Concentrations Of Sodium Arsenite Research Articles

The Role of BNIP3 and Blocked Autophagy Flux in Arsenic-Induced Oxidative Stress-Induced Liver Injury in Rats.

Arsenic is a widely distributed environmental toxic substance in nature. Chronic arsenic exposure can cause permanent damage to the liver, resulting in the death of poisoned patients. However, the mechanism of liver damage caused by arsenic poisoning is yet unclear. Here, four different concentrations of sodium arsenite (NaAsO2) (0mg/L (control group), 25mg/L, 50mg/L, and 100mg/L group)were established to induce liver injury in rats. Taking this into account, the relationship and potential mechanisms of oxidative stress, Bcl-2/adenovirus E1B-19-kDa-interacting protein 3 (BNIP3), and inhibition of autophagy flux in liver injury caused by arsenic poisoning were studied. The results indicated that long-term exposure to NaAsO2 could induce oxidative stress, leading to high expression of BNIP3, thereby impaired autophagy flux, and ultimately resulting in liver damage. This research provides an important basis for future research on liver damage caused by chronic arsenic exposure and prevention and treatment with BNIP3 as the target.

Oxidative Stress Induced by Arsenite is Involved in YTHDF2 Phase Separation.

YTH N6-methyladenosine RNA binding protein 2 (YTHDF2) undergoes phase separation in response to the stimulation of high concentration of arsenite, suggesting that oxidative stress, the major mechanism of arsenite toxicity, may play a role in YTHDF2 phase separation. However, whether arsenite-induced oxidative stress is involved in phase separation of YTHDF2 has yet to be established. To explore the effect of arsenite-induced oxidative stress on YTHDF2 phase separation, the levels of oxidative stress, YTHDF2 phase separation, and N6-methyladenosine (m6A) in human keratinocytes were detected after exposure to various concentrations of sodium arsenite (0-500 µM; 1h) and antioxidant N-acetylcysteine (0-10 mM; 2h). We found that arsenite promoted oxidative stress and YTHDF2 phase separation in a concentration-dependent manner. In contrast, pretreatment with N-acetylcysteine significantly relieved arsenate-induced oxidative stress and inhibited YTHDF2 phase separation. As one of the key factors to YTHDF2 phase separation, N6-methyladenosine (m6A) levels in human keratinocytes were significantly increased after arsenite exposure, accompanied by upregulation of m6A methylesterase levels and downregulation of m6A demethylases levels. On the contrary, N-acetylcysteine mitigated the arsenite-induced increase of m6A and m6A methylesterase and the arsenite-induced decrease in m6A demethylase. Collectively, our study firstly revealed that oxidative stress induced by arsenite plays an important role in YTHDF2 phase separation driven by m6A modification, which provides new insights into the arsenite toxicity from the phase-separation perspective.

Long-term exposure to arsenic in drinking water leads to myocardial damage by oxidative stress and reduction in NO

Chronic arsenic exposure causes myocardial damage. The aim of this study is to investigate if oxidative stress and reduction in NO is involved in the myocardial damage induced by arsenic in drinking water. Rats were divided into a control group and different doses of sodium arsenite. With increasing sodium arsenite concentrations in drinking water, localised inflammatory foci and necrotic myocardial tissues were gradually observed. Compared to the control group, the activities and gene expression of antioxidant enzymes in arsenic-exposed rats decreased. NO content and the NOS activity as well as the expression of NOS mRNA in the myocardial tissue of exposed rats, decreased, and the extracellular NO content of cardiomyocytes treated with sodium arsenite also decreased. The rate of cell apoptosis induced by sodium arsenite decreased after treatment with sodium nitroprusside (an NO donor). In conclusion, arsenic exposure in drinking water can lead to myocardial injury and cardiomyocyte apoptosis through oxidative stress and a reduction in NO content.

Mechanism underlying the targeted regulation of the SOD1 3′UTR by the AUF1/Dicer1/miR-155/SOD1 pathway in sodium arsenite-induced liver injury

Arsenic (As) is a natural hepatotoxicity inducer that is ubiquitous in water, soil, coal, and food. Studies have found that arsenite exposure elicits increased mRNA transcription and decreased protein expression of SOD1 in vivo and in vitro; however, the specific mechanisms remain unclear. Here, we established a model of arsenic-induced chronic liver injury by providing rats with drinking water containing different concentrations of sodium arsenite (NaAsO2) and found that NaAsO2 exposure decreased the mRNA and protein levels of AUF1 and the protein level of SOD1 and elevated the mRNA and protein levels of Dicer1 and miR-155 and the mRNA level of SOD1. Overexpression of AUF1 under NaAsO2 stress in vitro induced Dicer1 mRNA and protein expression and decreased miR-155 levels, which could be reversed by AUF1 siRNA. In addition, miR-155 overexpression downregulated SOD1 mRNA and protein levels, although this change was inhibited after transfection with an miR-155 inhibitor. Taken together, our findings showed that NaAsO2 could upregulate Dicer1 mRNA and protein, thereby increasing miR-155 expression by downregulating AUF1 mRNA and protein expression. A dual-luciferase reporter assay indicated that miR-155 decreased the mRNA and protein levels of SOD1 by targeting the SOD1 3′UTR, resulting in liver injury. This study provides an important research basis for further understanding the factors underlying arsenic-induced liver injury to improve the prevention and control strategies for arsenism.

Behavior and respiration responses of the earthworm Eisenia fetida to soil arsenite pollution

Soil arsenic (As) pollution from mining and industrial sources is a serious issue in China. Earthworms are considered ecosystem engineers and contribute to soil fertility development and maintenance of soil physico-chemical properties. In this study, earthworms were exposed to soils with different sodium arsenite concentrations (0, 5, 20, and 80 mg As kg-1) for 60 d to investigate the changes in soil properties and the responses of the earthworms (e.g., burrowing activity and respiration). Earthworm burrowing activity decreased with increasing arsenite concentrations, and earthworm respiration was significantly lower in soils with 20 and 80 mg As kg-1 compared to 0 mg As kg-1. Changes in soil properties were also observed after incubation of As-amended soil with earthworms. Specifically, soil pH decreased, while soil electrical conductivity and contents of soil NO3– -N, Olsen-P, and available K increased. Our results suggest that arsenite negatively impacts the metabolic activity of earthworms, leading to reduced burrowing activity, which in turn modifies the effects of earthworms on soil fertility and remediation.

Epigenetic effects of low-level sodium arsenite exposure on human liver HepaRG cells.

Chronic exposure to inorganic arsenic is associated with a variety of adverse health effects, including lung, bladder, kidney, and liver cancer. Several mechanisms have been proposed for arsenic-induced tumorigenesis; however, insufficient knowledge and many unanswered questions remain to explain the integrated molecular pathogenesis of arsenic carcinogenicity. In the present study, using non-tumorigenic human liver HepaRG cells, we investigated epigenetic alterations upon prolonged exposure to a noncytotoxic concentration of sodium arsenite (NaAsO2). We demonstrate that continuous exposure of HepaRG cells to 1µM sodium arsenite (NaAsO2) for 14days resulted in substantial cytosine DNA demethylation and hypermethylation across the genome, among which the claudin 14 (CLDN14) gene was hypermethylated and the most down-regulated gene. Another important finding was a profound loss of histone H3 lysine 36 (H3K36) trimethylation, which was accompanied by increased damage to genomic DNA and an elevated de novo mutation frequency. These results demonstrate that continuous exposure of HepaRG cells to a noncytotoxic concentration of NaAsO2 results in substantial epigenetic abnormalities accompanied by several carcinogenesis-related events, including induction of epithelial-to-mesenchymal transition, damage to DNA, inhibition of DNA repair genes, and induction of de novo mutations. Importantly, this study highlights the intimate mechanistic link and interplay between two fundamental cancer-associated events, epigenetic and genetic alterations, in arsenic-associated carcinogenesis.

In vitro administration of sodium arsenite in mouse prepubertal testis induces germ cell loss and apoptosis

High levels of arsenic contamination in drinking water pose serious health risks in numerous countries. The documentation reporting arsenic toxicity on reproduction and development is increasing, with evidence of arsenic inducing fertility and developmental issues. Nonetheless, the impact of arsenic exposure on the development of the male reproductive system is not fully elucidated. In the present study, we have investigated the direct effects of arsenic on prepubertal mouse testis using an in vitro testicular organ culture system. Culture medium was supplemented with a range of concentrations of sodium arsenite, examining effects of low (0.5 and 1 μM) and high (10, 50, 100 μM) concentrations, in cultures of post-natal day 5 CD1 mouse testis. In vitro exposure of low arsenic concentrations (0.5 or 1 μM) for 6 days did not cause any change in the testicular morphology, germ cells density, or apoptotic marker cleaved caspase 3 (CC3) expression. In contrast, exposure of prepubertal testis to high arsenic concentrations (10, 50 or 100 μM) induced drastic changes: severe destruction of testicular morphology, with loss of seminiferous tubule integrity; a dose-dependent decrease in germ cell density, and a hundred-fold increase in CC3 expression after 50 μM arsenic exposure. In conclusion, high arsenic treatment induced a dose-dependent induction of apoptosis and germ cell loss in prepubertal mouse testis.

Fungi and Arsenic: Tolerance and Bioaccumulation by Soil Saprotrophic Species

Increasing arsenic environmental concentrations are raising worldwide concern for its impacts on human health and ecosystem functionality. In order to cope with arsenic contamination, bioremediation using fungi can represent an efficient, sustainable, and cost-effective technological solution. Fungi can mitigate arsenic contamination through different mechanisms including bioaccumulation. In this work, four soil saprotrophic fungi Absidia spinosa, Purpureocillium lilacinum, Metarhizium marquandii, and Cephalotrichum nanum, isolated from soils with naturally high arsenic concentrations, were tested for their ability to tolerate different sodium arsenite concentrations and accumulate As in different cultural conditions. pH medium after fungal growth was measured to study pH variation and metabolic responses. Arsenic bioaccumulation and its influence on the uptake of other elements were investigated through multi-elemental analysis using hydride generation atomic fluorescence spectrometry (HG-AFS), inductively coupled plasma mass spectrometry (ICP-MS) and inductively coupled plasma optical emission spectroscopy (ICP-OES). Considering the increasing interest in siderophore application for metal bioremediation, the production of siderophores and their affinity for both Fe and As were also evaluated. All species were able to tolerate and accumulate As in their biomass in all of the tested conditions and produced siderophores with different affinities for Fe and As. The results suggest that the tested fungi are attractive potential candidates for the bioremediation of As contaminated soil and worthy of further investigation.

Mitigation of aflatoxin B1- and sodium arsenite-induced cytotoxicities in HUC-PC urinary bladder cells by curcumin and Khaya senegalensis.

Background Concomitant exposure to environmental/occupational toxicants such as aflatoxin B1 (AFB1) and arsenic in some regions of the world has been well reported. Therefore, this calls for the assessment of the efficacy of agents such as phytochemicals, which are already known for their ethno-medicinal uses in prophylaxis/remediation. We investigated the possible cytotoxic bio-interactions between AFB1 and sodium arsenite (SA) in urinary bladder cells. We also assessed the cytoprotective effects of curcumin and the ethanol stem bark extract of Khaya senegalensis (K2S). Methods The cells were exposed to graded levels of AFB1, SA, curcumin, and K2S for 24, 48, and 72 h. Subsequently, using optimum toxic concentrations of AFB1 and SA, respectively, the influence of non-toxic levels of curcumin and/or K2S was tested on exposure of the cells to AFB1 and/or SA. Hoechst 33342/propidium iodide staining technique was used to determine the end-points due to cytotoxicity with changes in adenosine triphosphate (ATP) levels determined using Promega's CellTiter-Glo luminescent assay. Results Co-treatment of the cells with AFB1 and SA resulted in synergy in cytotoxic effects. Cytotoxicity was reduced by 3.5- and 2.9-fold by pre-treatment of the cells with curcumin and K2S before treatment with AFB1, while post-treatment resulted in 1.1- and 2.6-fold reduction, respectively. Pre-exposure of the cells with curcumin and K2S before treatment with SA ameliorated cytotoxicity by 3.8- and 3.0-fold, but post-treatment caused a 1.2- and 1.3-fold reduction, respectively. Conclusions Pre-treatment of the cells with either curcumin or K2S exhibited cytoprotective effects by ameliorating AFB1- and SA-induced cytotoxicity with inferred tendencies to prevent carcinogenesis.

Phytotoxicity of Arsenite on Early Seedling Growth of Mung Bean: A Threat to Potential Pulse Cultivation

Arsenic toxicity has gained at present an alarming global importance. Pulse crop is very sensitive to arsenic contaminated groundwater. In order to determine the phytotoxicity, effects of Sodium arsenite (NaAsO2) on seed germination and early development of Mung bean (Vigna radiata (L.) Wilczek cv. B-105) seedlings were investigated. Sodium arsenite had a toxic effect and posed a stress over germination parameters and early growth of mungbean seedlings. Considerable reduction in seed germination percentage and seedling vigour index was recorded due to arsenite. Sodium arsenite inhibited growth at very small concentrations such as 0.5µM. With the increase in concentration of sodium arsenite (0.5µM, 1µM, 2µM), significant decrease in seedling length i.e., shoot length and root length was observed. Arsenite was found to be more toxic for root growth than for shoot growth. Decrease in primary leaf area was also observed with increase in concentration of sodium arsenite. Number of stomata decreased and hence, reduction in stomatal density and stomatal index was also observed. Fresh weight and dry weight also reduced appreciably in the arsenite stressed seedlings. Treatment with 2µM concentration proved to be the most sensitive concentration for arsenite application by giving least values for seedling length and seedling vigour index.

Low concentrations of sodium arsenite induce hepatotoxicity in prepubertal male rats.

Arsenic (As) can contaminate air, soil, water, and organisms through mobilization of natural mineralogical deposits or anthropogenic actions. Inorganic-As compounds are more toxic and widely available in aquatic environments, including drinking water reservoir catchments. Since little is known about its effects on prepubertal mammals, the present study focused on it. Hence, As was administered through drinking water to male Wistar rats from postnatal day 23 to 53. Negative control group received vehicle only (filtered water); As 1 group received AsNaO2 at 0.01 mg L-1 and As2 group received AsNaO2 at 10 mg L-1 . It was investigated hepatic and renal toxicity of AsNaO2 (ie, histopathology and apoptosis analysis), as well as its mutagenicity (ie, micronucleus test in liver and bone marrow), cytotoxicity (ie, frequency and type of erythrocytes in blood), and genotoxicity (ie, comet assay in blood). Also, As determination was performed in hepatic and renal tissues. Data obtained revealed that immature organisms present a pattern of arsenic accumulation similar to that observed in adults, suggesting similarity in metabolic processes. In addition, liver showed to be an important target tissue for As toxicity in these experimental conditions, exhibiting infiltrate of defense cells, DNA damages, and increased apoptosis rates.

Role of mitochondrial DNA in oxidative damage induced by sodium arsenite in human bronchial epithelial cells

ABSTRACTLong-term exposure to sodium arsenite was found to induce malignant transformation in human bronchial epithelial (HBE) cell line as evidenced by elevated ROS levels. Although chronic sodium arsenite-induced HBE cell line transformation was associated with elevated ROS generation, it was of interest to determine whether acute sodium arsenite exposure also initiated pulmonary damage. Thus, the aim of this study was to investigate oxidative-stress-related pulmonary damage using a human bronchial epithelial (HBE) cell line. Incubation of ρ+-HBE (in the presence of mitochondrial DNA) cells with various concentrations of sodium arsenite, significantly increased ROS and MDA levels accompanied by decreased SOD activity in a concentration-dependent manner. In contrast, treatment of ρ–HBE (without mitochondrial DNA) cells various concentrations of sodium arsenite a reduction in ROS and MDA levels were noted. However, the SOD activity remained decreased in ρ–HBE cells. This was accompanied by a significant rise in HO-1 protein expressions levels in both cell types with greater changes ρ–HBE cells at the lower sodium arsenite concentrations. Data indicate that acute sodium arsenite exposure exerted a greater effect ρ–HBE cells suggesting that absence of mitochondrial DNA appears to enhance sensitivity to the oxidant actions of inorganic As.

Sufficiency of hypoxia-inducible 2-oxoglutarate dioxygenases to block chemical oxidative stress-induced differentiation of human embryonic stem cells

Hypoxia benefits undifferentiated pluripotent stem cell renewal, and 2-oxoglutarate (2OG) dioxygenases have been implicated in pluripotent stem cell induction and renewal. We show in human embryonic stem cells (hESC) that an ambient oxygen-induced oxidative stress response elicited by culture in a hypoxic atmosphere (0.5% O2) correlates with the expression of 2OG dioxygenases, which oxidise DNA (TET1, 2, 3) and histone H3 (KDM4C), the former reflected by elevation in genomic 5-hydroxymethylcytosine (5hmC). siRNA-mediated targeting of KDM4C and TET1–3 induces hESC differentiation. Under ambient atmospheric oxygen (21% O2), exposure to a low inhibitory concentration of sodium arsenite (NaAsO2, IC10), as a model of chemically-induced oxidative stress, suppresses antioxidant gene expression, reduces mitochondrial membrane potential and induces hESC differentiation. Co-administration of the antioxidant N-acetyl-L-cysteine promoted anti-oxidant, pluripotency and 2OG dioxygenase gene expression, elevated genomic hydroxymethylation and blocked induction of differentiation. Transient ectopic expression of KDM4C or TET1 in ambient atmospheric oxygen achieved the same. Our study substantiates a role for 2OG-dependent dioxygenases in hypoxia's promotion of undifferentiated hESC self-renewal.

Sodium arsenite-induced detriment of cell function in Leydig and Sertoli cells: the potential relation of oxidative damage and antioxidant defense system

Arsenic is commonly found in the natural environment and is toxic agent for living organism in many countries in the world. Studies on animal models suggest that exposure to arsenic may cause reproductive toxicity; however, effect of arsenic on reproductive toxicity has still not been clearly described. This study was focused on cytotoxicity, oxidative stress, and the antioxidant defense system induced with exposure to sodium arsenite in Mus musculus Leydig and Sertoli cells. The cells were exposed to two different concentrations of sodium arsenite of 50 ppb (0.4 μM) and 1000 ppb (7.7 μM) for 24, 48, and 72 h. Following the exposure time, cell viability, cell proliferation, and lactate dehydrogenase (LDH) activity were determining using colorimetric method. Also, we evaluated oxidative stress markers such as glutathione (GSH), lipid peroxidation, hydroxyl radical, hydrogen peroxide levels, and cellular enzymatic antioxidants such as catalase (CAT), superoxide dismutase (SOD), glutathione peroxidase (GPx), glutathione-s-transferase, and γ-glutamyl transpeptidase (γ-GT). As a result, sodium arsenite exposure in Leydig and Sertoli cells caused cellular cytotoxicity and downregulated the antioxidant defense system by inducing oxidative stress depending on concentration and time. Furthermore, this study demonstrated that when compared with Sertoli cells, Leydig cells were more affected by arsenite toxicity.

Toxicity of arsenite to earthworms and subsequent effects on soil properties

Arsenic (As) is widely distributed in soil and is toxic to plants, animals and humans. In this study, earthworms (Eisenia fetida) were exposed to five concentrations of sodium arsenite (5, 10, 20, 40, and 80 mg As kg−1) in farm soils for 28 d. With increasing soil As(III) concentrations, As bioaccumulation in earthworms increased (maximum bioaccumulation factor 3.77), and levels of reactive oxygen species (ROS) and malondialdehyde (MDA) were elevated. The expression of nuclear factor erythroid 2- related factor 2 (Nrf2) and heme oxygenase -1 (HO-1) were upregulated by As in a dose-dependent pattern, and reached 5.93 and 2.94 times the control values for Nrf2 and HO-1 respectively, at 28 d in the 80 mg As kg−1 soil treatment. Similarly, DNA damage, as measured in earthworm sperm using the comet assay, increased with increasing As(III) concentrations, with ‘Olive tail moment’ values in the comet assay ranging from c. 0.5 in Control to c. 3.5 at 80 mg As kg−1 soil. In contrast, activity of the antioxidant enzymes, superoxide dismutase (SOD) and catalase (CAT), decreased. These results indicate that As(III) caused oxidative stress that resulted in damage to lipids and DNA. Nrf2 and HO-1 protein expression was demonstrated in earthworms for the first time to our knowledge, and found to be a sensitive biomarker of arsenic contamination. The presence of earthworms was also found to change the distribution of As in soil, in particular, reducing the proportion in the residual fraction and increasing the proportion in As bound to Fe-oxides. This may result in increased bioavailability of bound arsenic. Soil organic matter, NH4+-N, NO3−-N and available K were indirectly changed by the As(III) through its toxicity to earthworms. This study helps to inform future assessments and biomonitoring of soil arsenic contamination.

Low dose arsenite confers resistance to UV induced apoptosis via p53-MDM2 pathway in ketatinocytes

Chronic arsenite and ultraviolet (UV) exposure are associated with skin tumor. To investigate the details by low concentrations of arsenite and UV induced carcinogenesis in skin, hTERT-immortalized human keratinocytes were used as a cellular model with exposure to low concentrations of sodium arsenite and UV. The effect of NaAsO2 on UV treatment-induced apoptosis was measured by flow cytometry and Hoechst staining. We found that the cell apoptosis induced by UV exposure was significantly attenuated after exposure to low-dose arsenite, and knockdown of p53 could block UV-induced apoptosis indicating that this phenomenon depended on p53. Interestingly, the expression of murine double minute 2 (MDM2), including its protein and transcriptional levels, was remarkably high after exposure to low-dose arsenite. Moreover, low-dose arsenite treatment dramatically decreased the MDM2 gene promoter activity, suggesting that this effect has been mediated through transcription. In addition, treatment of PD98059 reversed low-dose arsenite-induced MDM2 expression, and the inhibition of ERK2 expression could significantly block MDM2 expression as a consequence, and p53 expression automatically was increased. To validate the role of p53 in exposure to low-dose arsenite, the expression of p53 was examined by immunohistochemistry in the skin of Sprague−Dawley rats model by chronic arsenite exposure for 6 months and in patients with arsenic keratosis, and the results showed that the expression of p53 was decreased in those samples. Taken together, our results demonstrated that low-dose arsenite-induced resistance to apoptosis through p53 mediated by MDM2 in keratinocytes.

The effect of arsenite on spatial learning: Involvement of autophagy and apoptosis

Spatial learning plays a major role in one's information recording. Arsenic is one of ubiquitous environmental toxins with known neurological effects. However, studies investigating the effects of arsenic on spatial learning and related mechanisms are limited. This study was planned toexaminethe effects of bilateral intra-hippocampal infusion of different concentrations of sodium arsenite (5, 10 and 100nM, 5µl/side) on spatial learning in Wistar rats. Moreover, we evaluated levels of LC3-II, Atg7 and Atg12 as reliable biomarkers of autophagy and caspase-3 and Bax/Bcl-2 ratio as indicators of apoptosis in the hippocampus. Interestingly, low concentrations of sodium arsenite (5 and 10nM) significantly increased spatial acquisition but pre-training administration of sodium arsenite100nM did not significantly alter spatial learning. LC3-II levels were significantly increased in groups treated with sodium arsenite 5 and 10nM and decreased in the group receiving arsenite 100nM compared to the control group. Atg7 and Atg12 levels were obviously higher in all groups treated with sodium arsenite compared to control. However, caspase-3 cleavage and Bax/Bcl-2 ratio were notably greater in 100nM, and lesser in 5nM arsenite group in comparison with control animals.The results of this study showed that the low concentrations of sodium arsenite could facilitate spatial learning. This facilitation could be attributed to neuronal autophagy induced by low concentrations of sodium arsenite. These findings may help to clarify the regulatory pathways for apoptosis and autophagy balance due to sodium arsenite.

How sodium arsenite improve amyloid β-induced memory deficit?

Evidence has shown that arsenic exposure, besides its toxic effects results in impairment of learning and memory, but its molecular mechanisms are not fully understood. In the present study, we examined sodium arsenite (1, 5, 10, 100nM) effects on contextual and tone memory of male rats in Pavlovian fear conditioning paradigm alone and in co-administration with β-amyloid. We detected changes in the level of caspase-3, nuclear factor kappa-B (NF-κB), cAMP response element-binding (CREB), heme oxygenase-1 and NF-E2-related factor-2 (Nrf2) by Western blot. Sodium arsenite in high doses induced significant memory impairment 9 and 16days after infusion. By contrast, low doses of sodium arsenite attenuate memory deficit in Aβ injected rats after 16days. Our data revealed that treatment with high concentration of sodium arsenite increased caspase-3 cleavage and NF-κB level, 9days after injection. Whereas, low doses of sodium arsenite cause Nrf2 and HO-1 activation and increased CREB phosphorylation in the hippocampus. These findings suggest the concentration dependent effects of sodium arsenite on contextual and tone memory. Moreover, it seems that the neuroprotective effects of ultra-low concentrations of sodium arsenite on Aβ-induced memory impairment is mediated via an increase Nrf2, HO-1 and CREB phosphorylation levels and decrease caspase-3 and NF-κB amount.

YAP, A Component of the Hippo Pathway, is Essential for Antioxidant Defense

The highly conserved Hippo signaling pathway which negatively regulates cell growth and survival is a key regulator of organ size and tumorigenesis. Emerging evidence suggests the important role of Hippo pathway in response to oxidative stress. However the mechanism was rarely explored. Here we reported that YAP protein, which is the terminal effector of Hippo signaling pathway, shuttled between cytoplasm and nucleus following different concentration of sodium arsenite treatment, thereby controlling cell death or survival under arsenite-induced oxidative stress. Low concentration of sodium arsenite inhibited phosphorylation of YAP S127 and promoted YAP translocation to nucleus, thus further enhanced cell proliferation. However, high concentration of sodium arsenite augmented phosphorylation of YAP at S127 and induced translocation of YAP into cytoplasm and further caused cell apoptosis. These results suggest that YAP translocation plays an important role in deciding cell fate under arsenite-induced oxidative stress.

Synergistic effect of radon and sodium arsenite on DNA damage in HBE cells.

Human epidemiological studies showed that radon and arsenic exposures are major risk factors for lung cancer in Yunnan tin miners. However, biological evidence for this phenomenon is absent. In this study, HBE cells were exposed to different concentrations of sodium arsenite, different radon exposure times, or a combination of these two factors. The results showed a synergistic effect of radon and sodium arsenite in cell cytotoxicity as determined by cell viability. Elevated intracellular ROS levels and increased DNA damage indexed by comet assay and γ-H2AX were detected. Moreover, DNA HR repair in terms of Rad51 declined when the cells were exposed to both radon and sodium arsenite. The synergistic effect of radon and sodium arsenite in HBE cells may be attributed to the enhanced DSBs and inhibited HR pathway upon co-exposure.