetic alterations. The frequencies of leakiness, allelic complementation, and classes of complementation patterns among the ad-3 mutants induced by both agents are higher than the frequencies among ICR-170-induced mutants and somewhat lower than those among NA- and AP-induced mutants. The results of reversion tests with NA, MNNG, and ICR-170 indicate that in addition to multilocus deletion, aflatoxin B₁-induced ad-3 mutants consist of frameshifts, base-pair transitions, and possibly other types of intragenic alterations.     

The influence of reference radiation photon energy on high-LET RBE: comparison of human peripheral lymphocytes and human–hamster hybrid A<Subscript>L</Subscript> cells

The relative biological effectiveness (RBE) based on the induction of dicentrics in any cell type is principally an important information for the increasing application of high-LET radiation in cancer therapy. Since the standard system of human lymphocytes for measuring dicentrics are not compatible with our microbeam irradiation setup where attaching cells are essential, we used human–hamster hybrid A_L cells which do attach on foils and fulfil the special experimental requirement for microbeam irradiations. In this work, the dose–response of A_L cells to photons of different energy, 70 and 200 kV X-rays and ⁶⁰Co γ-rays, is characterized and compared to human lymphocytes. The total number of induced dicentrics in A_L cells is approximately one order of magnitude smaller. Despite the smaller α and β parameters of the measured linear–quadratic dose–response relationship, the α/β-ratio versus photon energy dependence is identical within the accuracy of measurement for A_L cells and human lymphocytes. Thus, the influence of the reference radiation used for RBE determination is the same. For therapy relevant doses of 2 Gy (⁶⁰Co equivalent), the difference in RBE is around 20% only. These findings indicate that the biological effectiveness in A_L cells can give important information for human cells, especially for studies where attaching cells are essential.     

Comutagenesis of sodium arsenite with ultraviolet radiation in Chinese hamster V79 cells

Summary Solar ultraviolet radiation has been associated with the induction of skin cancer. Recent studies have indicated that near-ultraviolet, especially UVB, is mutagenic. Exposure to trivalent inorganic arsenic compounds has also been associated with increased skin cancer prevalence. Trivalent arsenic compounds are not mutagenicper se, but are comutagenic with a number of cancer agents. Here, we test the hypothesis that arsenite enhances skin cancer via its comutagenic action with solar ultraviolet radiation. Irradiation of Chinese hamster V79 cells with UVA (360 nm), UVB (310 nm) and UVC (254 nm) caused a fluence-dependent increase in mutations at thehprt locus. On an energy basis, UVC was the most mutagenic and UVA the least. However, when expressed as a function of toxicity, UVB was more mutagenic than UVC. Nontoxic concentrations of arsenite increased the toxicity of UVA, UVB and UVC. Arsenite acted as a comutagen at the three wavelengths; however, higher concentrations of arsenite were required to produce a significant (P < 0.05) comutagenic response with UVB. The increased mutagenicity of UVB and UVA by arsenite may play a role in arsenite-related skin cancers.     

Gene-mutation induction by arsenic compounds in the mouse lymphoma assay

Arsenic compounds are generally considered as poor inducers of gene mutations. To investigate the mutagenicity of several arsenic compounds at the thymidine kinase (Tk) gene, a reporter gene for mutation induction, we used the mouse lymphoma assay (MLA). This test is widely applied and detects a broad spectrum of mutational events, from point mutations to chromosome alterations. The selected arsenic compounds were two inorganic (sodium arsenite and arsenic trioxide) and four organic compounds (monomethylarsonic acid, dimethylarsinic acid, tetraphenylarsenium and arsenobetaine). The results show that sodium arsenite, arsenic trioxide, monomethylarsonic acid and dimethylarsinic acid are mutagenic, showing a clear dose–response pattern. On the other hand, tetraphenylarsenium and arsenobetaine are not mutagenic. Inorganic arsenic compounds are the more potent agents producing significant effects in the micromolar range, while the mutagenic organic arsenic compounds induce similar effects but in the millimolar range.     

Identification of an aox System That Requires Cytochrome c in the Highly Arsenic-Resistant Bacterium Ochrobactrum tritici SCII24

Microbial biotransformations have a major impact on environments contaminated with toxic elements, including arsenic, resulting in an increasing interest in strategies responsible for how bacteria cope with arsenic. In the present work, we investigated the metabolism of this metalloid in the bacterium Ochrobactrum tritici SCII24. This heterotrophic organism contains two different ars operons and is able to oxidize arsenite to arsenate. The presence of arsenite oxidase genes in this organism was evaluated, and sequence analysis revealed structural genes for an As(III) oxidase (aoxAB), a c-type cytochrome (cytC), and molybdopterin biosynthesis (moeA). Two other genes coding for a two-component signal transduction pair (aoxRS) were also identified upstream from the previous gene cluster. The involvement of aox genes in As(III) oxidation was confirmed by functionally expressing them into O. tritici 5bvl1, a non-As(III) oxidizer. Experiments showed that the As(III) oxidation process in O. tritici requires not only the enzyme arsenite oxidase but also the cytochrome c encoded in the operon. The fundamental role of this cytochrome c, reduced in the presence of arsenite in strain SCII24 but not in an O. tritici ΔaoxB mutant, is surprising, since to date this feature has not been found in other organisms. In this strain the presence of an aox system does not seem to confer an additional arsenite resistance capability; however, it might act as part of an As(III)-detoxifying strategy. Such mechanisms may have played a crucial role in the development of early stages of life on Earth and may one day be exploited as part of a potential bioremediation strategy in toxic environments.Arsenic is naturally present in soil, water, and air, and arsenic contamination of drinking water constitutes an important public health problem in numerous countries throughout the world (33). Arsenic occurs in nature in the oxidation states +5 (arsenate), +3 (arsenite), 0 (elemental arsenic), and −3 (arsine). Although arsenic is most notorious as a poison threatening human health, recent studies suggest that arsenic species may have been involved in the ancestral taming of energy and played a crucial role in early stages in the development of life on Earth (reviewed in reference 34). The two soluble arsenic species, arsenate [As(V) as H₂AsO₄⁻ and HAsO₄²⁻] and arsenite [As(III) as H₃AsO₃⁰ and H₂AsO₃⁻] are the most common forms and exhibit different toxicities for living organisms. Several studies have documented the role of bacteria on speciation and mobilization of arsenic in the environment (23). Microorganisms are known to influence arsenic geochemistry by their metabolism, i.e., reduction, oxidation, and methylation (for reviews, see references 5, 19, and 22), affecting both the speciation and the toxicity of this element. Arsenate is less toxic than arsenite, but paradoxically, resistance to As(V) requires its reduction to As(III), which is then extruded by an active efflux pump.Another well-documented arsenic transformation is the microbiological oxidation of arsenite to arsenate. This redox reaction is generally carried out by microorganisms either for detoxification or for energy generation to support cellular growth (23). The oxidation of As(III) by heterotrophic microorganisms is generally considered to be a detoxification strategy, since the microbes do not gain energy from this reaction (32). These heterotrophic As-oxidizing organisms include the most-studied Alcaligenes faecalis (3), Herminiimonas arsenoxidans (21), Thermus species (13, 14), Hydrogenophaga sp. strain NT-14 (35), and Agrobacterium tumefaciens (17). In contrast, other organisms have been described as autotrophic As(III) oxidizers able to use the energy gained from the oxidation reaction for growth. Autotrophic As(III) oxidation has been best studied in strain NT-26 (27, 28) but has also been reported for Thiomonas sp. (10), strain MLHE1 (24), and other environmental isolates (7, 16, 25, 26).Of the arsenite-oxidizing bacteria, A. faecalis (3), NT-26 (27), and NT-14 (35) have been studied in detail and their arsenite oxidases purified and characterized. Moreover, a crystal structure of the A. faecalis arsenite oxidase has been elucidated (11). Genes encoding As(III) oxidases (aox) have also been identified and sequenced in several organisms, showing a common genetic organization, aoxA-aoxB, that encodes the small and large subunits, respectively. These aox operons usually contain additional genes, e.g., cytC, which encodes a cytochrome c, and moeA, which encodes an enzyme involved in molybdenum cofactor biosynthesis (32).The genome exploration of the alphaproteobacterium Ochrobactrum tritici revealed that it possesses heretofore-unsuspected mechanisms for coping with arsenic. This work reports the identification of a locus involved in arsenic oxidation in a heterotrophic bacterium previously characterized as carrying two operons involved in arsenic resistance. One operon confers resistance to arsenite and antimonite, while the second one is responsible for resistance to arsenate.     

Hydraulic responses to height growth in maritime pine trees

As trees grow taller, decreased xylem path conductance imposes a major constraint on plant water and carbon balance, and is thus a key factor underlying forest productivity decline with age. The responses of stomatal conductance, leaf area: sapwood area ratio (A_L : A_S) and soil–leaf water potential gradient (ΔΨ_S–L) to height growth were investigated in maritime pine trees. Extensive measurements of in situ sap flow, stomatal conductance and (non‐gravitational) needle water potential (_L = Ψ_L ? ρ_wgh) were made during 2 years in a chronosequence of four even‐aged stands, under both wet and dry soil conditions. Under wet soil conditions, _L was systematically lower in taller trees on account of differences in gravitational potential. In contrast, under dry soil conditions, our measurements clearly showed that _L was maintained above a minimum threshold value of ?2.0 MPa independently of tree height, thus limiting the range of compensatory change in ΔΨ_S–L. Although a decrease in the A_L : A_S ratio occurred with tree height, this compensation was not sufficient to prevent a decline in leaf‐specific hydraulic conductance, K_L (50% lower in 30 m trees than in 10 m trees). An associated decline in stomatal conductance with tree height thus occurred to maintain a balance between water supply and demand. Both the increased investment in non‐productive versus productive tissues (A_S : A_L) and stomatal closure may have contributed to the observed decrease in tree growth efficiency with increasing tree height (by a factor of three from smallest to tallest trees), although other growth‐limiting responses (e.g. soil nutrient sequestration, increased respiratory costs) cannot be excluded.     

The genetic basis of anoxygenic photosynthetic arsenite oxidation

‘Photoarsenotrophy’, the use of arsenite as an electron donor for anoxygenic photosynthesis, is thought to be an ancient form of phototrophy along with the photosynthetic oxidation of Fe(II), H₂S, H₂ and . Photoarsenotrophy was recently identified from Paoha Island's (Mono Lake, CA) arsenic‐rich hot springs. The genomes of several photoarsenotrophs revealed a gene cluster, arxB2AB1CD, where arxA is predicted to encode for the sole arsenite oxidase. The role of arxA in photosynthetic arsenite oxidation was confirmed by disrupting the gene in a representative photoarsenotrophic bacterium, resulting in the loss of light‐dependent arsenite oxidation. In situ evidence of active photoarsenotrophic microbes was supported by arxA mRNA detection for the first time, in red‐pigmented microbial mats within the hot springs of Paoha Island. This work expands on the genetics for photosynthesis coupled to new electron donors and elaborates on known mechanisms for arsenic metabolism, thereby highlighting the complexities of arsenic biogeochemical cycling.     

Blood Biochemistry,Thyroid Hormones,and Oxidant/Antioxidant Status of Guinea Pigs Challenged with Sodium Arsenite or Arsenic Trioxide

The present experiment aimed to compare the two most commonly used compounds of arsenic (sodium arsenite and arsenic trioxide) for their effect on blood metabolites, thyroid hormones, and oxidant/antioxidant status in guinea pigs. Twenty-one adult guinea pigs were randomly divided into three equal groups. Animals in group T₁ (control) were fed a basal diet, whereas 50 ppm arsenic was added in the basal diet either as sodium arsenite (T₂) or arsenic trioxide (T₃) and fed for 11 weeks. Serum aspartate aminotransferase and alanine aminotransferase activities were significantly increased along with a decrease in blood hemoglobin level in both the arsenic-administered groups. The level of erythrocytic antioxidants (catalase, superoxide dismutase, reduced glutathione, glutathione-S-transferase, and glutathione reductase) was decreased and lipid peroxidation was elevated upon arsenic exposure. Serum thyroid hormone levels were reduced and arsenic levels in tissues increased in both the arsenic-exposed groups, irrespective of the arsenic compound. Thus, sodium arsenite and arsenic trioxide exerted similar adverse effects on blood metabolic profile, antioxidant status, and thyroid hormones in guinea pigs.     

Toxicity and metabolism of subcytotoxic inorganic arsenic in human renal proximal tubule epithelial cells (HK-2)

Arsenic is an environmental toxicant and a human carcinogen. The kidney, a known target organ of arsenic toxicity, is critical for both in vivo arsenic biotransformation and elimination. This study investigates the potential of an immortalized human proximal tubular epithelial cell line, HK-2, to serve as a representative model for low level exposures of the human kidney to arsenic. Subcytotoxic concentrations of arsenite (< or = 10 micromol/L) and arsenate (< 100 micromol/L) were determined by leakage of LDH from cells exposed for 24 h. Threshold concentrations of arsenite (between 1 and 10 micromol/L) and arsenate (between 10 and 25 micromol/L) were found to affect MTT processing by mitochondria. Biotransformation of subcytotoxic arsenite or arsenate was determined using HPLC-ICP-MS to detect metabolites in cell culture media and cell lysates. Following 24 h, analysis of media revealed that arsenite was minimally oxidized to arsenate and arsenate was reduced to arsenite. Only arsenite was detected in cell lysates. Pentavalent methylated arsenicals were not detected in media or lysates following exposure to either inorganic arsenical. The activities of key arsenic biotransformation enzymes--MMAV reductase and AsIII methyltransferase--were evaluated to determine whether HK-2 cells could reduce and methylate arsenicals. When compared to the activities of these enzymes in other animal tissues, the specific activities of HK-2 cells were indicative of a robust capacity to metabolize arsenic. It appears this human renal cell line is capable of biotransforming inorganic arsenic compounds, primarily reducing arsenate to arsenite. In addition, even at low concentrations, the mitochondria are a primary target for toxicity.     

Bacterial Degradation of N-Lauroyl-L-valine

Studies were conducted on the degradation of N-lauroyl-L-valine by type cultured bacteria. Many strains could utilize sodium N-lauroyl-L-valinate as carbon and nitrogen sources for their growth. Metabolism of N-lauroyl-L-valine was investigated in detail using Ps. aeruginosa AJ2116. Laurie acid was identified by gas chromatography suggesting cleavage of N-acyl linkage in N-lauroyl-L-valine.

Laurie acid might be metabolized to capric acid (C₁₀) and caprylic acid (C₈) becuase the accumulated substances gave nearly identical peaks with those of authentic fatty acids on gas chromatograms. The experiment using N-lauroyl-L-valine (¹⁴C) indicated that ¹⁴CO₂ was produced as a final product. Valine was not detected because it might be metabolized very rapidly immediately after its release.

It was supposed that the enzymes or enzyme systems degrading N-lauroyl-L-valine might be constitutive from the experiment using two kinds of cells grown in the medium containing N-lauroyl-L-valine or nutrient broth.     

A new aerobic chemolithoautotrophic arsenic oxidizing microorganism isolated from a high Andean watershed

Biological arsenic oxidation has been suggested as a key biogeochemical process that controls the mobilization and fate of this metalloid in aqueous environments. To the best of our knowledge, only four aerobic chemolithoautotrophic arsenite-oxidizing (CAO) bacteria have been shown to grow via direct arsenic oxidation and to have the essential genes for chemolithoautotrophic arsenite oxidation. In this study, a new CAO bacterium was isolated from a high Andean watershed evidencing natural dissolved arsenic attenuation. The bacterial isolate, designated TS-1, is closely related to the Ancylobacter genus, in the Alphaproteobacteria class. Results showed that TS-1 has genes for arsenite oxidation and carbon fixation. The dependence of bacterial growth from arsenite oxidation was demonstrated. In addition, a mathematical model was suggested and the kinetic parameters were obtained by simultaneously fitting the biomass growth, arsenite depletion curves, and arsenate production. This research increases the knowledge of chemolithoautotrophic arsenic oxidizing microorganisms and its potential role as a driver for natural arsenic attenuation.     

Heavy ion mutagenesis: Linear energy transfer effects and genetic linkage

We have characterized a series of 69 independent mutants at the endogenoushprt locus of human TK6 lymphoblasts and over 200 independent S 1-deficient mutants of the humanxhamster hybrid cell line A_L arising spontaneously or following low-fluence exposures to densely ionizing Fe ions (600 MeV/amu, linear energy transfer = 190 keV/µm). We find that large deletions are common. The entirehprt gene (>44 kb) was missing in 19/39 Fe-induced mutants, while only 2/30 spontaneous mutants lost the entirehprt coding sequence. When the gene of interest (S1 locus = M1C1 gene) is located on a nonessential human chromosome 11, multilocus deletions of several million base pairs are observed frequently. The S1 mutation frequency is more than 50-fold greater than the frequency ofhprt mutants in the same cells. Taken together, these results suggest that low-fluence exposures to Fe ions are often cytotoxic due to their ability to create multilocus deletions that may often include the loss of essential genes. In addition, the tumorigenic potential of these HZE heavy ions may be due to the high potential for loss of tumor suppressor genes. The relative insensitivity of thehprt locus to mutation is likely due to tight linkage to a gene that is required for viability.Invited paper presented at the International Symposium on Heavy Ion Research: Space, Radiation Protection and Therapy, Sophia-Antipolis, France, 21–24 March 1994     

Biological Responses to Arsenic Compounds

Arsenic is a metalloid that generates various biological effects on cells and tissues. Depending on the specific tissue exposed and the time and degree of exposure, diverse responses can be observed. In humans, prolonged and/or high dose exposure to arsenic can have a variety of outcomes, including the development of malignancies, severe gastrointestinal toxicities, diabetes, cardiac arrhythmias, and death. On the other hand, one arsenic derivative, arsenic trioxide (As₂O₃), has important antitumor properties. This agent is a potent inducer of antileukemic responses, and it is now approved by the Food and Drug Administration for the treatment of acute promyelocytic leukemia in humans. The promise and therapeutic potential of arsenic and its various derivatives have been exploited for hundreds of years. Remarkably, research focused on the potential use of arsenic compounds in the treatment of human diseases remains highly promising, and it is an area of active investigation. An emerging approach of interest and therapeutic potential involves efforts to target and block cellular pathways activated in a negative feedback manner during treatment of cells with As₂O₃. Such an approach may ultimately provide the means to selectively enhance the suppressive effects of this agent on malignant cells and render normally resistant tumors sensitive to its antineoplastic properties.Arsenic forms complexes with other elements, and it exists in inorganic and organic forms (1–3). The three major inorganic forms of arsenic are arsenic trisulfide (As₂S₃, yellow arsenic), arsenic disulfide (As₂S₂, red arsenic), and arsenic trioxide (As₂O₃, white arsenic) (1–3). There are two different oxidative states of arsenic that correlate with its cytotoxic potential, As(III) and As(V). Among them, As(III) is the most potent form and primarily accounts for its pro-apoptotic and inhibitory effects on target cells and tissues (3). The various forms of arsenic exist in nature primarily in a complex with pyrite (4, 5), although under certain circumstances, arsenic can dissociate from soil and enter natural waters (6), providing a contamination source for humans or animals who ingest such waters. In fact, most associations between long term exposure to arsenic and development of malignancies or other health disorders result from drinking contaminated water, especially in developing countries. Interestingly, pollution of the air with arsenic can also occur under certain circumstances, such as in the case of emissions from coal burning in China (7), providing an additional source of human exposure.The metabolism of arsenic in humans includes reduction to the trivalent state and oxidative methylation to the pentavalent state (reviewed in Ref. 2). There is also reduction of arsenic acid to the arsenous form and subsequent methylation (2). The generation of inorganic or organic trivalent arsenic forms has important implications with regard to the toxicity of this agent, as such compounds are more toxic to the cells and exhibit more carcinogenic properties (2, 3). Thus, many of the consequences of exposure to arsenic as discussed below are the result of the activities and toxicities of the various metabolic products of arsenic compounds. It should be also noted that arsenic has the ability to bind to reduced thiols, including sulfhydryl groups in some proteins (2). Depending on the cellular context, such protein targeting may explain some of its cellular effects and generation of its toxicities and/or therapeutic effects.     

Arsenic speciation in marine interstitial water. The occurrence of organoarsenicals

Arsenic speciation data are presented for pore waters squeezed from some native and anthropogenically influenced sediments.Ten stations were sampled with a box corer (to 20 cm) at two British Columbia coastal sites that are influenced by mine-tailings discharges. These are Rupert Inlet and Alice Arm as well as their associated systems of Quatsino Sound/Holberg Inlet and Hastings Arm respectively.Total dissolved arsenic concentrations (As _D) usually exhibited subsurface maxima at 5–10 cm and were generally related to solid phase arsenic (As _p) levels, but there was also a dependence on the nature of the substrate. Tailings exhibited both the lowest (Rupert Inlet) and the highest (Alice Arm) As _D values. Inorganic arsenicals, arsenate (AsV) and arsenite (AsIII) constituted the majority (>90%) of the dissolved species butevery sample contained organoarsenicals. This is the first report of mono-, di- and tri-methylated arsenic species in marine interstitial water.A strong positive correlation between the sum of the methylarsenic compounds (MeAs) and the total dissolved arsenic (As _D) was found, indicating in situ microbial methylation similar to that observed in non-aquatic systems. Flux values for arsenic at the sediment-water interface suggest that, at present, there is no significant mobilization of arsenic from these mine-derived sediments into the water column.