Comparative proteomic analysis reveals heart toxicity induced by chronic arsenic exposure in rats

DEFF Research Database (Denmark)

Huang, Qingyu; Xi, Guochen; Alamdar, Ambreen

2017-01-01

Arsenic is a widespread metalloid in the environment, which poses a broad spectrum of adverse effects on human health. However, a global view of arsenic-induced heart toxicity is still lacking, and the underlying molecular mechanisms remain unclear. By performing a comparative quantitative...... proteomic analysis, the present study aims to investigate the alterations of proteome profile in rat heart after long-term exposure to arsenic. As a result, we found that the abundance of 81 proteins were significantly altered by arsenic treatment (35 up-regulated and 46 down-regulated). Among these, 33...... proteins were specifically associated with cardiovascular system development and function, including heart development, heart morphology, cardiac contraction and dilation, and other cardiovascular functions. It is further proposed that the aberrant regulation of 14 proteins induced by arsenic would disturb...

Curcumin attenuates harmful effects of arsenic on neural stem/progenitor cells

Directory of Open Access Journals (Sweden)

Ali Jahanbazi Jahan-Abad

2017-06-01

Full Text Available Objective: Arsenic, an environmental pollutant, decreases neuronal migration as well as cellular maturation and inhibits the proliferation of neural progenitor cells. Curcumin has been described as an antioxidant and neuroprotective agent with strong therapeutic potential in some neurological disorders. Human adipose-derived stem cells (hADSCs, a source of multipotent stem cells, can self-renew and differentiate into neural cells. The aim of the present study was to investigate the preventive effect of curcumin against arsenic toxic effects on the viability, telomerase activity, and apoptosis of neural stem/progenitor cells (NSPCs derived from hADSCs. Materials and Methods: The characteristics of human adipose tissue were identified by immunocytochemistry for surface markers namely, CD105, CD73, and CD90. Using neurosphere assay, hADSCs were differentiated into neuronal cells. To characterize neural cells, expression of nestin, SOX2, MAP2, and GFAP were assessed by immunocytochemistry. Cytotoxicity and viability of NSPCs were evaluated by MTT assay. Reactive oxygen species (ROS generated by arsenic exposure, were measured and caspase 3/7 activity and caspase-3 processing as well as the telomerase activity were determined. Results: The isolated hADSCs positively expressed CD105, CD73, and CD90. Nestin, Sox2, GFAP, and MAP2 were expressed in the neurospheres derived from hADSCs. Curcumin/arsenic co-treatment significantly increased telomerase activity of NSPCs compared to arsenic group. Furthermore, curcumin significantly reduced arsenic-induced apoptosis (via inactivation of caspases as well as arsenic-associated ROS generation. Conclusion: Our findings revealed that curcumin has the potential to prevent harmful effects of arsenic on neurogenesis.

Arsenic-Induced Genotoxicity and Genetic Susceptibility to Arsenic-Related Pathologies

Directory of Open Access Journals (Sweden)

Fabrizio Bianchi

2013-04-01

Full Text Available The arsenic (As exposure represents an important problem in many parts of the World. Indeed, it is estimated that over 100 million individuals are exposed to arsenic, mainly through a contamination of groundwaters. Chronic exposure to As is associated with adverse effects on human health such as cancers, cardiovascular diseases, neurological diseases and the rate of morbidity and mortality in populations exposed is alarming. The purpose of this review is to summarize the genotoxic effects of As in the cells as well as to discuss the importance of signaling and repair of arsenic-induced DNA damage. The current knowledge of specific polymorphisms in candidate genes that confer susceptibility to arsenic exposure is also reviewed. We also discuss the perspectives offered by the determination of biological markers of early effect on health, incorporating genetic polymorphisms, with biomarkers for exposure to better evaluate exposure-response clinical relationships as well as to develop novel preventative strategies for arsenic- health effects.

Barium inhibits arsenic-mediated apoptotic cell death in human squamous cell carcinoma cells.

Science.gov (United States)

Yajima, Ichiro; Uemura, Noriyuki; Nizam, Saika; Khalequzzaman, Md; Thang, Nguyen D; Kumasaka, Mayuko Y; Akhand, Anwarul A; Shekhar, Hossain U; Nakajima, Tamie; Kato, Masashi

2012-06-01

Our fieldwork showed more than 1 μM (145.1 μg/L) barium in about 3 μM (210.7 μg/L) arsenic-polluted drinking well water (n = 72) in cancer-prone areas in Bangladesh, while the mean concentrations of nine other elements in the water were less than 3 μg/L. The types of cancer include squamous cell carcinomas (SCC). We hypothesized that barium modulates arsenic-mediated biological effects, and we examined the effect of barium (1 μM) on arsenic (3 μM)-mediated apoptotic cell death of human HSC-5 and A431 SCC cells in vitro. Arsenic promoted SCC apoptosis with increased reactive oxygen species (ROS) production and JNK1/2 and caspase-3 activation (apoptotic pathway). In contrast, arsenic also inhibited SCC apoptosis with increased NF-κB activity and X-linked inhibitor of apoptosis protein (XIAP) expression level and decreased JNK activity (antiapoptotic pathway). These results suggest that arsenic bidirectionally promotes apoptotic and antiapoptotic pathways in SCC cells. Interestingly, barium in the presence of arsenic increased NF-κB activity and XIAP expression and decreased JNK activity without affecting ROS production, resulting in the inhibition of the arsenic-mediated apoptotic pathway. Since the anticancer effect of arsenic is mainly dependent on cancer apoptosis, barium-mediated inhibition of arsenic-induced apoptosis may promote progression of SCC in patients in Bangladesh who keep drinking barium and arsenic-polluted water after the development of cancer. Thus, we newly showed that barium in the presence of arsenic might inhibit arsenic-mediated cancer apoptosis with the modulation of the balance between arsenic-mediated promotive and suppressive apoptotic pathways.

Possible mechanisms for arsenic-induced proliferative diseases

Energy Technology Data Exchange (ETDEWEB)

Wetterhahn, K.E.; Dudek, E.J.; Shumilla, J.A. [Dartmouth College and Medical School, Hanover, NH (United States)] [and others

1996-12-31

Possible mechanisms for cardiovascular diseases and cancers which have been observed on chronic exposure to arsenic have been investigated. We tested the hypothesis that nonlethal levels of arsenic are mitogenic, cause oxidative stress, increase nuclear translocation of trans-acting factors, and increase expression of genes involved in proliferation. Cultured porcine vascular (from aorta) endothelial cells were used as a model cell system to study the effects of arsenic on the target cells for cardiovascular diseases. Treatment of postconfluent cell cultures with nonovertly toxic concentrations of arsenite increased DNA synthesis, similar to the mitogenic response observed with hydrogen peroxide. Within 1 hour of adding noncytotoxic concentrations of arsenite, cellular levels of oxidants increased relative to control levels, indicating that arsenite promotes cellular oxidations. Arsenite treatment increased nuclear translocation of NF-{kappa}B, an oxidative stress-responsive transcription factor, in a manner similar to that observed with hydrogen peroxide. Pretreatment of intact cells with the antioxidants N-acetylcysteine and dimethylfumarate prevented the arsenite-induced increases in cellular oxidant formation and NF-KB translocation. Arsenite had little or no effect on binding of NF-KB to its DNA recognition sequence in vitro, indicating that it is unlikely that arsenite directly affects NF-KB. The steady-state mRNA levels of intracellular adhesion molecule and urokinase-like plasminogen activator, genes associated with the active endothelial phenotype in arteriosclerosis and cancer metastasis, were increased by nontoxic concentrations of arsenite. These data suggest that arsenite promotes proliferative diseases like heart disease and cancer by activating oxidant-sensitive endothelial cell signaling and gene expression. It is possible that antioxidant therapy would be useful in preventing arsenic-induced cardiovascular disease and cancer.

Deficiency in the nuclear factor E2-related factor 2 renders pancreatic β-cells vulnerable to arsenic-induced cell damage

International Nuclear Information System (INIS)

Yang, Bei; Fu, Jingqi; Zheng, Hongzhi; Xue, Peng; Yarborough, Kathy; Woods, Courtney G.; Hou, Yongyong; Zhang, Qiang; Andersen, Melvin E.; Pi, Jingbo

2012-01-01

Chronic human exposure to inorganic arsenic (iAs), a potent environmental oxidative stressor, is associated with increased prevalence of type 2 diabetes, where impairment of pancreatic β-cell function is a key pathogenic factor. Nuclear factor E2-related factor 2 (Nrf2) is a central transcription factor regulating cellular adaptive response to oxidative stress. However, persistent activation of Nrf2 in response to chronic oxidative stress, including inorganic arsenite (iAs 3+ ) exposure, blunts glucose-triggered reactive oxygen species (ROS) signaling and impairs glucose-stimulated insulin secretion (GSIS). In the current study, we found that MIN6 pancreatic β-cells with stable knockdown of Nrf2 (Nrf2-KD) by lentiviral shRNA and pancreatic islets isolated from Nrf2-knockout (Nrf2−/−) mice exhibited reduced expression of several antioxidant and detoxification enzymes in response to acute iAs 3+ exposure. As a result, Nrf2-KD MIN6 cells and Nrf2−/− islets were more susceptible to iAs 3+ and monomethylarsonous acid (MMA 3+ )-induced cell damage, as measured by decreased cell viability, augmented apoptosis and morphological change. Pretreatment of MIN6 cells with Nrf2 activator tert-butylhydroquinone protected the cells from iAs 3+ -induced cell damage in an Nrf2-dependent fashion. In contrast, antioxidant N‐acetyl cysteine protected Nrf2-KD MIN6 cells against acute cytotoxicity of iAs 3+ . The present study demonstrates that Nrf2-mediated antioxidant response is critical in the pancreatic β-cell defense mechanism against acute cytotoxicity by arsenic. The findings here, combined with our previous results on the inhibitory effect of antioxidants on ROS signaling and GSIS, suggest that Nrf2 plays paradoxical roles in pancreatic β-cell dysfunction induced by environmental arsenic exposure. -- Highlights: ► Lack of Nrf2 reduced expression of antioxidant genes induced by iAs 3+ in β-cells. ► Deficiency of Nrf2 in β-cells sensitized to iAs 3+ and MMA 3

Deficiency in the nuclear factor E2-related factor 2 renders pancreatic β-cells vulnerable to arsenic-induced cell damage

Energy Technology Data Exchange (ETDEWEB)

Yang, Bei [Institute for Chemical Safety Sciences, The Hamner Institutes for Health Sciences, 6 Davis Drive, Research Triangle Park, NC 27709 (United States); Department of Histology and Embryology, College of Basic Medical Sciences, China Medical University, Shenyang 110001 (China); Fu, Jingqi; Zheng, Hongzhi; Xue, Peng; Yarborough, Kathy; Woods, Courtney G.; Hou, Yongyong; Zhang, Qiang; Andersen, Melvin E. [Institute for Chemical Safety Sciences, The Hamner Institutes for Health Sciences, 6 Davis Drive, Research Triangle Park, NC 27709 (United States); Pi, Jingbo, E-mail: jpi@thehamner.org [Institute for Chemical Safety Sciences, The Hamner Institutes for Health Sciences, 6 Davis Drive, Research Triangle Park, NC 27709 (United States)

2012-11-01

Chronic human exposure to inorganic arsenic (iAs), a potent environmental oxidative stressor, is associated with increased prevalence of type 2 diabetes, where impairment of pancreatic β-cell function is a key pathogenic factor. Nuclear factor E2-related factor 2 (Nrf2) is a central transcription factor regulating cellular adaptive response to oxidative stress. However, persistent activation of Nrf2 in response to chronic oxidative stress, including inorganic arsenite (iAs{sup 3+}) exposure, blunts glucose-triggered reactive oxygen species (ROS) signaling and impairs glucose-stimulated insulin secretion (GSIS). In the current study, we found that MIN6 pancreatic β-cells with stable knockdown of Nrf2 (Nrf2-KD) by lentiviral shRNA and pancreatic islets isolated from Nrf2-knockout (Nrf2−/−) mice exhibited reduced expression of several antioxidant and detoxification enzymes in response to acute iAs{sup 3+} exposure. As a result, Nrf2-KD MIN6 cells and Nrf2−/− islets were more susceptible to iAs{sup 3+} and monomethylarsonous acid (MMA{sup 3+})-induced cell damage, as measured by decreased cell viability, augmented apoptosis and morphological change. Pretreatment of MIN6 cells with Nrf2 activator tert-butylhydroquinone protected the cells from iAs{sup 3+}-induced cell damage in an Nrf2-dependent fashion. In contrast, antioxidant N‐acetyl cysteine protected Nrf2-KD MIN6 cells against acute cytotoxicity of iAs{sup 3+}. The present study demonstrates that Nrf2-mediated antioxidant response is critical in the pancreatic β-cell defense mechanism against acute cytotoxicity by arsenic. The findings here, combined with our previous results on the inhibitory effect of antioxidants on ROS signaling and GSIS, suggest that Nrf2 plays paradoxical roles in pancreatic β-cell dysfunction induced by environmental arsenic exposure. -- Highlights: ► Lack of Nrf2 reduced expression of antioxidant genes induced by iAs{sup 3+} in β-cells. ► Deficiency of Nrf2 in β-cells

The potential biological mechanisms of arsenic-induced diabetes mellitus

International Nuclear Information System (INIS)

Tseng, C.-H.

2004-01-01

Although epidemiologic studies carried out in Taiwan, Bangladesh, and Sweden have demonstrated a diabetogenic effect of arsenic, the mechanisms remain unclear and require further investigation. This paper reviewed the potential biological mechanisms of arsenic-induced diabetes mellitus based on the current knowledge of the biochemical properties of arsenic. Arsenate can substitute phosphate in the formation of adenosine triphosphate (ATP) and other phosphate intermediates involved in glucose metabolism, which could theoretically slow down the normal metabolism of glucose, interrupt the production of energy, and interfere with the ATP-dependent insulin secretion. However, the concentration of arsenate required for such reaction is high and not physiologically relevant, and these effects may only happen in acute intoxication and may not be effective in subjects chronically exposed to low-dose arsenic. On the other hand, arsenite has high affinity for sulfhydryl groups and thus can form covalent bonds with the disulfide bridges in the molecules of insulin, insulin receptors, glucose transporters (GLUTs), and enzymes involved in glucose metabolism (e.g., pyruvate dehydrogenase and α-ketoglutarate dehydrogenase). As a result, the normal functions of these molecules can be hampered. However, a direct effect on these molecules caused by arsenite at physiologically relevant concentrations seems unlikely. Recent evidence has shown that treatment of arsenite at lower and physiologically relevant concentrations can stimulate glucose transport, in contrary to an inhibitory effect exerted by phenylarsine oxide (PAO) or by higher doses of arsenite. Induction of oxidative stress and interferences in signal transduction or gene expression by arsenic or by its methylated metabolites are the most possible causes to arsenic-induced diabetes mellitus through mechanisms of induction of insulin resistance and β cell dysfunction. Recent studies have shown that, in subjects with chronic

Study on the toxic effects induced by different arsenicals in primary cultured rat astroglia

International Nuclear Information System (INIS)

Jin Yaping; Sun Guifan; Li Xin; Li Gexin; Lu Chunwei; Qu Long

2004-01-01

Arsenic toxicity is a global health problem affecting millions of people. The objectives of this study were to determine if the toxic effects on primary cultured rat astroglia would be induced by different arsenicals. Based on alamarBlue assay and the single cell gel electrophoresis (SCGE, comet assay), the cell viability and DNA damage in the cells exposed to different arsenicals were evaluated. Treatment of astroglia with methylated arsenicals, that is, pentavalent monomethylarsonic acid (MMAV) and dimethylarsinic acid (DMAV), resulted in no obvious changes in cell viability and DNA damage at micromolar concentrations. However, treatment of astroglia with inorganic arsenicals, that is, arsenite and arsenate, caused decreased cell viability and increased DNA damage at micromolar levels, and showing a dose-related decrease in mean alamarBlue reduced rate and a dose-related increase in mean comet length. Our study is therefore highly suggestive for a link between inorganic exposure and cellular toxicity or DNA damage. Based on the results of this study, the toxic effects induced by arsenite were stronger than those induced by arsenate

Arsenic induced apoptosis in rat liver following repeated 60 days exposure

International Nuclear Information System (INIS)

Bashir, Somia; Sharma, Yukti; Irshad, M.; Nag, T.C.; Tiwari, Monica; Kabra, M.; Dogra, T.D.

2006-01-01

Background: Accumulation of the wide spread environmental toxin arsenic in liver results in hepatotoxcity. Exposure to arsenite and other arsenicals has been previously shown to induce apoptosis in certain tumor cell lines at low (1-3 μM) concentration. Aim: The present study was focused to elucidate the role of free radicals in arsenic toxicity and to investigate the nature of in vivo sodium arsenite induced cell death in liver. Methods: Male wistar rats were exposed to arsenite at three different doses of 0.05, 2.5 and 5 mg/l for 60 days. Oxidative stress in liver was measured by estimating pro-oxidant and antioxidant activity in liver. Histopathological examination of liver was carried out by light and transmission electron microscopy. Analysis of DNA fragmentation by gel electrophoresis was used to identify apoptosis after the exposure. Terminal deoxy-nucleotidyl transferase mediated dUTP Nick end-labeling (TUNEL) assay was used to qualify and quantify apoptosis. Results: A significant increase in cytochrome-P450 and lipid peroxidation accompanied with a significant alteration in the activity of many of the antioxidants was observed, all suggestive of arsenic induced oxidative stress. Histopathological examination under light and transmission electron microscope suggested a combination of ongoing necrosis and apoptosis. DNA-TUNEL showed an increase in apoptotic cells in liver. Agarose gel electrophoresis of DNA of hepatocytes resulted in a characteristic ladder pattern. Conclusion: Chronic arsenic administration induces a specific pattern of apoptosis called post-mitotic apoptosis

Unfolded Protein Response Signaling and MAP Kinase Pathways Underlie Pathogenesis of Arsenic-induced Cutaneous Inflammation

OpenAIRE

Li, Changzhao; Xu, Jianmin; Li, Fugui; Chaudhary, Sandeep C.; Weng, Zhiping; Wen, Jianming; Elmets, Craig A.; Ahsan, Habibul; Athar, Mohammad

2011-01-01

Arsenic exposure through drinking water is a major global public health problem and is associated with an enhanced risk of various cancers including skin cancer. In human skin, arsenic induces precancerous melanosis and keratosis, which may progress to basal cell and squamous cell carcinoma. However, the mechanism by which these pathophysiological alterations occur remains elusive. In this study, we showed that sub-chronic arsenic exposure to SKH-1 mice induced unfolded protein response (UPR)...

Chronic occupational exposure to arsenic induces carcinogenic gene signaling networks and neoplastic transformation in human lung epithelial cells

International Nuclear Information System (INIS)

Stueckle, Todd A.; Lu, Yongju; Davis, Mary E.; Wang, Liying; Jiang, Bing-Hua; Holaskova, Ida; Schafer, Rosana; Barnett, John B.; Rojanasakul, Yon

2012-01-01

exposure to lung epithelial cells resulted in a cancer-like phenotype. ► Mice injected with arsenic transformed (B-As) cells displayed metastatic tumors. ► Microarray profiling revealed changes in mitochondrial metabolism and ROS response. ► p21, EF1α, Akt, MAPK, PPARα and NF-κB networks promoted pro-cancer signaling. ► B-As cells represent a lung cancer model to explore As-associated carcinogenesis.

Chronic occupational exposure to arsenic induces carcinogenic gene signaling networks and neoplastic transformation in human lung epithelial cells

Energy Technology Data Exchange (ETDEWEB)

Stueckle, Todd A., E-mail: tstueckle@hsc.wvu.edu [Department of Basic Pharmaceutical Sciences, West Virginia University, Morgantown, WV 26506 (United States); Health Effects Laboratory Division, National Institute for Occupational Safety and Health, Morgantown, WV 26505 (United States); Lu, Yongju, E-mail: yongju6@hotmail.com [Department of Basic Pharmaceutical Sciences, West Virginia University, Morgantown, WV 26506 (United States); Davis, Mary E., E-mail: mdavis@wvu.edu [Department of Physiology, West Virginia University, Morgantown, WV 26506 (United States); Wang, Liying, E-mail: lmw6@cdc.gov [Health Effects Laboratory Division, National Institute for Occupational Safety and Health, Morgantown, WV 26505 (United States); Jiang, Bing-Hua, E-mail: bhjiang@jefferson.edu [Department of Pathology, Anatomy and Cell Biology, Thomas Jefferson University, Philadelphia, PA 19107 (United States); Holaskova, Ida, E-mail: iholaskova@hsc.wvu.edu [Department of Microbiology, Immunology and Cell Biology, West Virginia University, Morgantown, WV 26506 (United States); Schafer, Rosana, E-mail: rschafer@hsc.wvu.edu [Department of Microbiology, Immunology and Cell Biology, West Virginia University, Morgantown, WV 26506 (United States); Barnett, John B., E-mail: jbarnett@hsc.wvu.edu [Department of Microbiology, Immunology and Cell Biology, West Virginia University, Morgantown, WV 26506 (United States); Rojanasakul, Yon, E-mail: yrojan@hsc.wvu.edu [Department of Basic Pharmaceutical Sciences, West Virginia University, Morgantown, WV 26506 (United States)

2012-06-01

{sub 3} exposure to lung epithelial cells resulted in a cancer-like phenotype. ► Mice injected with arsenic transformed (B-As) cells displayed metastatic tumors. ► Microarray profiling revealed changes in mitochondrial metabolism and ROS response. ► p21, EF1α, Akt, MAPK, PPARα and NF-κB networks promoted pro-cancer signaling. ► B-As cells represent a lung cancer model to explore As-associated carcinogenesis.

All-trans retinoic acid protects against arsenic-induced uterine toxicity in female Sprague–Dawley rats

International Nuclear Information System (INIS)

Chatterjee, A.; Chatterji, U.

2011-01-01

Background and purpose: Arsenic exposure frequently leads to reproductive failures by disrupting the rat uterine histology, hormonal integrity and estrogen signaling components of the rat uterus, possibly by generating reactive oxygen species. All-trans retinoic acid (ATRA) was assessed as a prospective therapeutic agent for reversing reproductive disorders. Experimental approach: Rats exposed to arsenic for 28 days were allowed to either recover naturally or were treated simultaneously with ATRA for 28 days or treatment continued up to 56 days. Hematoxylin–eosin double staining was used to evaluate changes in the uterine histology. Serum gonadotropins and estradiol were assayed by ELISA. Expression of the estrogen receptor (ERα), an estrogen responsive gene vascular endothelial growth factor (VEGF), and cell cycle regulatory proteins, cyclin D1 and CDK4, was assessed by RT-PCR, immunohistochemistry and western blot analysis. Key results: ATRA ameliorated sodium arsenite-induced decrease in circulating estradiol and gonadotropin levels in a dose- and time-dependent manner, along with recovery of luminal epithelial cells and endometrial glands. Concomitant up regulation of ERα, VEGF, cyclin D1, CDK4 and Ki-67 was also observed to be more prominent for ATRA-treated rats as compared to the rats that were allowed to recover naturally for 56 days. Conclusions and implications: Collectively, the results reveal that ATRA reverses arsenic-induced disruption of the circulating levels of gonadotropins and estradiol, and degeneration of luminal epithelial cells and endometrial glands of the rat uterus, indicating resumption of their functional status. Since structural and functional maintenance of the pubertal uterus is under the influence of estradiol, ATRA consequently up regulated the estrogen receptor and resumed cellular proliferation, possibly by an antioxidant therapeutic approach against arsenic toxicity. Highlights: ► Arsenic disrupts the uterine histology and

All-trans retinoic acid protects against arsenic-induced uterine toxicity in female Sprague-Dawley rats

Energy Technology Data Exchange (ETDEWEB)

Chatterjee, A.; Chatterji, U., E-mail: urmichatterji@gmail.com

2011-12-15

Background and purpose: Arsenic exposure frequently leads to reproductive failures by disrupting the rat uterine histology, hormonal integrity and estrogen signaling components of the rat uterus, possibly by generating reactive oxygen species. All-trans retinoic acid (ATRA) was assessed as a prospective therapeutic agent for reversing reproductive disorders. Experimental approach: Rats exposed to arsenic for 28 days were allowed to either recover naturally or were treated simultaneously with ATRA for 28 days or treatment continued up to 56 days. Hematoxylin-eosin double staining was used to evaluate changes in the uterine histology. Serum gonadotropins and estradiol were assayed by ELISA. Expression of the estrogen receptor (ER{alpha}), an estrogen responsive gene vascular endothelial growth factor (VEGF), and cell cycle regulatory proteins, cyclin D1 and CDK4, was assessed by RT-PCR, immunohistochemistry and western blot analysis. Key results: ATRA ameliorated sodium arsenite-induced decrease in circulating estradiol and gonadotropin levels in a dose- and time-dependent manner, along with recovery of luminal epithelial cells and endometrial glands. Concomitant up regulation of ER{alpha}, VEGF, cyclin D1, CDK4 and Ki-67 was also observed to be more prominent for ATRA-treated rats as compared to the rats that were allowed to recover naturally for 56 days. Conclusions and implications: Collectively, the results reveal that ATRA reverses arsenic-induced disruption of the circulating levels of gonadotropins and estradiol, and degeneration of luminal epithelial cells and endometrial glands of the rat uterus, indicating resumption of their functional status. Since structural and functional maintenance of the pubertal uterus is under the influence of estradiol, ATRA consequently up regulated the estrogen receptor and resumed cellular proliferation, possibly by an antioxidant therapeutic approach against arsenic toxicity. Highlights: Black-Right-Pointing-Pointer Arsenic

Arsenic induces cell apoptosis in cultured osteoblasts through endoplasmic reticulum stress

International Nuclear Information System (INIS)

Tang, C.-H.; Chiu, Y.-C.; Huang, C.-F.; Chen, Y.-W.; Chen, P.-C.

2009-01-01

Osteoporosis is characterized by low bone mass resulting from an imbalance between bone resorption by osteoclasts and bone formation by osteoblasts. Therefore, decreased bone formation by osteoblasts may lead to the development of osteoporosis, and rate of apoptosis is responsible for the regulation of bone formation. Arsenic (As) exists ubiquitously in our environment and increases the risk of neurotoxicity, liver injury, peripheral vascular disease and cancer. However, the effect of As on apoptosis of osteoblasts is mostly unknown. Here, we found that As induced cell apoptosis in osteoblastic cell lines (including hFOB, MC3T3-E1 and MG-63) and mouse bone marrow stromal cells (M2-10B4). As also induced upregulation of Bax and Bak, downregulation of Bcl-2 and dysfunction of mitochondria in osteoblasts. As also triggered endoplasmic reticulum (ER) stress, as indicated by changes in cytosolic-calcium levels. We found that As increased the expression and activities of glucose-regulated protein 78 (GRP78) and calpain. Transfection of cells with GRP78 or calpain siRNA reduced As-mediated cell apoptosis in osteoblasts. Therefore, our results suggest that As increased cell apoptosis in cultured osteoblasts and increased the risk of osteoporosis.

The cell biology of disease: Acute promyelocytic leukemia, arsenic, and PML bodies.

Science.gov (United States)

de Thé, Hugues; Le Bras, Morgane; Lallemand-Breitenbach, Valérie

2012-07-09

Acute promyelocytic leukemia (APL) is driven by a chromosomal translocation whose product, the PML/retinoic acid (RA) receptor α (RARA) fusion protein, affects both nuclear receptor signaling and PML body assembly. Dissection of APL pathogenesis has led to the rediscovery of PML bodies and revealed their role in cell senescence, disease pathogenesis, and responsiveness to treatment. APL is remarkable because of the fortuitous identification of two clinically effective therapies, RA and arsenic, both of which degrade PML/RARA oncoprotein and, together, cure APL. Analysis of arsenic-induced PML or PML/RARA degradation has implicated oxidative stress in the biogenesis of nuclear bodies and SUMO in their degradation.

Unraveling the mechanism of neuroprotection of curcumin in arsenic induced cholinergic dysfunctions in rats

Energy Technology Data Exchange (ETDEWEB)

Srivastava, Pranay [CSIR-Indian Institute of Toxicology Research, Post Box 80, MG Marg, Lucknow 226 001 (India); Yadav, Rajesh S. [CSIR-Indian Institute of Toxicology Research, Post Box 80, MG Marg, Lucknow 226 001 (India); Department of Crimnology and Forensic Science, Harisingh Gour University, Sagar 470 003 (India); Chandravanshi, Lalit P.; Shukla, Rajendra K.; Dhuriya, Yogesh K.; Chauhan, Lalit K.S. [CSIR-Indian Institute of Toxicology Research, Post Box 80, MG Marg, Lucknow 226 001 (India); Dwivedi, Hari N. [Babu Banarasi Das University, BBD City, Faizabad Road, Lucknow 227 015 (India); Pant, Aditiya B. [CSIR-Indian Institute of Toxicology Research, Post Box 80, MG Marg, Lucknow 226 001 (India); Khanna, Vinay K., E-mail: vkkhanna1@gmail.com [CSIR-Indian Institute of Toxicology Research, Post Box 80, MG Marg, Lucknow 226 001 (India)

2014-09-15

Earlier, we found that arsenic induced cholinergic deficits in rat brain could be protected by curcumin. In continuation to this, the present study is focused to unravel the molecular mechanisms associated with the protective efficacy of curcumin in arsenic induced cholinergic deficits. Exposure to arsenic (20 mg/kg body weight, p.o) for 28 days in rats resulted to decrease the expression of CHRM2 receptor gene associated with mitochondrial dysfunctions as evident by decrease in the mitochondrial membrane potential, activity of mitochondrial complexes and enhanced apoptosis both in the frontal cortex and hippocampus in comparison to controls. The ultrastructural images of arsenic exposed rats, assessed by transmission electron microscope, exhibited loss of myelin sheath and distorted cristae in the mitochondria both in the frontal cortex and hippocampus as compared to controls. Simultaneous treatment with arsenic (20 mg/kg body weight, p.o) and curcumin (100 mg/kg body weight, p.o) for 28 days in rats was found to protect arsenic induced changes in the mitochondrial membrane potential and activity of mitochondrial complexes both in frontal cortex and hippocampus. Alterations in the expression of pro- and anti-apoptotic proteins and ultrastructural damage in the frontal cortex and hippocampus following arsenic exposure were also protected in rats simultaneously treated with arsenic and curcumin. The data of the present study reveal that curcumin could protect arsenic induced cholinergic deficits by modulating the expression of pro- and anti-apoptotic proteins in the brain. More interestingly, arsenic induced functional and ultrastructural changes in the brain mitochondria were also protected by curcumin. - Highlights: • Neuroprotective mechanism of curcumin in arsenic induced cholinergic deficits studied • Curcumin protected arsenic induced enhanced expression of stress markers in rat brain • Arsenic compromised mitochondrial electron transport chain protected

Unraveling the mechanism of neuroprotection of curcumin in arsenic induced cholinergic dysfunctions in rats

International Nuclear Information System (INIS)

Srivastava, Pranay; Yadav, Rajesh S.; Chandravanshi, Lalit P.; Shukla, Rajendra K.; Dhuriya, Yogesh K.; Chauhan, Lalit K.S.; Dwivedi, Hari N.; Pant, Aditiya B.; Khanna, Vinay K.

2014-01-01

Earlier, we found that arsenic induced cholinergic deficits in rat brain could be protected by curcumin. In continuation to this, the present study is focused to unravel the molecular mechanisms associated with the protective efficacy of curcumin in arsenic induced cholinergic deficits. Exposure to arsenic (20 mg/kg body weight, p.o) for 28 days in rats resulted to decrease the expression of CHRM2 receptor gene associated with mitochondrial dysfunctions as evident by decrease in the mitochondrial membrane potential, activity of mitochondrial complexes and enhanced apoptosis both in the frontal cortex and hippocampus in comparison to controls. The ultrastructural images of arsenic exposed rats, assessed by transmission electron microscope, exhibited loss of myelin sheath and distorted cristae in the mitochondria both in the frontal cortex and hippocampus as compared to controls. Simultaneous treatment with arsenic (20 mg/kg body weight, p.o) and curcumin (100 mg/kg body weight, p.o) for 28 days in rats was found to protect arsenic induced changes in the mitochondrial membrane potential and activity of mitochondrial complexes both in frontal cortex and hippocampus. Alterations in the expression of pro- and anti-apoptotic proteins and ultrastructural damage in the frontal cortex and hippocampus following arsenic exposure were also protected in rats simultaneously treated with arsenic and curcumin. The data of the present study reveal that curcumin could protect arsenic induced cholinergic deficits by modulating the expression of pro- and anti-apoptotic proteins in the brain. More interestingly, arsenic induced functional and ultrastructural changes in the brain mitochondria were also protected by curcumin. - Highlights: • Neuroprotective mechanism of curcumin in arsenic induced cholinergic deficits studied • Curcumin protected arsenic induced enhanced expression of stress markers in rat brain • Arsenic compromised mitochondrial electron transport chain protected

Arsenic transformation predisposes human skin keratinocytes to UV-induced DNA damage yet enhances their survival apparently by diminishing oxidant response

International Nuclear Information System (INIS)

Sun Yang; Kojima, Chikara; Chignell, Colin; Mason, Ronald; Waalkes, Michael P.

2011-01-01

Inorganic arsenic and UV, both human skin carcinogens, may act together as skin co-carcinogens. We find human skin keratinocytes (HaCaT cells) are malignantly transformed by low-level arsenite (100 nM, 30 weeks; termed As-TM cells) and with transformation concurrently undergo full adaptation to arsenic toxicity involving reduced apoptosis and oxidative stress response to high arsenite concentrations. Oxidative DNA damage (ODD) is a possible mechanism in arsenic carcinogenesis and a hallmark of UV-induced skin cancer. In the current work, inorganic arsenite exposure (100 nM) did not induce ODD during the 30 weeks required for malignant transformation. Although acute UV-treatment (UVA, 25 J/cm 2 ) increased ODD in passage-matched control cells, once transformed by arsenic to As-TM cells, acute UV actually further increased ODD (> 50%). Despite enhanced ODD, As-TM cells were resistant to UV-induced apoptosis. The response of apoptotic factors and oxidative stress genes was strongly mitigated in As-TM cells after UV exposure including increased Bcl2/Bax ratio and reduced Caspase-3, Nrf2, and Keap1 expression. Several Nrf2-related genes (HO-1, GCLs, SOD) showed diminished responses in As-TM cells after UV exposure consistent with reduced oxidant stress response. UV-exposed As-TM cells showed increased expression of cyclin D1 (proliferation gene) and decreased p16 (tumor suppressor). UV exposure enhanced the malignant phenotype of As-TM cells. Thus, the co-carcinogenicity between UV and arsenic in skin cancer might involve adaptation to chronic arsenic exposure generally mitigating the oxidative stress response, allowing apoptotic by-pass after UV and enhanced cell survival even in the face of increased UV-induced oxidative stress and increased ODD. - Highlights: → Arsenic transformation adapted to UV-induced apoptosis. → Arsenic transformation diminished oxidant response. → Arsenic transformation enhanced UV-induced DNA damage.

Arsenic-induced dose-dependent modulation of the NF-κB/IL-6 axis in thymocytes triggers differential immune responses

International Nuclear Information System (INIS)

Choudhury, Sreetama; Gupta, Payal; Ghosh, Sayan; Mukherjee, Sudeshna; Chakraborty, Priyanka; Chatterji, Urmi; Chattopadhyay, Sreya

2016-01-01

Highlights: • We for the first time explicitly show that arsenic exposure causes morphological damage to the thymus and results in heightened death of thymocytes. • Our data suggests that arsenic-induced apoptosis occurs due to increase in cellular oxidative and nitrosative stress. • We have for the first time established a non-classical role of NF-κB, correlating it with increase in FoxP3 expression. • The % of CD4+ CD25+ T cells were high and expression of FoxP3 has also increased at higher doses of arsenic indicating an nTreg bias. - Abstract: Arsenic contamination of drinking water is a matter of global concern. Arsenic intake impairs immune responses and leads to a variety of pathological conditions including cancer. In order to understand the intricate tuning of immune responses elicited by chronic exposure to arsenic, a mouse model was established by subjecting mice to different environmentally relevant concentrations of arsenic in drinking water for 30 days. Detailed study of the thymus, a primary immune organ, revealed arsenic-mediated tissue damage in both histological specimens and scanning electron micrographs. Analysis of molecular markers of apoptosis by Western blot revealed a dose-dependent activation of the apoptotic cascade. Enzymatic assays supported oxidative stress as an instigator of cell death. Interestingly, assessment of inflammatory responses revealed disparity in the NF-κB/IL-6/STAT3 axis, where it was found that in animals consuming higher amounts of arsenic NF-κB activation did not lead to the classical IL-6 upregulation response. This deviation from the canonical pathway was accompanied with a significant rise in numbers of CD4+ CD25+ FoxP3 expressing cells in the thymus. The cytokine profile of the animals exposed to higher doses of arsenic also indicated an immune-suppressed milieu, thus validating that arsenic shapes the immune environment in context to its dose of exposure and that at higher doses it leads to immune

Arsenic-induced alterations in the contact hypersensitivity response in Balb/c mice

International Nuclear Information System (INIS)

Patterson, Rachel; Vega, Libia; Trouba, Kevin; Bortner, Carl; Germolec, Dori

2004-01-01

Previous studies in our laboratory indicate that arsenic alters secretion of growth promoting and inflammatory cytokines in the skin that can regulate the migration and maturation of Langerhans cells (LC) during allergic contact dermatitis. Therefore, we hypothesized that arsenic may modulate hypersensitivity responses to cutaneous sensitizing agents by altering cytokine production, LC migration, and T-cell proliferation. To investigate this hypothesis, we examined the induction and elicitation phases of dermal sensitization. Mice exposed to 50 mg/l arsenic in the drinking water for 4 weeks demonstrated a reduction in lymph node cell (LNC) proliferation and ear swelling following sensitization with 2,4-dinitrofluorobenzene (DNFB), compared to control mice. LC and T-cell populations in the draining lymph nodes of DNFB-sensitized mice were evaluated by fluorescence-activated cell sorting; activated LC were reduced in cervical lymph nodes, suggesting that LC migration may be altered following arsenic exposure. Lymphocytes from arsenic-treated animals sensitized with fluorescein isothiocyanate (FITC) exhibited reduced proliferative responses following T-cell mitogen stimulation in vitro; however, lymphocyte proliferation from nonsensitized, arsenic-treated mice was comparable to controls. Arsenic exposure also reduced the number of thioglycollate-induced peritoneal macrophages and circulating neutrophils. These studies demonstrate that repeated, prolonged exposure to nontoxic concentrations of sodium arsenite alters immune cell populations and results in functional changes in immune responses, specifically attenuation of contact hypersensitivity

Arsenic induces apoptosis in mouse liver is mitochondria dependent and is abrogated by N-acetylcysteine

International Nuclear Information System (INIS)

Santra, Amal; Chowdhury, Abhijit; Ghatak, Subhadip; Biswas, Ayan; Dhali, Gopal Krishna

2007-01-01

Arsenicosis, caused by arsenic contamination of drinking water supplies, is a major public health problem in India and Bangladesh. Chronic liver disease, often with portal hypertension occurs in chronic arsenicosis, contributes to the morbidity and mortality. The early cellular events that initiate liver cell injury due to arsenicosis have not been studied. Our aim was to identify the possible mechanisms related to arsenic-induced liver injury in mice. Liver injury was induced in mice by arsenic treatment. The liver was used for mitochondrial oxidative stress, mitochondrial permeability transition (MPT). Evidence of apoptosis was sought by TUNEL test, caspase assay and histology. Pretreatment with N-acetyl-L-cysteine (NAC) was done to modulate hepatic GSH level. Arsenic treatment in mice caused liver injury associated with increased oxidative stress in liver mitochondria and alteration of MPT. Altered MPT facilitated cytochrome c release in the cytosol, activation of caspase 9 and caspase 3 activities and apoptotic cell death. Pretreatment of NAC to arsenic-treated mice abrogated all these alteration suggesting a glutathione (GSH)-dependent mechanism. Oxidative stress in mitochondria and inappropriate MPT are important in the pathogenesis of arsenic induced apoptotic liver cell injury. The phenomenon is GSH dependent and supplementation of NAC might have beneficial effects

Atorvastatin restores arsenic-induced vascular dysfunction in rats: Modulation of nitric oxide signaling and inflammatory mediators

International Nuclear Information System (INIS)

Kesavan, Manickam; Sarath, Thengumpallil Sasindran; Kannan, Kandasamy; Suresh, Subramaniyam; Gupta, Priyanka; Vijayakaran, Karunakaran; Sankar, Palanisamy; Kurade, Nitin Pandurang; Mishra, Santosh Kumar; Sarkar, Souvendra Nath

2014-01-01

We evaluated whether atorvastatin, an extensively prescribed statin for reducing the risks of cardiovascular diseases, can reduce the risk of arsenic-induced vascular dysfunction and inflammation in rats and whether the modulation could be linked to improvement in vascular NO signaling. Rats were exposed to sodium arsenite (100 ppm) through drinking water for 90 consecutive days. Atorvastatin (10 mg/kg bw, orally) was administered once daily during the last 30 days of arsenic exposure. On the 91 st day, blood was collected for measuring serum C-reactive protein. Thoracic aorta was isolated for assessing reactivity to phenylephrine, sodium nitroprusside and acetylcholine; evaluating eNOS and iNOS mRNA expression and measuring NO production, while abdominal aorta was used for ELISA of cytokines, chemokine and vascular cell adhesion molecules. Histopathology was done in aortic arches. Arsenic did not alter phenylephrine-elicited contraction. Atorvastatin inhibited E max of phenylephrine, but it augmented the contractile response in aortic rings from arsenic-exposed animals. Sodium nitroprusside-induced relaxation was not altered with any treatment. However, arsenic reduced acetylcholine-induced relaxation and affected aortic eNOS at the levels of mRNA expression, protein concentration, phosphorylation and NO production. Further, it increased aortic iNOS mRNA expression, iNOS-derived NO synthesis, production of pro-inflammatory mediators (IL-1β, IL-6, MCP-1, VCAM, sICAM) and serum C-reactive protein and aortic vasculopathic lesions. Atorvastatin attenuated these arsenic-mediated functional, biochemical and structural alterations. Results show that atorvastatin has the potential to ameliorate arsenic-induced vascular dysfunction and inflammation by restoring endothelial function with improvement in NO signaling and attenuating production of pro-inflammatory mediators and cell adhesion molecules. - Highlights: • We evaluated if atorvastatin reduce arsenic-induced

Atorvastatin restores arsenic-induced vascular dysfunction in rats: Modulation of nitric oxide signaling and inflammatory mediators

Energy Technology Data Exchange (ETDEWEB)

Kesavan, Manickam; Sarath, Thengumpallil Sasindran; Kannan, Kandasamy; Suresh, Subramaniyam; Gupta, Priyanka; Vijayakaran, Karunakaran; Sankar, Palanisamy; Kurade, Nitin Pandurang; Mishra, Santosh Kumar; Sarkar, Souvendra Nath, E-mail: snsarkar1911@rediffmail.com

2014-10-01

We evaluated whether atorvastatin, an extensively prescribed statin for reducing the risks of cardiovascular diseases, can reduce the risk of arsenic-induced vascular dysfunction and inflammation in rats and whether the modulation could be linked to improvement in vascular NO signaling. Rats were exposed to sodium arsenite (100 ppm) through drinking water for 90 consecutive days. Atorvastatin (10 mg/kg bw, orally) was administered once daily during the last 30 days of arsenic exposure. On the 91{sup st} day, blood was collected for measuring serum C-reactive protein. Thoracic aorta was isolated for assessing reactivity to phenylephrine, sodium nitroprusside and acetylcholine; evaluating eNOS and iNOS mRNA expression and measuring NO production, while abdominal aorta was used for ELISA of cytokines, chemokine and vascular cell adhesion molecules. Histopathology was done in aortic arches. Arsenic did not alter phenylephrine-elicited contraction. Atorvastatin inhibited E{sub max} of phenylephrine, but it augmented the contractile response in aortic rings from arsenic-exposed animals. Sodium nitroprusside-induced relaxation was not altered with any treatment. However, arsenic reduced acetylcholine-induced relaxation and affected aortic eNOS at the levels of mRNA expression, protein concentration, phosphorylation and NO production. Further, it increased aortic iNOS mRNA expression, iNOS-derived NO synthesis, production of pro-inflammatory mediators (IL-1β, IL-6, MCP-1, VCAM, sICAM) and serum C-reactive protein and aortic vasculopathic lesions. Atorvastatin attenuated these arsenic-mediated functional, biochemical and structural alterations. Results show that atorvastatin has the potential to ameliorate arsenic-induced vascular dysfunction and inflammation by restoring endothelial function with improvement in NO signaling and attenuating production of pro-inflammatory mediators and cell adhesion molecules. - Highlights: • We evaluated if atorvastatin reduce arsenic-induced

Disruption of canonical TGFβ-signaling in murine coronary progenitor cells by low level arsenic

Energy Technology Data Exchange (ETDEWEB)

Allison, Patrick; Huang, Tianfang; Broka, Derrick; Parker, Patti [Department of Pharmacology and Toxicology College of Pharmacy, Southwest Environmental Health Sciences Center, Steele Children' s Research Center and Bio5 Institute, University of Arizona, Tucson, AZ 85721 (United States); Barnett, Joey V. [Department of Pharmacology, Vanderbilt Medical University, Nashville, TN (United States); Camenisch, Todd D., E-mail: camenisch@pharmacy.arizona.edu [Department of Pharmacology and Toxicology College of Pharmacy, Southwest Environmental Health Sciences Center, Steele Children' s Research Center and Bio5 Institute, University of Arizona, Tucson, AZ 85721 (United States)

2013-10-01

Exposure to arsenic results in several types of cancers as well as heart disease. A major contributor to ischemic heart pathologies is coronary artery disease, however the influences by environmental arsenic in this disease process are not known. Similarly, the impact of toxicants on blood vessel formation and function during development has not been studied. During embryogenesis, the epicardium undergoes proliferation, migration, and differentiation into several cardiac cell types including smooth muscle cells which contribute to the coronary vessels. The TGFβ family of ligands and receptors is essential for developmental cardiac epithelial to mesenchymal transition (EMT) and differentiation into coronary smooth muscle cells. In this in vitro study, 18 hour exposure to 1.34 μM arsenite disrupted developmental EMT programming in murine epicardial cells causing a deficit in cardiac mesenchyme. The expression of EMT genes including TGFβ2, TGFβ receptor-3, Snail, and Has-2 are decreased in a dose-dependent manner following exposure to arsenite. TGFβ2 cell signaling is abrogated as detected by decreases in phosphorylated Smad2/3 when cells are exposed to 1.34 μM arsenite. There is also loss of nuclear accumulation pSmad due to arsenite exposure. These observations coincide with a decrease in vimentin positive mesenchymal cells invading three-dimensional collagen gels. However, arsenite does not block TGFβ2 mediated smooth muscle cell differentiation by epicardial cells. Overall these results show that arsenic exposure blocks developmental EMT gene programming in murine coronary progenitor cells by disrupting TGFβ2 signals and Smad activation, and that smooth muscle cell differentiation is refractory to this arsenic toxicity. - Highlights: • Arsenic blocks TGFβ2 induced expression of EMT genes. • Arsenic blocks TGFβ2 triggered Smad2/3 phosphorylation and nuclear translocation. • Arsenic blocks epicardial cell differentiation into cardiac mesenchyme. �

Fluoxetine treatment ameliorates depression induced by perinatal arsenic exposure via a neurogenic mechanism

Science.gov (United States)

Tyler, Christina R.; Solomon, Benjamin R.; Ulibarri, Adam L.; Allan, Andrea M.

2014-01-01

Several epidemiological studies have reported an association between arsenic exposure and increased rates of psychiatric disorders, including depression, in exposed populations. We have previously demonstrated that developmental exposure to low amounts of arsenic induces depression in adulthood along with several morphological and molecular aberrations, particularly associated with the hippocampus and the hypothalamic–pituitary–adrenal (HPA) axis. The extent and potential reversibility of this toxin-induced damage has not been characterized to date. In this study, we assessed the effects of fluoxetine, a selective serotonin reuptake inhibitor antidepressant, on adult animals exposed to arsenic during development. Perinatal arsenic exposure (PAE) induced depressive-like symptoms in a mild learned helplessness task and in the forced swim task after acute exposure to a predator odor (2,4,5-trimethylthiazoline, TMT). Chronic fluoxetine treatment prevented these behaviors in both tasks in arsenic-exposed animals and ameliorated arsenic-induced blunted stress responses, as measured by corticosterone (CORT) levels before and after TMT exposure. Morphologically, chronic fluoxetine treatment reversed deficits in adult hippocampal neurogenesis (AHN) after PAE, specifically differentiation and survival of neural progenitor cells. Protein expression of BDNF, CREB, the glucocorticoid receptor (GR), and HDAC2 was significantly increased in the dentate gyrus of arsenic animals after fluoxetine treatment. This study demonstrates that damage induced by perinatal arsenic exposure is reversible with chronic fluoxetine treatment resulting in restored resiliency to depression via a neurogenic mechanism. PMID:24952232

Arsenic compromises conducting airway epithelial barrier properties in primary mouse and immortalized human cell cultures.

Directory of Open Access Journals (Sweden)

Cara L Sherwood

Full Text Available Arsenic is a lung toxicant that can lead to respiratory illness through inhalation and ingestion, although the most common exposure is through contaminated drinking water. Lung effects reported from arsenic exposure include lung cancer and obstructive lung disease, as well as reductions in lung function and immune response. As part of their role in innate immune function, airway epithelial cells provide a barrier that protects underlying tissue from inhaled particulates, pathogens, and toxicants frequently found in inspired air. We evaluated the effects of a five-day exposure to environmentally relevant levels of arsenic {<4μM [~300 μg/L (ppb] as NaAsO2} on airway epithelial barrier function and structure. In a primary mouse tracheal epithelial (MTE cell model we found that both micromolar (3.9 μM and submicromolar (0.8 μM arsenic concentrations reduced transepithelial resistance, a measure of barrier function. Immunofluorescent staining of arsenic-treated MTE cells showed altered patterns of localization of the transmembrane tight junction proteins claudin (Cl Cl-1, Cl-4, Cl-7 and occludin at cell-cell contacts when compared with untreated controls. To better quantify arsenic-induced changes in tight junction transmembrane proteins we conducted arsenic exposure experiments with an immortalized human bronchial epithelial cell line (16HBE14o-. We found that arsenic exposure significantly increased the protein expression of Cl-4 and occludin as well as the mRNA levels of Cl-4 and Cl-7 in these cells. Additionally, arsenic exposure resulted in altered phosphorylation of occludin. In summary, exposure to environmentally relevant levels of arsenic can alter both the function and structure of airway epithelial barrier constituents. These changes likely contribute to the observed arsenic-induced loss in basic innate immune defense and increased infection in the airway.

High soil and groundwater arsenic levels induce high body arsenic loads, health risk and potential anemia for inhabitants of northeastern Iran.

Science.gov (United States)

Taheri, Masumeh; Mehrzad, Jalil; Mahmudy Gharaie, Mohamad Hosein; Afshari, Reza; Dadsetan, Ahmad; Hami, Shakiba

2016-04-01

Arsenic bioavailability in rock, soil and water resources is notoriously hazardous. Geogenic arsenic enters the body and adversely affects many biochemical processes in animals and humans, posing risk to public health. Chelpu is located in NE Iran, where realgar, orpiment and pyrite mineralization is the source of arsenic in the macroenvironment. Using cluster random sampling strategy eight rocks, 23 soils, 12 drinking water resources, 36 human urine and hair samples and 15 adult sheep urine and wool samples in several large-scale herds in the area were randomly taken for quantification of arsenic in rock/soil/water, wool/hair/urine. Arsenic levels in rock/soil/water and wool/hair/urine were measured using inductively coupled plasma spectroscopy and atomic absorption spectrophotometry, respectively. While arsenic levels in rocks, soils and water resources hazardously ranged 9.40-25,873.3 mg kg(-1), 7.10-1448.80 mg kg(-1) and 12-606 μg L(-1), respectively, arsenic concentrations in humans' hair and urine and sheep's wool and urine varied from 0.37-1.37 μg g(-1) and 9-271.4 μg L(-1) and 0.3-3.11 μg g(-1) and 29.1-1015 μg L(-1), respectively. Local sheep and human were widely sick and slightly anemic. Hematological examination of the inhabitants revealed that geogenic arsenic could harm blood cells, potentially resulting in many other hematoimmunological disorders including cancer. The findings warn widespread exposure of animals and human in this agroecologically and geopolitically important region (i.e., its proximity with Afghanistan, Pakistan and Turkmenistan) and give a clue on how arsenic could induce infectious and non-infectious diseases in highly exposed human/animals.

Sensitivity to sodium arsenite in human melanoma cells depends upon susceptibility to arsenite-induced mitotic arrest

International Nuclear Information System (INIS)

McNeely, Samuel C.; Belshoff, Alex C.; Taylor, B. Frazier; Fan, Teresa W-M.; McCabe, Michael J.; Pinhas, Allan R.

2008-01-01

Arsenic induces clinical remission in patients with acute promyelocytic leukemia and has potential for treatment of other cancers. The current study examines factors influencing sensitivity to arsenic using human malignant melanoma cell lines. A375 and SK-Mel-2 cells were sensitive to clinically achievable concentrations of arsenite, whereas SK-Mel-3 and SK-Mel-28 cells required supratherapeutic levels for toxicity. Inhibition of glutathione synthesis, glutathione S-transferase (GST) activity, and multidrug resistance protein (MRP) transporter function attenuated arsenite resistance, consistent with studies suggesting that arsenite is extruded from the cell as a glutathione conjugate by MRP-1. However, MRP-1 was not overexpressed in resistant lines and GST-π was only slightly elevated. ICP-MS analysis indicated that arsenite-resistant SK-Mel-28 cells did not accumulate less arsenic than arsenite-sensitive A375 cells, suggesting that resistance was not attributable to reduced arsenic accumulation but rather to intrinsic properties of resistant cell lines. The mode of arsenite-induced cell death was apoptosis. Arsenite-induced apoptosis is associated with cell cycle alterations. Cell cycle analysis revealed arsenite-sensitive cells arrested in mitosis whereas arsenite-resistant cells did not, suggesting that induction of mitotic arrest occurs at lower intracellular arsenic concentrations. Higher intracellular arsenic levels induced cell cycle arrest in the S-phase and G 2 -phase in SK-Mel-3 and SK-Mel-28 cells, respectively. The lack of arsenite-induced mitotic arrest in resistant cell lines was associated with a weakened spindle checkpoint resulting from reduced expression of spindle checkpoint protein BUBR1. These data suggest that arsenite has potential for treatment of solid tumors but a functional spindle checkpoint is a prerequisite for a positive response to its clinical application

Arsenic and urinary bladder cell proliferation

International Nuclear Information System (INIS)

Luster, Michael I.; Simeonova, Petia P.

2004-01-01

Epidemiologic studies have demonstrated that a close association exists between the elevated levels of arsenic in drinking water and the incidence of certain cancers, including transitional cell carcinomas of the urinary bladder. We have employed in vitro and in vivo models to examine the effects of sodium arsenite on the urinary bladder epithelium. Mice exposed to 0.01% sodium arsenite in drinking water demonstrated hyperproliferation of the bladder uroepithelium within 4 weeks after initiating treatment. This occurred in the absence of amorphous precipitates and was accompanied by the accumulation of trivalent arsenite (iAs 3+ ), and to a lesser extent dimethylarsenic (DMA), arsenate (iAs 5+ ), and monomethylarsenic (MMA) in bladder tissue. In contrast to the bladder, urinary secretion was primarily in the form of DMA and MMA. Arsenic-induced cell proliferation in the bladder epithelium was correlated with activation of the MAP kinase pathway, leading to extracellular signal-regulated kinase (ERK) kinase activity, AP-1 activation, and expression of AP-1-associated genes involved in cell proliferation. Activation of the MAP kinase pathway involved both epidermal growth factor (EGF) receptor-dependent and -independent events, the latter involving Src activation. Studies summarized in this review suggest that arsenic accumulates in urinary bladder epithelium causing activation of specific signaling pathways that lead to chronic increased cell proliferation. This may play a non-epigenetic role in carcinogenesis by increasing the proliferation of initiated cells or increasing the mutational rate

Blockage of JNK pathway enhances arsenic trioxide-induced apoptosis in human keratinocytes

International Nuclear Information System (INIS)

Huang, H.-S.; Liu, Z.-M.; Hong, D.-Y.

2010-01-01

Arsenic is well known as a carcinogen predisposing humans to some severe diseases and also as an effective medicine for treating acute promyelocytic leukemia, syphilis, and psoriasis. Multiple active mechanisms, including cell cycle arrest and apoptosis, have been proposed in therapy; however, the opposing effects of arsenic remain controversial. Our previous study found that arsenic trioxide (ATO)-induced activation of p21 WAF1/CIP1 (p21) led to A431 cell death through the antagonistic effects of the signaling of ERK1/2 and JNK1. In the current study, the inhibitory effects of JNK1 on ATO-induced p21 expression were explored. Over-expression of JNK1 in A431 cells could inhibit p21 expression, which was associated with HDAC1 and TGIF. Using the GST pull-down assay and fluorescence resonance energy transfer analysis, N-terminal domain (amino acids 1-108) of TGIF, critical to its binding with c-Jun, was found. Using reporter assays, requirement of the C-terminal domain (amino acids 138-272) of TGIF to suppress ATO-induced p21 expression was observed. Thus, the domains of TGIF that carried out its inhibitory effects on p21 were identified. Finally, treatment with JNK inhibitor SP600125 could enhance ATO-induced apoptosis of HaCaT keratinocytes by using flow cytometry.

Acetylated H4K16 by MYST1 protects UROtsa cells from arsenic toxicity and is decreased following chronic arsenic exposure

International Nuclear Information System (INIS)

Jo, William Jaime; Ren, Xuefeng; Chu, Feixia; Aleshin, Maria; Wintz, Henri; Burlingame, Alma; Smith, Martyn Thomas; Vulpe, Chris Dillon; Zhang Luoping

2009-01-01

Arsenic, a human carcinogen that is associated with an increased risk of bladder cancer, is commonly found in drinking water. An important mechanism by which arsenic is thought to be carcinogenic is through the induction of epigenetic changes that lead to aberrant gene expression. Previously, we reported that the SAS2 gene is required for optimal growth of yeast in the presence of arsenite (As III ). Yeast Sas2p is orthologous to human MYST1, a histone 4 lysine 16 (H4K16) acetyltransferase. Here, we show that H4K16 acetylation is necessary for the resistance of yeast to As III through the modulation of chromatin state. We further explored the role of MYST1 and H4K16 acetylation in arsenic toxicity and carcinogenesis in human bladder epithelial cells. The expression of MYST1 was knocked down in UROtsa cells, a model of bladder epithelium that has been used to study arsenic-induced carcinogenesis. Silencing of MYST1 reduced acetylation of H4K16 and induced sensitivity to As III and to its more toxic metabolite monomethylarsonous acid (MMA III ) at doses relevant to high environmental human exposures. In addition, both As III and MMA III treatments decreased global H4K16 acetylation levels in a dose- and time-dependent manner. This indicates that acetylated H4K16 is required for resistance to arsenic and that a reduction in its levels as a consequence of arsenic exposure may contribute to toxicity in UROtsa cells. Based on these findings, we propose a novel role for the MYST1 gene in human sensitivity to arsenic.

Protective effect of nitric oxide against arsenic-induced oxidative ...

African Journals Online (AJOL)

The effects of NO on alleviating arsenic-induced oxidative damage in tall fescue leaves were investigated. Arsenic (25 M) treatment induced significantly accumulation of reactive oxygen species (ROS) and led to serious lipid peroxidation in tall fescue leaves and the application of 100 M SNP before arsenic stress resulted ...

Knockdown of TWIST1 enhances arsenic trioxide- and ionizing radiation-induced cell death in lung cancer cells by promoting mitochondrial dysfunction

Energy Technology Data Exchange (ETDEWEB)

Seo, Sung-Keum; Kim, Jae-Hee; Choi, Ha-Na [Division of Radiation Cancer Research, Korea Institute of Radiological and Medical Sciences, 215-4 Gongneung-dong, Nowon-gu, Seoul (Korea, Republic of); Choe, Tae-Boo [Department of Microbiological Engineering, Kon-Kuk University, Gwangjin-gu, Seoul (Korea, Republic of); Hong, Seok-Il [Department of Laboratory Medicine, Korea Cancer Center Hospital, Korea Institute of Radiological and Medical Sciences, 215-4 Gongneung-dong, Nowon-gu, Seoul (Korea, Republic of); Yi, Jae-Youn [Laboratory of Modulation of Radiobiological Responses, Korea Institute of Radiological and Medical Sciences, 215-4 Gongneung-dong, Nowon-gu, Seoul (Korea, Republic of); Hwang, Sang-Gu [Division of Radiation Cancer Research, Korea Institute of Radiological and Medical Sciences, 215-4 Gongneung-dong, Nowon-gu, Seoul (Korea, Republic of); Lee, Hyun-Gyu [Department of Microbiology and Immunology, College of Medicine, Yonsei University, 250 Seongsan-no, Seodaemun-gu, Seoul (Korea, Republic of); Lee, Yun-Han, E-mail: yhlee87@yuhs.ac [Department of Radiation Oncology, College of Medicine, Yonsei University, 250 Seongsan-no, Seodaemun-gu, Seoul (Korea, Republic of); Park, In-Chul, E-mail: parkic@kcch.re.kr [Division of Radiation Cancer Research, Korea Institute of Radiological and Medical Sciences, 215-4 Gongneung-dong, Nowon-gu, Seoul (Korea, Republic of)

2014-07-11

Highlights: • Knockdown of TWIST1 enhanced ATO- and IR-induced cell death in NSCLCs. • Intracellular ROS levels were increased in cells treated with TWIST1 siRNA. • TWIST1 siRNA induced MMP loss and mitochondrial fragmentation. • TWIST1 siRNA upregulated the fission-related proteins FIS1 and DRP1. - Abstract: TWIST1 is implicated in the process of epithelial mesenchymal transition, metastasis, stemness, and drug resistance in cancer cells, and therefore is a potential target for cancer therapy. In the present study, we found that knockdown of TWIST1 by small interfering RNA (siRNA) enhanced arsenic trioxide (ATO)- and ionizing radiation (IR)-induced cell death in non-small-cell lung cancer cells. Interestingly, intracellular reactive oxygen species levels were increased in cells treated with TWIST1 siRNA and further increased by co-treatment with ATO or IR. Pretreatment of lung cancer cells with the antioxidant N-acetyl-cysteine markedly suppressed the cell death induced by combined treatment with TWIST1 siRNA and ATO or IR. Moreover, treatment of cells with TWIST1 siRNA induced mitochondrial membrane depolarization and significantly increased mitochondrial fragmentation (fission) and upregulated the fission-related proteins FIS1 and DRP1. Collectively, our results demonstrate that siRNA-mediated TWIST1 knockdown induces mitochondrial dysfunction and enhances IR- and ATO-induced cell death in lung cancer cells.

Study of arsenic accumulation in rice and evaluation of protective effects of Chorchorus olitorius leaves against arsenic contaminated rice induced toxicities in Wistar albino rats.

Science.gov (United States)

Hosen, Saeed Mohammed Imran; Das, Dipesh; Kobi, Rupkanowar; Chowdhury, Dil Umme Salma; Alam, Md Jibran; Rudra, Bashudev; Bakar, Muhammad Abu; Islam, Saiful; Rahman, Zillur; Al-Forkan, Mohammad

2016-10-14

In the present study, we investigated the arsenic accumulation in different parts of rice irrigated with arsenic contaminated water. Besides, we also evaluated the protective effects of Corchorus olitorius leaves against arsenic contaminated rice induced toxicities in animal model. A pot experiment was conducted with arsenic amended irrigation water (0.0, 25.0, 50.0 and 75.0 mg/L As) to investigate the arsenic accumulation in different parts of rice. In order to evaluate the protective effects of Corchorus olitorius leaves, twenty Wistar albino rats were divided into four different groups. The control group (Group-I) was supplied with normal laboratory pellets while groups II, III, and IV received normal laboratory pellets supplemented with arsenic contaminated rice, C. olitorius leaf powder (4 %), arsenic contaminated rice plus C. olitorius leaf powder (4 %) respectively. Different haematological parameters and serum indices were analyzed to evaluate the protective effects of Corchorus olitorius leaves against arsenic intoxication. To gather more supportive evidences of Corchorus olitorius potentiality against arsenic intoxication, histopathological analysis of liver, kidney, spleen and heart tissues was also performed. From the pot experiment, we have found a significant (p ≤ 0.05) increase of arsenic accumulation in different parts of rice with the increase of arsenic concentrations in irrigation water and the trend of accumulation was found as root > straw > husk > grain. Another part of the experiment revealed that supplementation of C. olitorius leaves with arsenic contaminated rice significantly (p rice induced toxicities. Arsenic accumulation in different parts of rice increased dose-dependently. Hence, for irrigation purpose arsenic contaminated water cannot be used. Furthermore, arsenic contaminated rice induced several toxicities in animal model, most of which could be minimized with the food supplementation of Corchorus olitorius

Role and mechanism of arsenic in regulating angiogenesis.

Directory of Open Access Journals (Sweden)

Ling-Zhi Liu

Full Text Available Arsenic is a wide spread carcinogen associated with several kinds of cancers including skin, lung, bladder, and liver cancers. Lung is one of the major targets of arsenic exposure. Angiogenesis is the pivotal process during carcinogenesis and chronic pulmonary diseases, but the role and mechanism of arsenic in regulating angiogenesis remain to be elucidated. In this study we show that short time exposure of arsenic induces angiogenesis in both human immortalized lung epithelial cells BEAS-2B and adenocarcinoma cells A549. To study the molecular mechanism of arsenic-inducing angiogenesis, we find that arsenic induces reactive oxygen species (ROS generation, which activates AKT and ERK1/2 signaling pathways and increases the expression of hypoxia-inducible factor 1 (HIF-1 and vascular endothelial growth factor (VEGF. Inhibition of ROS production suppresses angiogenesis by decreasing AKT and ERK activation and HIF-1 expression. Inhibition of ROS, AKT and ERK1/2 signaling pathways is sufficient to attenuate arsenic-inducing angiogenesis. HIF-1 and VEGF are downstream effectors of AKT and ERK1/2 that are required for arsenic-inducing angiogenesis. These results shed light on the mechanism of arsenic in regulating angiogenesis, and are helpful to develop mechanism-based intervention to prevent arsenic-induced carcinogenesis and angiogenesis in the future.

IDENTIFICATION OF INTERSPECIES CONCORDANCE OF MECHANISMS OF ARSENIC-INDUCED BLADDER CANCER

Science.gov (United States)

Exposure to arsenic causes cancer by inducing a variety of responses that affect the expression of genes associated with numerous biological pathways leading to altered cell growth and proliferation, signaling, apoptosis and oxidative stress response. Affymetrix GeneChip® arrays ...

Arsenic promotes centrosome abnormalities and cell colony formation in p53 compromised human lung cells

International Nuclear Information System (INIS)

Liao Weiting; Lin Pinpin; Cheng, T.-S.; Yu, H.-S.; Chang, Louis W.

2007-01-01

Epidemiological evidence indicated that residents, especially cigarette smokers, in arseniasis areas had significantly higher lung cancer risk than those living in non-arseniasis areas. Thus, an interaction between arsenic and cigarette smoking in lung carcinogenesis was suspected. p53 dysfunction or mutation in lung epithelial cells was frequently observed in cigarette smokers. Our present study was to explore the differential effects by arsenic on H1355 cells (human lung adenocarcinoma cell line with mutation in p53), BEAS-2B (immortalized lung epithelial cell with functional p53) and pifithrin-α-treated BEAS-2B cells (p53-inhibited cells). These cells were treated with different doses of sodium arsenite (0, 0.1, 1, 5 and 10 μM) for 48 h. A greater reduction in cell viability was observed in the BEAS-2B cells vs. p53 compromised cells (H1355 or p53-inhibited BEAS-2B). Similar observation was also made on 7-day cell survival (growth) study. TUNEL analysis confirmed that there was indeed a significantly reduced arsenite-induced apoptosis found in p53-compromised cells. Centrosomal abnormality has been attributed to eventual chromosomal missegregation, aneuploidy and tumorigenesis. In our present study, reduced p21 and Gadd45a expressions and increased centrosomal abnormality (atopic and multiple centrosomes) were observed in both arsenite-treated H1355 and p53-inhibited BEAS-2B cells as compared with similarly treated BEAS-2B cells. Increased anchorage-independent growth (colony formation) of BEAS-2B cells co-treated with pifithrin-α and 5 μM sodium arsenite was also observed in soft agar. Our present investigation demonstrated that arsenic would act specifically on p53 compromised cells (either with p53 dysfunction or inhibited) to induce centrosomal abnormality and colony formation. These findings provided strong evidence on the carcinogenic promotional role of arsenic, especially under the condition of p53 dysfunction

TG-interacting factor transcriptionally induced by AKT/FOXO3A is a negative regulator that antagonizes arsenic trioxide-induced cancer cell apoptosis

International Nuclear Information System (INIS)

Liu, Zi-Miao; Tseng, Hong-Yu; Cheng, Ya-Ling; Yeh, Bi-Wen; Wu, Wen-Jeng; Huang, Huei-Sheng

2015-01-01

Arsenic trioxide (ATO) is a multi-target drug approved by the Food and Drug Administration as the first-line chemotherapeutic agent for the treatment of acute promyelocytic leukemia. In addition, several clinical trials are being conducted with arsenic-based drugs for the treatment of other hematological malignancies and solid tumors. However, ATO's modest clinical efficacy on some cancers, and potential toxic effects on humans have been reported. Determining how best to reduce these adverse effects while increasing its therapeutic efficacy is obviously a critical issue. Previously, we demonstrated that the JNK-induced complex formation of phosphorylated c-Jun and TG-interacting factor (TGIF) antagonizes ERK-induced cyclin-dependent kinase inhibitor CDKN1A (p21 WAF1/CIP1 ) expression and resultant apoptosis in response to ATO in A431 cells. Surprisingly, at low-concentrations (0.1–0.2 μM), ATO increased cellular proliferation, migration and invasion, involving TGIF expression, however, at high-concentrations (5–20 μM), ATO induced cell apoptosis. Using a promoter analysis, TGIF was transcriptionally regulated by ATO at the FOXO3A binding site (− 1486 to − 1479 bp) via the c-Src/EGFR/AKT pathway. Stable overexpression of TGIF promoted advancing the cell cycle into the S phase, and attenuated 20 μM ATO-induced apoptosis. Furthermore, blockage of the AKT pathway enhanced ATO-induced CDKN1A expression and resultant apoptosis in cancer cells, but overexpression of AKT1 inhibited CDKN1A expression. Therefore, we suggest that TGIF is transcriptionally regulated by the c-Src/EGFR/AKT pathway, which plays a role as a negative regulator in antagonizing ATO-induced CDKN1A expression and resultant apoptosis. Suppression of these antagonistic effects might be a promising therapeutic strategy toward improving clinical efficacy of ATO. - Highlights: • ATO-induced biphasic survival responses of cancer cells depend on low- or high-concentrations. • TGIF mediates

TG-interacting factor transcriptionally induced by AKT/FOXO3A is a negative regulator that antagonizes arsenic trioxide-induced cancer cell apoptosis

Energy Technology Data Exchange (ETDEWEB)

Liu, Zi-Miao; Tseng, Hong-Yu; Cheng, Ya-Ling [Department of Medical Laboratory Science and Biotechnology, College of Medicine, National Cheng Kung University, Tainan 701, Taiwan (China); Yeh, Bi-Wen [Department of Medical Laboratory Science and Biotechnology, College of Medicine, National Cheng Kung University, Tainan 701, Taiwan (China); Department of Urology, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan (China); Department of Urology, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan (China); Wu, Wen-Jeng [Department of Urology, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan (China); Department of Urology, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan (China); Huang, Huei-Sheng, E-mail: huanghs@mail.ncku.edu.tw [Department of Medical Laboratory Science and Biotechnology, College of Medicine, National Cheng Kung University, Tainan 701, Taiwan (China)

2015-05-15

Arsenic trioxide (ATO) is a multi-target drug approved by the Food and Drug Administration as the first-line chemotherapeutic agent for the treatment of acute promyelocytic leukemia. In addition, several clinical trials are being conducted with arsenic-based drugs for the treatment of other hematological malignancies and solid tumors. However, ATO's modest clinical efficacy on some cancers, and potential toxic effects on humans have been reported. Determining how best to reduce these adverse effects while increasing its therapeutic efficacy is obviously a critical issue. Previously, we demonstrated that the JNK-induced complex formation of phosphorylated c-Jun and TG-interacting factor (TGIF) antagonizes ERK-induced cyclin-dependent kinase inhibitor CDKN1A (p21{sup WAF1/CIP1}) expression and resultant apoptosis in response to ATO in A431 cells. Surprisingly, at low-concentrations (0.1–0.2 μM), ATO increased cellular proliferation, migration and invasion, involving TGIF expression, however, at high-concentrations (5–20 μM), ATO induced cell apoptosis. Using a promoter analysis, TGIF was transcriptionally regulated by ATO at the FOXO3A binding site (− 1486 to − 1479 bp) via the c-Src/EGFR/AKT pathway. Stable overexpression of TGIF promoted advancing the cell cycle into the S phase, and attenuated 20 μM ATO-induced apoptosis. Furthermore, blockage of the AKT pathway enhanced ATO-induced CDKN1A expression and resultant apoptosis in cancer cells, but overexpression of AKT1 inhibited CDKN1A expression. Therefore, we suggest that TGIF is transcriptionally regulated by the c-Src/EGFR/AKT pathway, which plays a role as a negative regulator in antagonizing ATO-induced CDKN1A expression and resultant apoptosis. Suppression of these antagonistic effects might be a promising therapeutic strategy toward improving clinical efficacy of ATO. - Highlights: • ATO-induced biphasic survival responses of cancer cells depend on low- or high-concentrations. • TGIF

Arsenic induces structural and compositional colonic microbiome change and promotes host nitrogen and amino acid metabolism

International Nuclear Information System (INIS)

Dheer, Rishu; Patterson, Jena; Dudash, Mark; Stachler, Elyse N.; Bibby, Kyle J.; Stolz, Donna B.; Shiva, Sruti; Wang, Zeneng; Hazen, Stanley L.; Barchowsky, Aaron; Stolz, John F.

2015-01-01

Chronic exposure to arsenic in drinking water causes cancer and non-cancer diseases. However, mechanisms for chronic arsenic-induced pathogenesis, especially in response to lower exposure levels, are unclear. In addition, the importance of health impacts from xeniobiotic-promoted microbiome changes is just being realized and effects of arsenic on the microbiome with relation to disease promotion are unknown. To investigate impact of arsenic exposure on both microbiome and host metabolism, the stucture and composition of colonic microbiota, their metabolic phenotype, and host tissue and plasma metabolite levels were compared in mice exposed for 2, 5, or 10 weeks to 0, 10 (low) or 250 (high) ppb arsenite (As(III)). Genotyping of colonic bacteria revealed time and arsenic concentration dependent shifts in community composition, particularly the Bacteroidetes and Firmicutes, relative to those seen in the time-matched controls. Arsenic-induced erosion of bacterial biofilms adjacent to the mucosal lining and changes in the diversity and abundance of morphologically distinct species indicated changes in microbial community structure. Bacterical spores increased in abundance and intracellular inclusions decreased with high dose arsenic. Interestingly, expression of arsenate reductase (arsA) and the As(III) exporter arsB, remained unchanged, while the dissimilatory nitrite reductase (nrfA) gene expression increased. In keeping with the change in nitrogen metabolism, colonic and liver nitrite and nitrate levels and ratios changed with time. In addition, there was a concomitant increase in pathogenic arginine metabolites in the mouse circulation. These data suggest that arsenic exposure impacts the microbiome and microbiome/host nitrogen metabolism to support disease enhancing pathogenic phenotypes. - Highlights: • Arsenic exposure induces changes in host and host nitrogen metabolism that cause progresive change in the microbiome. • A polyphasic approach reveals changes

Arsenic induces structural and compositional colonic microbiome change and promotes host nitrogen and amino acid metabolism

Energy Technology Data Exchange (ETDEWEB)

Dheer, Rishu; Patterson, Jena; Dudash, Mark [Department of Biological Sciences, Duquesne University, Pittsburgh, PA 15282 (United States); Stachler, Elyse N.; Bibby, Kyle J. [Department of Civil and Environmental Engineering, University of Pittsburgh Swanson School of Engineering, Pittsburgh, PA 15261 (United States); Stolz, Donna B. [Department of Cell Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261 (United States); Shiva, Sruti [Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh 15261 (United States); Vascular Medicine Institute, University of Pittsburgh, Pittsburgh 15261 (United States); Wang, Zeneng; Hazen, Stanley L. [Department of Cellular and Molecular Medicine, Cleveland Clinic Lerner Research Institute, Cleveland, OH 44195 (United States); Barchowsky, Aaron, E-mail: aab20@pitt.edu [Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh 15261 (United States); Vascular Medicine Institute, University of Pittsburgh, Pittsburgh 15261 (United States); Department of Environmental and Occupational Health, University of Pittsburgh Graduate School of Public Health, Pittsburgh, PA 15219 (United States); Stolz, John F. [Department of Biological Sciences, Duquesne University, Pittsburgh, PA 15282 (United States)

2015-12-15

Chronic exposure to arsenic in drinking water causes cancer and non-cancer diseases. However, mechanisms for chronic arsenic-induced pathogenesis, especially in response to lower exposure levels, are unclear. In addition, the importance of health impacts from xeniobiotic-promoted microbiome changes is just being realized and effects of arsenic on the microbiome with relation to disease promotion are unknown. To investigate impact of arsenic exposure on both microbiome and host metabolism, the stucture and composition of colonic microbiota, their metabolic phenotype, and host tissue and plasma metabolite levels were compared in mice exposed for 2, 5, or 10 weeks to 0, 10 (low) or 250 (high) ppb arsenite (As(III)). Genotyping of colonic bacteria revealed time and arsenic concentration dependent shifts in community composition, particularly the Bacteroidetes and Firmicutes, relative to those seen in the time-matched controls. Arsenic-induced erosion of bacterial biofilms adjacent to the mucosal lining and changes in the diversity and abundance of morphologically distinct species indicated changes in microbial community structure. Bacterical spores increased in abundance and intracellular inclusions decreased with high dose arsenic. Interestingly, expression of arsenate reductase (arsA) and the As(III) exporter arsB, remained unchanged, while the dissimilatory nitrite reductase (nrfA) gene expression increased. In keeping with the change in nitrogen metabolism, colonic and liver nitrite and nitrate levels and ratios changed with time. In addition, there was a concomitant increase in pathogenic arginine metabolites in the mouse circulation. These data suggest that arsenic exposure impacts the microbiome and microbiome/host nitrogen metabolism to support disease enhancing pathogenic phenotypes. - Highlights: • Arsenic exposure induces changes in host and host nitrogen metabolism that cause progresive change in the microbiome. • A polyphasic approach reveals changes

(--Epigallocatechin-3-Gallate Inhibits Arsenic-Induced Inflammation and Apoptosis through Suppression of Oxidative Stress in Mice

Directory of Open Access Journals (Sweden)

Nan-Hui Yu

2017-04-01

Full Text Available Background/Aims: Exposure to arsenic in individuals has been found to be associated with various health-related problems including skin lesions, cancer, and cardiovascular and immunological disorders. (--Epigallocatechin-3-gallate (EGCG, the main and active polyphenolic catechin present in green tea, has shown potent antioxidant, anti-apoptotic and anti-inflammatory activity in vivo and in vitro. Thus, the present study was conducted to investigate the protective effects of EGCG against arsenic-induced inflammation and immunotoxicity in mice. Methods: Serum IL-1β, IL-6 and TNF-α were determined by ELISA, tissue catalase (CAT, malonyldialdehyde (MDA, superoxide dismutase (SOD, glutathione (GSH, nitric oxide and caspase 3 by commercial kits, mitochondrial membrane potential with Rh 123, mitochondrial ROS with 2’,7’-dichlorofluorescin diacetate (DCFH-DA, apoptotic and necrotic cells and T-cell phenotyping with Flow cytometry analysis. Results: The results showed that arsenic treatment significantly increased oxidative stress levels (as indicated by catalase, malonyldialdehyde, superoxide dismutase, glutathione and reactive oxygen species, increased levels of inflammatory cytokines and promoted apoptosis. Arsenic exposure increased the relative frequency of the CD8+(Tc cell subpopulation (from 2.8 to 18.9% and decreased the frequency of CD4+(Th cells (from 5.2 to 2.7%. Arsenic exposure also significantly decreased the frequency of T(CD3 (from 32.5% to 19.2% and B(CD19 cells (from 55.1 to 32.5%. All of these effects induced by NaAsO2 were attenuated by EGCG. Conclusions: The present in vitro findings indicate that EGCG attenuates not only NaAsO2-induced immunosuppression but also inflammation and apoptosis.

Inhibition of insulin-dependent glucose uptake by trivalent arsenicals: possible mechanism of arsenic-induced diabetes

International Nuclear Information System (INIS)

Walton, Felecia S.; Harmon, Anne W.; Paul, David S.; Drobna, Zuzana; Patel, Yashomati M.; Styblo, Miroslav

2004-01-01

Chronic exposures to inorganic arsenic (iAs) have been associated with increased incidence of noninsulin (type-2)-dependent diabetes mellitus. Although mechanisms by which iAs induces diabetes have not been identified, the clinical symptoms of the disease indicate that iAs or its metabolites interfere with insulin-stimulated signal transduction pathway or with critical steps in glucose metabolism. We have examined effects of iAs and methylated arsenicals that contain trivalent or pentavalent arsenic on glucose uptake by 3T3-L1 adipocytes. Treatment with inorganic and methylated pentavalent arsenicals (up to 1 mM) had little or no effect on either basal or insulin-stimulated glucose uptake. In contrast, trivalent arsenicals, arsenite (iAs III ), methylarsine oxide (MAs III O), and iododimethylarsine (DMAs III O) inhibited insulin-stimulated glucose uptake in a concentration-dependent manner. Subtoxic concentrations of iAs III (20 μM), MAs III O (1 μM), or DMAs III I (2 μM) decreased insulin-stimulated glucose uptake by 35-45%. Basal glucose uptake was significantly inhibited only by cytotoxic concentrations of iAs III or MAs III O. Examination of the components of the insulin-stimulated signal transduction pathway showed that all trivalent arsenicals suppressed expression and possibly phosphorylation of protein kinase B (PKB/Akt). The concentration of an insulin-responsive glucose transporter (GLUT4) was significantly lower in the membrane region of 3T3-L1 adipocytes treated with trivalent arsenicals as compared with untreated cells. These results suggest that trivalent arsenicals inhibit insulin-stimulated glucose uptake by interfering with the PKB/Akt-dependent mobilization of GLUT4 transporters in adipocytes. This mechanism may be, in part, responsible for the development of type-2 diabetes in individuals chronically exposed to iAs

Taurine prevents arsenic-induced cardiac oxidative stress and apoptotic damage: Role of NF-κB, p38 and JNK MAPK pathway

International Nuclear Information System (INIS)

Ghosh, Jyotirmoy; Das, Joydeep; Manna, Prasenjit; Sil, Parames C.

2009-01-01

Cardiac dysfunction is a major cause of morbidity and mortality worldwide due to its complex pathogenesis. However, little is known about the mechanism of arsenic-induced cardiac abnormalities and the use of antioxidants as the possible protective agents in this pathophysiology. Conditionally essential amino acid, taurine, accounts for 25% to 50% of the amino acid pool in myocardium and possesses antioxidant properties. The present study has, therefore, been carried out to investigate the underlying mechanism of the beneficial role of taurine in arsenic-induced cardiac oxidative damage and cell death. Arsenic reduced cardiomyocyte viability, increased reactive oxygen species (ROS) production and intracellular calcium overload, and induced apoptotic cell death by mitochondrial dependent caspase-3 activation and poly-ADP ribose polymerase (PARP) cleavage. These changes due to arsenic exposure were found to be associated with increased IKK and NF-κB (p65) phosphorylation. Pre-exposure of myocytes to an IKK inhibitor (PS-1145) prevented As-induced caspase-3 and PARP cleavage. Arsenic also markedly increased the activity of p38 and JNK MAPKs, but not ERK to that extent. Pre-treatment with SP600125 (JNK inhibitor) and SB203580 (p38 MAPK inhibitor) attenuated NF-κB and IKK phosphorylation indicating that p38 and JNK MAPKs are mainly involved in arsenic-induced NF-κB activation. Taurine treatment suppressed these apoptotic actions, suggesting that its protective role in arsenic-induced cardiomyocyte apoptosis is mediated by attenuation of p38 and JNK MAPK signaling pathways. Similarly, arsenic intoxication altered a number of biomarkers related to cardiac oxidative stress and other apoptotic indices in vivo and taurine supplementation could reduce it. Results suggest that taurine prevented arsenic-induced myocardial pathophysiology, attenuated NF-κB activation via IKK, p38 and JNK MAPK signaling pathways and could possibly provide a protection against As-induced

The effects of arsenic or the combination of arsenic and radiation exposure is enhanced through the overexpression of the GSTO family member p28

International Nuclear Information System (INIS)

Giri, U.; Story, M.D.; Terry, N.H.A.; Giri, D.K.; Calkins, P.R.

2003-01-01

Full text: p28 is a member of the GST omega superfamily and has dehydroascorbate reductase, GST, and glutaredoxin activities. Furthermore, p28 is the rate-limiting enzyme in the bio-transformation of arsenic. The monomethyl arsenous reducatase activity of p28 produces dimethylarseniate, the most toxic form of arsenic. We investigated how p28 modulated arsenic cellular sensitivity in two mammalian models: 1) in LY-ar and LY-as cells where p28 is over-expressed and not expressed, respectively; and 2) in stably transfected A549 cells where p28 is over-expressed via a CMV promoter. The LY-ar mouse lymphoma cell line is radio and chemo-resistant and apoptosis refractory, whereas the parental cell line, LY-as, is radiosensitive and apoptotically permissive. In addition, we studied the effect of arsenic as a radiosensitizer in both cell systems. In LY-ar cells arsenic induced a dose- and time- dependent increase in apoptosis, which is comparable to that seen in LY-as cells. Arsenic plus 2.5Gy radiation induced apoptosis in LY-ar cells, which was more than additive. Survival in LY-ar cells was reduced to that of LY-as cells as well as p28 overexpression induced G2/M arrest in A549 cells and the combination of radiation with arsenic decreased the clonogenic survival of both the A549 and A549-p28 cells but the effect is more pronounced in the A549-P28 cell line. A549 and A549-p28 cells did not show a differential response to Taxol, which induces G2/M arrest and cell death via an inhibition of tubulin depolarization. Arsenic modulated the level of reduced GSH in both cell systems in a dose- and time- dependent manner, which correlated with survival outcome. This study illustrated that arsenic acts as a radiosensitizer and p28 augmented the potential of arsenic in inducing apoptosis, G2/M arrest, and radiosensitization. Further studies are underway to examine the bio-chemical pathways involved in arsenic-mediated cell death and the role of p28 therein

Arsenic activates the expression of 3β-HSD in mouse Leydig cells through repression of histone H3K9 methylation

International Nuclear Information System (INIS)

Alamdar, Ambreen; Xi, Guochen; Huang, Qingyu; Tian, Meiping; Eqani, Syed Ali Musstjab Akber Shah; Shen, Heqing

2017-01-01

Arsenic exposure has been associated with male reproductive dysfunction by disrupting steroidogenesis; however, the roles of epigenetic drivers, especially histone methylation in arsenic-induced steroidogenic toxicity remain not well documented. In this study, we investigated the role of histone H3 lysine 9 (H3K9) methylation in steroidogenesis disturbance in mouse Leydig cells (MLTC-1) due to arsenic exposure. Our results indicated that mRNA and protein expression levels of 3β-hydroxysteroid dehydrogenase (3β-HSD) were both significantly up-regulated while the rest of key genes involved in steroidogenesis were down-regulated. Moreover, arsenic exposure significantly decreased the histone H3K9 di- and tri-methylation (H3K9me2/3) levels in MLTC-1 cells. Since H3K9 demethylation leads to gene activation, we further investigated whether the induction of 3β-HSD expression was ascribed to reduced H3K9 methylation. The results showed that H3K9me2/3 demethylase (JMJD2A) inhibitor, quercetin (Que) significantly attenuated the decrease of H3K9me2/3 and increase of 3β-HSD expression induced by arsenic. To further elucidate the mechanism for the activation of 3β-HSD, we determined the histone H3K9 methylation levels in Hsd3b gene promoter, which also showed significant decrease of H3K9me2/3 in the investigated region after arsenic exposure. Considering these results, we conclude that arsenic exposure induced 3β-HSD up-regulation by suppressing H3K9me2/3 status, which is suggested as a compensatory mechanism for steroidogenic disturbance in MLTC-1 cells. - Highlights: • Epigenetic mechanisms of arsenic-induced male reproductive toxicity remain unclear. • Arsenic disturbs the expression of key steroidogenic genes in MLTC-1 cells. • Histone H3K9 di- and tri-methylation was suppressed in arsenic-exposed cells. • Arsenic activates 3β-HSD expression through repression of histone H3K9 methylation.

Arsenic activates the expression of 3β-HSD in mouse Leydig cells through repression of histone H3K9 methylation

Energy Technology Data Exchange (ETDEWEB)

Alamdar, Ambreen; Xi, Guochen [Key Laboratory of Urban Environment and Health, Institute of Urban Environment, Chinese Academy of Sciences, Xiamen 361021 (China); Huang, Qingyu, E-mail: qyhuang@iue.ac.cn [Key Laboratory of Urban Environment and Health, Institute of Urban Environment, Chinese Academy of Sciences, Xiamen 361021 (China); Centre for Epigenetics, Department of Biochemistry and Molecular Biology, University of Southern Denmark, Odense M (Denmark); Tian, Meiping [Key Laboratory of Urban Environment and Health, Institute of Urban Environment, Chinese Academy of Sciences, Xiamen 361021 (China); Eqani, Syed Ali Musstjab Akber Shah [Key Laboratory of Urban Environment and Health, Institute of Urban Environment, Chinese Academy of Sciences, Xiamen 361021 (China); Public Health and Environment Division, Department of Biosciences, COMSAT Institute of Information & Technology, Islamabad (Pakistan); Shen, Heqing, E-mail: hqshen@iue.ac.cn [Key Laboratory of Urban Environment and Health, Institute of Urban Environment, Chinese Academy of Sciences, Xiamen 361021 (China)

2017-07-01

Arsenic exposure has been associated with male reproductive dysfunction by disrupting steroidogenesis; however, the roles of epigenetic drivers, especially histone methylation in arsenic-induced steroidogenic toxicity remain not well documented. In this study, we investigated the role of histone H3 lysine 9 (H3K9) methylation in steroidogenesis disturbance in mouse Leydig cells (MLTC-1) due to arsenic exposure. Our results indicated that mRNA and protein expression levels of 3β-hydroxysteroid dehydrogenase (3β-HSD) were both significantly up-regulated while the rest of key genes involved in steroidogenesis were down-regulated. Moreover, arsenic exposure significantly decreased the histone H3K9 di- and tri-methylation (H3K9me2/3) levels in MLTC-1 cells. Since H3K9 demethylation leads to gene activation, we further investigated whether the induction of 3β-HSD expression was ascribed to reduced H3K9 methylation. The results showed that H3K9me2/3 demethylase (JMJD2A) inhibitor, quercetin (Que) significantly attenuated the decrease of H3K9me2/3 and increase of 3β-HSD expression induced by arsenic. To further elucidate the mechanism for the activation of 3β-HSD, we determined the histone H3K9 methylation levels in Hsd3b gene promoter, which also showed significant decrease of H3K9me2/3 in the investigated region after arsenic exposure. Considering these results, we conclude that arsenic exposure induced 3β-HSD up-regulation by suppressing H3K9me2/3 status, which is suggested as a compensatory mechanism for steroidogenic disturbance in MLTC-1 cells. - Highlights: • Epigenetic mechanisms of arsenic-induced male reproductive toxicity remain unclear. • Arsenic disturbs the expression of key steroidogenic genes in MLTC-1 cells. • Histone H3K9 di- and tri-methylation was suppressed in arsenic-exposed cells. • Arsenic activates 3β-HSD expression through repression of histone H3K9 methylation.

Biomarkers of exposure, effect, and susceptibility of arsenic-induced health hazards in Taiwan

International Nuclear Information System (INIS)

Chen, C.-J.; Hsu, L.-I; Wang, C.-H.

2005-01-01

Long-term exposure to inorganic arsenic from drinking water has been documented to induce cancers and vascular diseases in a dose-response relationship. A series of molecular environmental epidemiological studies have been carried out to elucidate biomarkers of exposure, effect, and susceptibility for arsenic-related health hazards in Taiwan. Arsenic levels in urine, hair, and nail are biomarkers for short-term (<1 year) internal dose, skin hyperpigmentation and palmoplantar hyperkeratosis are for long-term (many years) internal dose, and percentage of monomethylarsonic acid in total metabolites of inorganic arsenic in urine may be considered as an exposure marker for biologically effective dose. The biomarkers of early biological effects of ingested inorganic arsenic included blood levels of reactive oxidants and anti-oxidant capacity, genetic expression of inflammatory molecules, as well as cytogenetic changes including sister chromatid exchange, micronuclei, and chromosome aberrations of peripheral lymphocytes. Both mutation type and hot spots of p53 gene were significantly different in arsenic-induced and non-arsenic-induced TCCs. The frequency of chromosomal imbalances analyzed by comparative genomic hybridization and the frequency of loss of heterozygosity were significantly higher in arsenic-induced TCC than non-arsenic-induced TCC at specific sites. Biomarkers of susceptibility to arsenic-induced health hazards included genetic polymorphisms of enzymes involved in xenobiotic metabolism, DNA repair, and oxidative stress, as well as serum level of carotenoids. Gene-gene and gene-environment interactions are involved in arsenic-induced health hazards through toxicological mechanisms including genomic instability and oxidative stress

Arsenic inhibits hedgehog signaling during P19 cell differentiation

Energy Technology Data Exchange (ETDEWEB)

Liu, Jui Tung [Environmental Toxicology Program, Clemson University, 132 Long Hall, Clemson, SC 29634 (United States); Bain, Lisa J., E-mail: lbain@clemson.edu [Environmental Toxicology Program, Clemson University, 132 Long Hall, Clemson, SC 29634 (United States); Department of Biological Sciences, Clemson University, 132 Long Hall, Clemson, SC 29634 (United States)

2014-12-15

Arsenic is a toxicant found in ground water around the world, and human exposure mainly comes from drinking water or from crops grown in areas containing arsenic in soils or water. Epidemiological studies have shown that arsenic exposure during development decreased intellectual function, reduced birth weight, and altered locomotor activity, while in vitro studies have shown that arsenite decreased muscle and neuronal cell differentiation. The sonic hedgehog (Shh) signaling pathway plays an important role during the differentiation of both neurons and skeletal muscle. The purpose of this study was to investigate whether arsenic can disrupt Shh signaling in P19 mouse embryonic stem cells, leading to changes muscle and neuronal cell differentiation. P19 embryonic stem cells were exposed to 0, 0.25, or 0.5 μM of sodium arsenite for up to 9 days during cell differentiation. We found that arsenite exposure significantly reduced transcript levels of genes in the Shh pathway in both a time and dose-dependent manner. This included the Shh ligand, which was decreased 2- to 3-fold, the Gli2 transcription factor, which was decreased 2- to 3-fold, and its downstream target gene Ascl1, which was decreased 5-fold. GLI2 protein levels and transcriptional activity were also reduced. However, arsenic did not alter GLI2 primary cilium accumulation or nuclear translocation. Moreover, additional extracellular SHH rescued the inhibitory effects of arsenic on cellular differentiation due to an increase in GLI binding activity. Taken together, we conclude that arsenic exposure affected Shh signaling, ultimately decreasing the expression of the Gli2 transcription factor. These results suggest a mechanism by which arsenic disrupts cell differentiation. - Highlights: • Arsenic exposure decreases sonic hedgehog pathway-related gene expression. • Arsenic decreases GLI2 protein levels and transcriptional activity in P19 cells. • Arsenic exposure does not alter the levels of SHH

Arsenic responsive microRNAs in vivo and their potential involvement in arsenic-induced oxidative stress

International Nuclear Information System (INIS)

Ren, Xuefeng; Gaile, Daniel P.; Gong, Zhihong; Qiu, Wenting; Ge, Yichen; Zhang, Chuanwu; Huang, Chenping; Yan, Hongtao; Olson, James R.; Kavanagh, Terrance J.; Wu, Hongmei

2015-01-01

Arsenic exposure is postulated to modify microRNA (miRNA) expression, leading to changes of gene expression and toxicities, but studies relating the responses of miRNAs to arsenic exposure are lacking, especially with respect to in vivo studies. We utilized high-throughput sequencing technology and generated miRNA expression profiles of liver tissues from Sprague Dawley (SD) rats exposed to various concentrations of sodium arsenite (0, 0.1, 1, 10 and 100 mg/L) for 60 days. Unsupervised hierarchical clustering analysis of the miRNA expression profiles clustered the SD rats into different groups based on the arsenic exposure status, indicating a highly significant association between arsenic exposure and cluster membership (p-value of 0.0012). Multiple miRNA expressions were altered by arsenic in an exposure concentration-dependent manner. Among the identified arsenic-responsive miRNAs, several are predicted to target Nfe2l2-regulated antioxidant genes, including glutamate–cysteine ligase (GCL) catalytic subunit (GCLC) and modifier subunit (GCLM) which are involved in glutathione (GSH) synthesis. Exposure to low concentrations of arsenic increased mRNA expression for Gclc and Gclm, while high concentrations significantly reduced their expression, which were correlated to changes in hepatic GCL activity and GSH level. Moreover, our data suggested that other mechanisms, e.g., miRNAs, rather than Nfe2l2-signaling pathway, could be involved in the regulation of mRNA expression of Gclc and Gclm post-arsenic exposure in vivo. Together, our findings show that arsenic exposure disrupts the genome-wide expression of miRNAs in vivo, which could lead to the biological consequence, such as an altered balance of antioxidant defense and oxidative stress. - Highlights: • Chronic arsenic exposure induces changes of hepatic miRNA expression profiles. • Hepatic GCL activity and GSH level in rats are altered following arsenic exposure. • Arsenic induced GCL expression change is

Arsenic responsive microRNAs in vivo and their potential involvement in arsenic-induced oxidative stress

Energy Technology Data Exchange (ETDEWEB)

Ren, Xuefeng, E-mail: xuefengr@buffalo.edu [Department of Epidemiology and Environmental Health, School of Public Health and Health Professions, The State University of New York, Buffalo, NY 14214 (United States); Department of Pharmacology and Toxicology, School of Biomedical Sciences, The State University of New York, Buffalo, NY 14214 (United States); Gaile, Daniel P. [Department of Biostatistics, School of Public Health and Health Professions, the State University of New York, Buffalo, NY 14214 (United States); Gong, Zhihong [Department of Epidemiology and Environmental Health, School of Public Health and Health Professions, The State University of New York, Buffalo, NY 14214 (United States); Qiu, Wenting [School of Public Health, Wenzhou Medical University, Wenzhou, Zhejiang 325035 (China); Ge, Yichen [Department of Epidemiology and Environmental Health, School of Public Health and Health Professions, The State University of New York, Buffalo, NY 14214 (United States); Zhang, Chuanwu; Huang, Chenping; Yan, Hongtao [School of Public Health, Wenzhou Medical University, Wenzhou, Zhejiang 325035 (China); Olson, James R. [Department of Epidemiology and Environmental Health, School of Public Health and Health Professions, The State University of New York, Buffalo, NY 14214 (United States); Department of Pharmacology and Toxicology, School of Biomedical Sciences, The State University of New York, Buffalo, NY 14214 (United States); Kavanagh, Terrance J. [Department of Environmental and Occupational Health Sciences, University of Washington, Seattle, WA 98195 (United States); Wu, Hongmei, E-mail: hongmeiwwu@hotmail.com [School of Public Health, Wenzhou Medical University, Wenzhou, Zhejiang 325035 (China)

2015-03-15

Arsenic exposure is postulated to modify microRNA (miRNA) expression, leading to changes of gene expression and toxicities, but studies relating the responses of miRNAs to arsenic exposure are lacking, especially with respect to in vivo studies. We utilized high-throughput sequencing technology and generated miRNA expression profiles of liver tissues from Sprague Dawley (SD) rats exposed to various concentrations of sodium arsenite (0, 0.1, 1, 10 and 100 mg/L) for 60 days. Unsupervised hierarchical clustering analysis of the miRNA expression profiles clustered the SD rats into different groups based on the arsenic exposure status, indicating a highly significant association between arsenic exposure and cluster membership (p-value of 0.0012). Multiple miRNA expressions were altered by arsenic in an exposure concentration-dependent manner. Among the identified arsenic-responsive miRNAs, several are predicted to target Nfe2l2-regulated antioxidant genes, including glutamate–cysteine ligase (GCL) catalytic subunit (GCLC) and modifier subunit (GCLM) which are involved in glutathione (GSH) synthesis. Exposure to low concentrations of arsenic increased mRNA expression for Gclc and Gclm, while high concentrations significantly reduced their expression, which were correlated to changes in hepatic GCL activity and GSH level. Moreover, our data suggested that other mechanisms, e.g., miRNAs, rather than Nfe2l2-signaling pathway, could be involved in the regulation of mRNA expression of Gclc and Gclm post-arsenic exposure in vivo. Together, our findings show that arsenic exposure disrupts the genome-wide expression of miRNAs in vivo, which could lead to the biological consequence, such as an altered balance of antioxidant defense and oxidative stress. - Highlights: • Chronic arsenic exposure induces changes of hepatic miRNA expression profiles. • Hepatic GCL activity and GSH level in rats are altered following arsenic exposure. • Arsenic induced GCL expression change is

Nicotinamide enhances repair of arsenic and ultraviolet radiation-induced DNA damage in HaCaT keratinocytes and ex vivo human skin.

Directory of Open Access Journals (Sweden)

Benjamin C Thompson

Full Text Available Arsenic-induced skin cancer is a significant global health burden. In areas with arsenic contamination of water sources, such as China, Pakistan, Myanmar, Cambodia and especially Bangladesh and West Bengal, large populations are at risk of arsenic-induced skin cancer. Arsenic acts as a co-carcinogen with ultraviolet (UV radiation and affects DNA damage and repair. Nicotinamide (vitamin B3 reduces premalignant keratoses in sun-damaged skin, likely by prevention of UV-induced cellular energy depletion and enhancement of DNA repair. We investigated whether nicotinamide modifies DNA repair following exposure to UV radiation and sodium arsenite. HaCaT keratinocytes and ex vivo human skin were exposed to 2μM sodium arsenite and low dose (2J/cm2 solar-simulated UV, with and without nicotinamide supplementation. DNA photolesions in the form of 8-oxo-7,8-dihydro-2'-deoxyguanosine and cyclobutane pyrimidine dimers were detected by immunofluorescence. Arsenic exposure significantly increased levels of 8-oxo-7,8-dihydro-2'-deoxyguanosine in irradiated cells. Nicotinamide reduced both types of photolesions in HaCaT keratinocytes and in ex vivo human skin, likely by enhancing DNA repair. These results demonstrate a reduction of two different photolesions over time in two different models in UV and arsenic exposed cells. Nicotinamide is a nontoxic, inexpensive agent with potential for chemoprevention of arsenic induced skin cancer.

Arsenic downregulates tight junction claudin proteins through p38 and NF-κB in intestinal epithelial cell line, HT-29

International Nuclear Information System (INIS)

Jeong, Chang Hee; Seok, Jin Sil; Petriello, Michael C.; Han, Sung Gu

2017-01-01

Arsenic is a naturally occurring metalloid that often is found in foods and drinking water. Human exposure to arsenic is associated with the development of gastrointestinal problems such as fluid loss, diarrhea and gastritis. Arsenic is also known to induce toxic responses including oxidative stress in cells of the gastrointestinal track. Tight junctions (TJs) regulate paracellular permeability and play a barrier role by inhibiting the movement of water, solutes and microorganisms in the paracellular space. Since oxidative stress and TJ damage are known to be associated, we examined whether arsenic produces TJ damage such as downregulation of claudins in the human colorectal cell line, HT-29. To confirm the importance of oxidative stress in arsenic-induced TJ damage, effects of the antioxidant compound (e.g., N-acetylcysteine (NAC)) were also determined in cells. HT-29 cells were treated with arsenic trioxide (40 μM, 12 h) to observe the modified expression of TJ proteins. Arsenic decreased expression of TJ proteins (i.e., claudin-1 and claudin-5) and transepithelial electrical resistance (TEER) whereas pretreatment of NAC (5–10 mM, 1 h) attenuated the observed claudins downregulation and TEER. Arsenic treatment produced cellular oxidative stress via superoxide generation and lowering glutathione (GSH) levels, while NAC restored cellular GSH levels and decreased oxidative stress. Arsenic increased phosphorylation of p38 and nuclear translocation of nuclear factor-kappa B (NF-κB) p65, while NAC attenuated these intracellular events. Results demonstrated that arsenic can damage intestinal epithelial cells by proinflammatory process (oxidative stress, p38 and NF-κB) which resulted in the downregulation of claudins and NAC can protect intestinal TJs from arsenic toxicity.

Induction of Human Squamous Cell-Type Carcinomas by Arsenic

International Nuclear Information System (INIS)

Martinez, V. D.; Becker-Santos, D. D.; Vucic, E. A.; Lam, S.; Lam, W. L.

2011-01-01

Arsenic is a potent human carcinogen. Around one hundred million people worldwide have potentially been exposed to this metalloid at concentrations considered unsafe. Exposure occurs generally through drinking water from natural geological sources, making it difficult to control this contamination. Arsenic biotransformation is suspected to have a role in arsenic-related health effects ranging from acute toxicities to development of malignancies associated with chronic exposure. It has been demonstrated that arsenic exhibits preference for induction of squamous cell carcinomas in the human, especially skin and lung cancer. Interestingly, keratins emerge as a relevant factor in this arsenic-related squamous cell-type preference. Additionally, both genomic and epi genomic alterations have been associated with arsenic-driven neoplastic process. Some of these aberrations, as well as changes in other factors such as keratins, could explain the association between arsenic and squamous cell carcinomas in humans.

Combination of siRNA-directed Kras oncogene silencing and arsenic-induced apoptosis using a nanomedicine strategy for the effective treatment of pancreatic cancer.

Science.gov (United States)

Zeng, Linjuan; Li, Jingguo; Wang, Yong; Qian, Chenchen; Chen, Yinting; Zhang, Qiubo; Wu, Wei; Lin, Zhong; Liang, Jianzhong; Shuai, Xintao; Huang, Kaihong

2014-02-01

The synergetic inhibitory effects on human pancreatic cancer by nanoparticle-mediated siRNA and arsenic therapy were investigated both in vitro and in vivo. Poly(ethylene glycol)-block-poly(L-lysine) were prepared to form siRNA-complexed polyplex and poly(ethylene glycol)-block-poly(DL-lactide) were prepared to form arsenic-encapsulated vesicle, respectively. Down-regulation of the mutant Kras gene by siRNA caused defective abilities of proliferation, clonal formation, migration, and invasion of pancreatic cancer cells, as well as cell cycle arrest at the G0/G1 phase, which substantially enhanced the apoptosis-inducing effect of arsenic administration. Consequently, co-administration of the two nanomedicines encapsulating siRNA or arsenic showed ideal tumor growth inhibition both in vitro and in vivo as a result of synergistic effect of the siRNA-directed Kras oncogene silencing and arsenic-induced cell apoptosis. These results suggest that the combination of mutant Kras gene silencing and arsenic therapy using nanoparticle-mediated delivery strategy is promising for pancreatic cancer treatment. Treatment of pancreatic cancer remains a major challenge. These authors demonstrate a method that combines a siRNA-based Kras silencing with arsenic delivery to pancreatic cancer cells using nanoparticles, resulting in enhanced apoptosis induction in the treated cells. © 2013.

Arsenic mediated disruption of promyelocytic leukemia protein nuclear bodies induces ganciclovir susceptibility in Epstein-Barr positive epithelial cells

International Nuclear Information System (INIS)

Sides, Mark D.; Block, Gregory J.; Shan, Bin; Esteves, Kyle C.; Lin, Zhen; Flemington, Erik K.; Lasky, Joseph A.

2011-01-01

Promyelocytic leukemia protein nuclear bodies (PML NBs) have been implicated in host immune response to viral infection. PML NBs are targeted for degradation during reactivation of herpes viruses, suggesting that disruption of PML NB function supports this aspect of the viral life cycle. The Epstein-Barr virus (EBV) Latent Membrane Protein 1 (LMP1) has been shown to suppress EBV reactivation. Our finding that LMP1 induces PML NB immunofluorescence intensity led to the hypothesis that LMP1 may modulate PML NBs as a means of maintaining EBV latency. Increased PML protein and morphometric changes in PML NBs were observed in EBV infected alveolar epithelial cells and nasopharyngeal carcinoma cells. Treatment with low dose arsenic trioxide disrupted PML NBs, induced expression of EBV lytic proteins, and conferred ganciclovir susceptibility. This study introduces an effective modality to induce susceptibility to ganciclovir in epithelial cells with implications for the treatment of EBV associated pathologies.

Protective effect of nitric oxide against arsenic-induced oxidative ...

African Journals Online (AJOL)

STORAGESEVER

2010-03-15

Mar 15, 2010 ... 1Department of Soil and Water Science, College of Resources and Environment, ... alleviated arsenic-induced electrolyte leakage and malondiadehyde (MDA) content in ..... gene construct for environmental arsenic detection.

Inorganic arsenic impairs differentiation and functions of human dendritic cells

International Nuclear Information System (INIS)

Macoch, Mélinda; Morzadec, Claudie; Fardel, Olivier; Vernhet, Laurent

2013-01-01

Experimental studies have demonstrated that the antileukemic trivalent inorganic arsenic prevents the development of severe pro-inflammatory diseases mediated by excessive Th1 and Th17 cell responses. Differentiation of Th1 and Th17 subsets is mainly regulated by interleukins (ILs) secreted from dendritic cells (DCs) and the ability of inorganic arsenic to impair interferon-γ and IL-17 secretion by interfering with the physiology of DCs is unknown. In the present study, we demonstrate that high concentrations of sodium arsenite (As(III), 1–2 μM) clinically achievable in plasma of arsenic-treated patients, block differentiation of human peripheral blood monocytes into immature DCs (iDCs) by inducing their necrosis. Differentiation of monocytes in the presence of non-cytotoxic concentrations of As(III) (0.1 to 0.5 μM) only slightly impacts endocytotic activity of iDCs or expression of co-stimulatory molecules in cells activated with lipopolysaccharide. However, this differentiation in the presence of As(III) strongly represses secretion of IL-12p70 and IL-23, two major regulators of Th1 and Th17 activities, from iDCs stimulated with different toll-like receptor (TLR) agonists in metalloid-free medium. Such As(III)-exposed DCs also exhibit reduced mRNA levels of IL12A and/or IL12B genes when activated with TLR agonists. Finally, differentiation of monocytes with non-cytotoxic concentrations of As(III) subsequently reduces the ability of activated DCs to stimulate the release of interferon-γ and IL-17 from Th cells. In conclusion, our results demonstrate that clinically relevant concentrations of inorganic arsenic markedly impair in vitro differentiation and functions of DCs, which may contribute to the putative beneficial effects of the metalloid towards inflammatory autoimmune diseases. Highlights: ► Inorganic arsenic impairs differentiation and functions of human dendritic cells (DCs) ► Arsenite (> 1 μM) blocks differentiation of dendritic cells by

Inorganic arsenic impairs differentiation and functions of human dendritic cells

Energy Technology Data Exchange (ETDEWEB)

Macoch, Mélinda; Morzadec, Claudie [UMR INSERM U1085, Institut de Recherche sur la Santé, l' Environnement et le Travail (IRSET), Université de Rennes 1, 2 avenue du Professeur Léon Bernard, 35043 Rennes (France); Fardel, Olivier [UMR INSERM U1085, Institut de Recherche sur la Santé, l' Environnement et le Travail (IRSET), Université de Rennes 1, 2 avenue du Professeur Léon Bernard, 35043 Rennes (France); Pôle Biologie, Centre Hospitalier Universitaire (CHU) Rennes, 2 rue Henri Le Guilloux, 35033 Rennes (France); Vernhet, Laurent, E-mail: laurent.vernhet@univ-rennes1.fr [UMR INSERM U1085, Institut de Recherche sur la Santé, l' Environnement et le Travail (IRSET), Université de Rennes 1, 2 avenue du Professeur Léon Bernard, 35043 Rennes (France)

2013-01-15

Experimental studies have demonstrated that the antileukemic trivalent inorganic arsenic prevents the development of severe pro-inflammatory diseases mediated by excessive Th1 and Th17 cell responses. Differentiation of Th1 and Th17 subsets is mainly regulated by interleukins (ILs) secreted from dendritic cells (DCs) and the ability of inorganic arsenic to impair interferon-γ and IL-17 secretion by interfering with the physiology of DCs is unknown. In the present study, we demonstrate that high concentrations of sodium arsenite (As(III), 1–2 μM) clinically achievable in plasma of arsenic-treated patients, block differentiation of human peripheral blood monocytes into immature DCs (iDCs) by inducing their necrosis. Differentiation of monocytes in the presence of non-cytotoxic concentrations of As(III) (0.1 to 0.5 μM) only slightly impacts endocytotic activity of iDCs or expression of co-stimulatory molecules in cells activated with lipopolysaccharide. However, this differentiation in the presence of As(III) strongly represses secretion of IL-12p70 and IL-23, two major regulators of Th1 and Th17 activities, from iDCs stimulated with different toll-like receptor (TLR) agonists in metalloid-free medium. Such As(III)-exposed DCs also exhibit reduced mRNA levels of IL12A and/or IL12B genes when activated with TLR agonists. Finally, differentiation of monocytes with non-cytotoxic concentrations of As(III) subsequently reduces the ability of activated DCs to stimulate the release of interferon-γ and IL-17 from Th cells. In conclusion, our results demonstrate that clinically relevant concentrations of inorganic arsenic markedly impair in vitro differentiation and functions of DCs, which may contribute to the putative beneficial effects of the metalloid towards inflammatory autoimmune diseases. Highlights: ► Inorganic arsenic impairs differentiation and functions of human dendritic cells (DCs) ► Arsenite (> 1 μM) blocks differentiation of dendritic cells by

Exiguobacterium mediated arsenic removal and its protective effect against arsenic induced toxicity and oxidative damage in freshwater fish, Channa striata

Directory of Open Access Journals (Sweden)

Neha Pandey

2015-01-01

Full Text Available Arsenic is a toxic metalloid existing widely in the environment, and its removal from contaminated water has become a global challenge. The use of bacteria in this regard finds a promising solution. In the present study, Exiguobacterium sp. As-9, which is an arsenic resistant bacterium, was selected with respect to its arsenic removal efficiency. Quantification of arsenic in the water treated with bacterium showed that Exiguobacterium efficiently removed up to 99% of arsenic in less than 20 h. In order to reveal the possible effect of this bacterium in removal of arsenic from water and protecting fishes from the detrimental effects of arsenic, we initiated a range of studies on fresh water fish, Channa striata. It was observed that the fishes introduced into bacteria treated water displayed no symptoms of arsenic toxicity which was marked by a decreased oxidative damage, whereas the fishes exposed to arsenic revealed a significant (p < 0.05 increase in the oxidative stress together with the elevated levels of malondialdehyde. Determination of the bioaccumulation of arsenic in the liver tissues of C. striata using hydride generation atomic absorption spectrophotometry (HG-AAS revealed an increased As(III accumulation in the fishes exposed to arsenic whereas the arsenic level in the control and bacteria treated fishes were found below the detectable limit. In conclusion, this study presents the strategies of bacterial arsenic removal with possible directions for future research.

Oxidative stress and hepatic stellate cell activation are key events in arsenic induced liver fibrosis in mice

International Nuclear Information System (INIS)

Ghatak, Subhadip; Biswas, Ayan; Dhali, Gopal Krishna; Chowdhury, Abhijit; Boyer, James L.; Santra, Amal

2011-01-01

Arsenic is an environmental toxicant and carcinogen. Exposure to arsenic is associated with development of liver fibrosis and portal hypertension through ill defined mechanisms. We evaluated hepatic fibrogenesis after long term arsenic exposure in a murine model. BALB/c mice were exposed to arsenic by daily gavages of 6 μg/gm body weight for 1 year and were evaluated for markers of hepatic oxidative stress and fibrosis, as well as pro-inflammatory, pro-apoptotic and pro-fibrogenic factors at 9 and 12 months. Hepatic NADPH oxidase activity progressively increased in arsenic exposure with concomitant development of hepatic oxidative stress. Hepatic steatosis with occasional collection of mononuclear inflammatory cells and mild portal fibrosis were the predominant liver lesion observed after 9 months of arsenic exposure, while at 12 months, the changes included mild hepatic steatosis, inflammation, necrosis and significant fibrosis in periportal areas. The pathologic changes in the liver were associated with markers of hepatic stellate cells (HSCs) activation, matrix reorganization and fibrosis including α-smooth muscle actin, transforming growth factor-β1, PDGF-Rβ, pro-inflammatory cytokines and enhanced expression of tissue inhibitor of metalloproteinase-1 and pro(α) collagen type I. Moreover, pro-apoptotic protein Bax was dominantly expressed and Bcl-2 was down-regulated along with increased number of TUNEL positive hepatocytes in liver of arsenic exposed mice. Furthermore, HSCs activation due to increased hepatic oxidative stress observed after in vivo arsenic exposure was recapitulated in co-culture model of isolated HSCs and hepatocytes exposed to arsenic. These findings have implications not only for the understanding of the pathology of arsenic related liver fibrosis but also for the design of preventive strategies in chronic arsenicosis.

MiADMSA reverses impaired mitochondrial energy metabolism and neuronal apoptotic cell death after arsenic exposure in rats

Energy Technology Data Exchange (ETDEWEB)

Dwivedi, Nidhi; Mehta, Ashish; Yadav, Abhishek [Division of Pharmacology and Toxicology, Defence Research and Development Establishment, Gwalior-474 002 (India); Binukumar, B.K.; Gill, Kiran Dip [Department of Biochemistry, Postgraduate Institute of Medical Education and Research, Chandigarh-160 012 (India); Flora, Swaran J.S., E-mail: sjsflora@hotmail.com [Division of Pharmacology and Toxicology, Defence Research and Development Establishment, Gwalior-474 002 (India)

2011-11-15

Arsenicosis, due to contaminated drinking water, is a serious health hazard in terms of morbidity and mortality. Arsenic induced free radicals generated are known to cause cellular apoptosis through mitochondrial driven pathway. In the present study, we investigated the effect of arsenic interactions with various complexes of the electron transport chain and attempted to evaluate if there was any complex preference of arsenic that could trigger apoptosis. We also evaluated if chelation with monoisoamyl dimercaptosuccinic acid (MiADMSA) could reverse these detrimental effects. Our results indicate that arsenic exposure induced free radical generation in rat neuronal cells, which diminished mitochondrial potential and enzyme activities of all the complexes of the electron transport chain. Moreover, these complexes showed differential responses towards arsenic. These early events along with diminished ATP levels could be co-related with the later events of cytosolic migration of cytochrome c, altered bax/bcl{sub 2} ratio, and increased caspase 3 activity. Although MiADMSA could reverse most of these arsenic-induced altered variables to various extents, DNA damage remained unaffected. Our study for the first time demonstrates the differential effect of arsenic on the complexes leading to deficits in bioenergetics leading to apoptosis in rat brain. However, more in depth studies are warranted for better understanding of arsenic interactions with the mitochondria. -- Research highlights: Black-Right-Pointing-Pointer Arsenic impairs mitochondrial energy metabolism leading to neuronal apoptosis. Black-Right-Pointing-Pointer Arsenic differentially affects mitochondrial complexes, I - III and IV being more sensitive than complex II. Black-Right-Pointing-Pointer Arsenic-induced apoptosis initiates through ROS generation or impaired [Ca{sup 2+}]i homeostasis. Black-Right-Pointing-Pointer MiADMSA reverses arsenic toxicity via intracellular arsenic- chelation, antioxidant

IDENTIFICATION OF INTERSPECIES CONCORDANCE OF MECHANISMS OF ARSENIC INDUCED BLADDER CANCER BY GENE EXPRESSION.

Science.gov (United States)

Arsenic is a human carcinogen that induces urinary bladder cancer. Several mechanisms have been proposed for arsenic-induced cancer. Although inorganic arsenic (iAs) does not induce tumors in adult rodents, dimethylarsinic acid (DMA), a major metabolite of iAs, is a rat bladder c...

The Role of Antioxidants in Biochemical Disorders Induced by Arsenic in Adult male Rats

International Nuclear Information System (INIS)

Hassanin, M.M.; Zaki, Z.T.; Emarah, E.A.M.; Hussein, A.M.M.

2010-01-01

The present investigation included biochemical, radiometric, molecular studies and histopathological examination to evaluate the protective role of Antox tablets toward Arsenic toxicity in adult male albino rats (Rattus rattus). Arsenic were given as sodium arsenate to different groups in drinking water at a dose of 100 mg/L, for 3 and 6 weeks led to severe tissue damage as revealed by an elevation of serum total protein and alteration of serum protein fractions. Using radioimmunoassay it was found that serum total testosterone level was significantly decreased. The decreased level of total testosterone paralleled the observed testicular damage. Treatment of male rats with antioxidant (Antox) along with arsenic led to an improvement in both the biochemical and histological alterations induced by arsenic. Thus the protective role of Antox is attributed to its antioxidant and free radicals scavenging properties of its components (selenium, vitamin A acetate, ascorbic acid and vitamin E).

Arsenic toxicity induced endothelial dysfunction and dementia: Pharmacological interdiction by histone deacetylase and inducible nitric oxide synthase inhibitors

Energy Technology Data Exchange (ETDEWEB)

Sharma, Bhupesh, E-mail: drbhupeshresearch@gmail.com; Sharma, P.M.

2013-11-15

Arsenic toxicity has been reported to damage all the major organs including the brain and vasculature. Dementia including Alzheimer's disease (AD) and vascular dementia (VaD) are posing greater risk to the world population as it is now increasing at a faster rate. We have investigated the role of sodium butyrate, a selective histone deacetylase (HDAC) inhibitor and aminoguanidine, a selective inducible nitric oxide synthase (iNOS) inhibitor in pharmacological interdiction of arsenic toxicity induced vascular endothelial dysfunction and dementia in rats. Arsenic toxicity was done by administering arsenic drinking water to rats. Morris water-maze (MWM) test was used for assessment of learning and memory. Endothelial function was assessed using student physiograph. Oxidative stress (aortic superoxide anion, serum and brain thiobarbituric acid reactive species, brain glutathione) and nitric oxide levels (serum nitrite/nitrate) were also measured. Arsenic treated rats have shown impairment of endothelial function, learning and memory, reduction in serum nitrite/nitrate and brain GSH levels along with increase in serum and brain TBARS. Sodium butyrate as well as aminoguanidine significantly convalesce arsenic induced impairment of learning, memory, endothelial function, and alterations in various biochemical parameters. It may be concluded that arsenic induces endothelial dysfunction and dementia, whereas, sodium butyrate, a HDAC inhibitor as well as aminoguanidine, a selective iNOS inhibitor may be considered as potential agents for the management of arsenic induced endothelial dysfunction and dementia. - Highlights: • As has induced endothelial dysfunction (Edf) and vascular dementia (VaD). • As has increased oxidative stress, AChE activity and decreased serum NO. • Inhibitors of HDAC and iNOS have attenuated As induced Edf and VaD. • Both the inhibitors have attenuated As induced biochemical changes. • Inhibitor of HDAC and iNOS has shown good potential

Arsenic toxicity induced endothelial dysfunction and dementia: Pharmacological interdiction by histone deacetylase and inducible nitric oxide synthase inhibitors

International Nuclear Information System (INIS)

Sharma, Bhupesh; Sharma, P.M.

2013-01-01

Arsenic toxicity has been reported to damage all the major organs including the brain and vasculature. Dementia including Alzheimer's disease (AD) and vascular dementia (VaD) are posing greater risk to the world population as it is now increasing at a faster rate. We have investigated the role of sodium butyrate, a selective histone deacetylase (HDAC) inhibitor and aminoguanidine, a selective inducible nitric oxide synthase (iNOS) inhibitor in pharmacological interdiction of arsenic toxicity induced vascular endothelial dysfunction and dementia in rats. Arsenic toxicity was done by administering arsenic drinking water to rats. Morris water-maze (MWM) test was used for assessment of learning and memory. Endothelial function was assessed using student physiograph. Oxidative stress (aortic superoxide anion, serum and brain thiobarbituric acid reactive species, brain glutathione) and nitric oxide levels (serum nitrite/nitrate) were also measured. Arsenic treated rats have shown impairment of endothelial function, learning and memory, reduction in serum nitrite/nitrate and brain GSH levels along with increase in serum and brain TBARS. Sodium butyrate as well as aminoguanidine significantly convalesce arsenic induced impairment of learning, memory, endothelial function, and alterations in various biochemical parameters. It may be concluded that arsenic induces endothelial dysfunction and dementia, whereas, sodium butyrate, a HDAC inhibitor as well as aminoguanidine, a selective iNOS inhibitor may be considered as potential agents for the management of arsenic induced endothelial dysfunction and dementia. - Highlights: • As has induced endothelial dysfunction (Edf) and vascular dementia (VaD). • As has increased oxidative stress, AChE activity and decreased serum NO. • Inhibitors of HDAC and iNOS have attenuated As induced Edf and VaD. • Both the inhibitors have attenuated As induced biochemical changes. • Inhibitor of HDAC and iNOS has shown good potential in

Neuroprotective efficacy of curcumin in arsenic induced cholinergic dysfunctions in rats.

Science.gov (United States)

Yadav, Rajesh S; Chandravanshi, Lalit P; Shukla, Rajendra K; Sankhwar, Madhu L; Ansari, Reyaz W; Shukla, Pradeep K; Pant, Aditya B; Khanna, Vinay K

2011-12-01

Our recent studies have shown that curcumin protects arsenic induced neurotoxicity by modulating oxidative stress, neurotransmitter levels and dopaminergic system in rats. As chronic exposure to arsenic has been associated with cognitive deficits in humans, the present study has been carried out to implore the neuroprotective potential of curcumin in arsenic induced cholinergic dysfunctions in rats. Rats treated with arsenic (sodium arsenite, 20mg/kg body weight, p.o., 28 days) exhibited a significant decrease in the learning activity, assessed by passive avoidance response associated with decreased binding of (3)H-QNB, known to label muscarinic-cholinergic receptors in hippocampus (54%) and frontal cortex (27%) as compared to controls. Decrease in the activity of acetylcholinesterase in hippocampus (46%) and frontal cortex (33%), staining of Nissl body, immunoreactivity of choline acetyltransferase (ChAT) and expression of ChAT protein in hippocampal region was also observed in arsenic treated rats as compared to controls. Simultaneous treatment with arsenic and curcumin (100mg/kg body weight, p.o., 28 days) increased learning and memory performance associated with increased binding of (3)H-QNB in hippocampus (54%), frontal cortex (25%) and activity of acetylcholinesterase in hippocampus (41%) and frontal cortex (29%) as compared to arsenic treated rats. Increase in the expression of ChAT protein, immunoreactivity of ChAT and staining of Nissl body in hippocampal region was also observed in rats simultaneously treated with arsenic and curcumin as compared to those treated with arsenic alone. The results of the present study suggest that curcumin significantly modulates arsenic induced cholinergic dysfunctions in brain and also exhibits neuroprotective efficacy of curcumin. Copyright © 2011 Elsevier Inc. All rights reserved.

Arsenic-induced oxidative myocardial injury: protective role of arjunolic acid

Energy Technology Data Exchange (ETDEWEB)

Manna, Prasenjit; Sinha, Mahua; Sil, Parames C. [Bose Institute, Department of Chemistry, Kolkata, West Bengal (India)

2008-03-15

Arsenic, one of the most harmful metalloids, is ubiquitous in the environment. The present study has been carried out to investigate the protective role of a triterpenoid saponin, arjunolic acid (AA) against arsenic-induced cardiac oxidative damage. In the study, NaAsO{sub 2} was chosen as the source of arsenic. The free radical scavenging activity and the effect of AA on the intracellular antioxidant power were determined from its 2,2-diphenyl-1-picryl hydrazyl radical scavenging ability and ferric reducing/antioxidant power assay, respectively. Oral administration of NaAsO{sub 2} at a dose of 10 mg/kg body weight for 2 days caused significant accumulation of arsenic in cardiac tissues of the experimental mice in association with the reduction in cardiac antioxidant enzymes activities, namely superoxide dismutase, catalase, glutathione-S-transferase, glutathione reductase and glutathione peroxidase. Arsenic intoxication also decreased the cardiac glutathione (GSH) and total thiol contents and increased the levels of oxidized glutathione (GSSG), lipid peroxidation end products and protein carbonyl content. Treatment with AA at a dose of 20 mg/kg body weight for 4 days prior to NaAsO{sub 2} intoxication protected the cardiac tissue from arsenic-induced oxidative impairment. In addition to oxidative stress, arsenic administration increased total cholesterol level as well as the reduced high-density lipoprotein cholesterol level in the sera of the experimental mice. AA pretreatment, however, could prevent this hyperlipidemia. Histological studies on the ultrastructural changes in cardiac tissue supported the protective activity of AA also. Combining all, results suggest that AA could protect cardiac tissues against arsenic-induced oxidative stress probably due to its antioxidant property. (orig.)

Arsenic induces diabetic effects through beta-cell dysfunction and increased gluconeogenesis in mice

Science.gov (United States)

Liu, Su; Guo, Xuechao; Wu, Bing; Yu, Haiyan; Zhang, Xuxiang; Li, Mei

2014-11-01

Arsenic as a potential risk factor for type 2 diabetes has been received attention recently. However, the roles of arsenic on development of diabetes are unclear. In this study, we compared the influences of inorganic arsenic (iAs) on normal and diabetic mice by systems toxicology approaches. Although iAs exposure did not change glucose tolerance in normal mice, it caused the pancreatic β-cell dysfunction and increased gluconeogenesis and oxidative damages in liver. However, iAs exposure worsened the glucose tolerance in diabetic mice, which might be due to increased gluconeogenesis and impairment of pancreatic β-cell function. It is interesting that iAs exposure could improve the insulin sensitivity based on the insulin tolerance testing by the activation of glucose uptake-related genes and enzymes in normal and diabetic individuals. Our data suggested that iAs exposure could cause pre-diabetic effects by altering the lipid metabolism, gluconeogenesis and insulin secretion in normal individual, and worsen diabetic effects in diabetes individual by these processes. Insulin resistance might be not the reason of diabetic effects caused by iAs, indicating that mechanism of the diabetogenic effects of iAs exposure is different from the mechanism associated with traditional risk factors (such as obesity)-reduced type 2 diabetes.

Arsenic induces diabetic effects through beta-cell dysfunction and increased gluconeogenesis in mice.

Science.gov (United States)

Liu, Su; Guo, Xuechao; Wu, Bing; Yu, Haiyan; Zhang, Xuxiang; Li, Mei

2014-11-04

Arsenic as a potential risk factor for type 2 diabetes has been received attention recently. However, the roles of arsenic on development of diabetes are unclear. In this study, we compared the influences of inorganic arsenic (iAs) on normal and diabetic mice by systems toxicology approaches. Although iAs exposure did not change glucose tolerance in normal mice, it caused the pancreatic β-cell dysfunction and increased gluconeogenesis and oxidative damages in liver. However, iAs exposure worsened the glucose tolerance in diabetic mice, which might be due to increased gluconeogenesis and impairment of pancreatic β-cell function. It is interesting that iAs exposure could improve the insulin sensitivity based on the insulin tolerance testing by the activation of glucose uptake-related genes and enzymes in normal and diabetic individuals. Our data suggested that iAs exposure could cause pre-diabetic effects by altering the lipid metabolism, gluconeogenesis and insulin secretion in normal individual, and worsen diabetic effects in diabetes individual by these processes. Insulin resistance might be not the reason of diabetic effects caused by iAs, indicating that mechanism of the diabetogenic effects of iAs exposure is different from the mechanism associated with traditional risk factors (such as obesity)-reduced type 2 diabetes.

Arsenic-induced alteration in intracellular calcium homeostasis induces head kidney macrophage apoptosis involving the activation of calpain-2 and ERK in Clarias batrachus

International Nuclear Information System (INIS)

Banerjee, Chaitali; Goswami, Ramansu; Datta, Soma; Rajagopal, R.; Mazumder, Shibnath

2011-01-01

We had earlier shown that exposure to arsenic (0.50 μM) caused caspase-3 mediated head kidney macrophage (HKM) apoptosis involving the p38-JNK pathway in Clarias batrachus. Here we examined the roles of calcium (Ca 2+ ) and extra-cellular signal-regulated protein kinase (ERK), the other member of MAPK-pathway on arsenic-induced HKM apoptosis. Arsenic-induced HKM apoptosis involved increased expression of ERK and calpain-2. Nifedipine, verapamil and EGTA pre-treatment inhibited the activation of calpain-2, ERK and reduced arsenic-induced HKM apoptosis as evidenced from reduced caspase-3 activity, Annexin V-FITC-propidium iodide and Hoechst 33342 staining. Pre-incubation with ERK inhibitor U 0126 inhibited the activation of calpain-2 and interfered with arsenic-induced HKM apoptosis. Additionally, pre-incubation with calpain-2 inhibitor also interfered with the activation of ERK and inhibited arsenic-induced HKM apoptosis. The NADPH oxidase inhibitor apocynin and diphenyleneiodonium chloride also inhibited ERK activation indicating activation of ERK in arsenic-exposed HKM also depends on signals from NADPH oxidase pathway. Our study demonstrates the critical role of Ca 2+ homeostasis on arsenic-induced HKM apoptosis. We suggest that arsenic-induced alteration in intracellular Ca 2+ levels initiates pro-apoptotic ERK and calpain-2; the two pathways influence each other positively and induce caspase-3 mediated HKM apoptosis. Besides, our study also indicates the role of ROS in the activation of ERK pathway in arsenic-induced HKM apoptosis in C. batrachus. - Highlights: → Altered Ca 2+ homeostasis leads to arsenic-induced HKM apoptosis. → Calpain-2 plays a critical role in the process. → ERK is pro-apoptotic in arsenic-induced HKM apoptosis. → Arsenic-induced HKM apoptosis involves cross talk between calpain-2 and ERK.

Nrf2 activation ameliorates cytotoxic effects of arsenic trioxide in acute promyelocytic leukemia cells through increased glutathione levels and arsenic efflux from cells

Energy Technology Data Exchange (ETDEWEB)

Nishimoto, Shoichi; Suzuki, Toshihiro; Koike, Shin [Department of Analytical Biochemistry, Meiji Pharmaceutical University, 2-522-1 Noshio, Kiyose, Tokyo 204-8588 (Japan); Yuan, Bo; Takagi, Norio [Department of Applied Biochemistry, School of Pharmacy, Tokyo University of Pharmacy and Life Sciences, Hachioji, Tokyo 192-0392 (Japan); Ogasawara, Yuki, E-mail: yo@my-pharm.ac.jp [Department of Analytical Biochemistry, Meiji Pharmaceutical University, 2-522-1 Noshio, Kiyose, Tokyo 204-8588 (Japan)

2016-08-15

Carnosic acid (CA), a phenolic diterpene isolated from Rosmarinus officinalis, has been shown to activate nuclear transcription factor E2-related factor 2 (Nrf2), which plays a central role in cytoprotective responses to oxidative and electrophilic stress. Recently, the Nrf2-Kelch ECH associating protein 1 (Keap1) pathway has been associated with cancer drug resistance attributable to modulation of the expression and activation of antioxidant and detoxification enzymes. However, the exact mechanisms by which Nrf2 activation results in chemoresistance are insufficiently understood to date. This study investigated the mechanisms by which the cytotoxic effects of arsenic trioxide (ATO), an anticancer drug, were decreased in acute promyelocytic leukemia cells treated with CA, a typical activator of Nrf2 used to stimulate the Nrf2/Keap1 system. Our findings suggest that arsenic is non-enzymatically incorporated into NB4 cells and forms complexes that are dependent on intracellular glutathione (GSH) concentrations. In addition, the arsenic complexes are recognized as substrates by multidrug resistance proteins and subsequently excreted from the cells. Therefore, Nrf2-associated activation of the GSH biosynthetic pathway, followed by increased levels of intracellular GSH, are key mechanisms underlying accelerated arsenic efflux and attenuation of the cytotoxic effects of ATO. - Highlights: • Nrf2 activation attenuates the effect of arsenic trioxide to acute promyelocytic leukemia cells. • The sensitivity of arsenic trioxide to NB4 cells was dependent on efflux rate of arsenic. • Activation of the GSH biosynthesis is essential in Nrf2-regulated responses for arsenic efflux.

Oxidative DNA damage of peripheral blood polymorphonuclear leukocytes, selectively induced by chronic arsenic exposure, is associated with extent of arsenic-related skin lesions

International Nuclear Information System (INIS)

Pei, Qiuling; Ma, Ning; Zhang, Jing; Xu, Wenchao; Li, Yong; Ma, Zhifeng; Li, Yunyun; Tian, Fengjie; Zhang, Wenping; Mu, Jinjun; Li, Yuanfei; Wang, Dongxing; Liu, Haifang; Yang, Mimi; Ma, Caifeng; Yun, Fen

2013-01-01

There is increasing evidence that oxidative stress is an important risk factor for arsenic-related diseases. Peripheral blood leukocytes constitute an important defense against microorganisms or pathogens, while the research on the impact of chronic arsenic exposure on peripheral blood leukocytes is much more limited, especially at low level arsenic exposure. The purpose of the present study was to explore whether chronic arsenic exposure affects oxidative stress of peripheral blood leukocytes and possible linkages between oxidative stress and arsenic-induced skin lesions. 75 male inhabitants recruited from an As-endemic region of China were investigated in the present study. The classification of arsenicosis was based on the degree of skin lesions. Arsenic levels were measured in drinking water and urine by Atomic Fluorescence Spectroscopy. Urinary 8-hydroxy-2′-deoxyguanosine (8-OHdG) was tested by Enzyme-Linked Immunosorbent Assay. 8-OHdG of peripheral blood leukocytes was evaluated using immunocytochemical staining. 8-OHdG-positive reactions were only present in polymorphonuclear leukocytes (PMNs), but not in monocytes (MNs). The 8-OHdG staining of PMN cytoplasm was observed in all investigated populations, while the 8-OHdG staining of PMN nuclei was frequently found along with the elevated amounts of cell debris in individuals with skin lesion. Urinary arsenic levels were increased in the severe skin lesion group compared with the normal group. No relationship was observed between drinking water arsenic or urine 8-OHdG and the degree of skin lesions. These findings indicated that the target and persistent oxidative stress in peripheral blood PMNs may be employed as a sensitive biomarker directly to assess adverse health effects caused by chronic exposure to lower levels of arsenic. -- Highlights: ► Male inhabitants were investigated from an As-endemic region of China. ► 8-OHdG-positive reactions were only present in polymorphonuclear leukocytes (PMNs). �

Environmental Arsenic Exposure and Microbiota in Induced Sputum

Directory of Open Access Journals (Sweden)

Allison G. White

2014-02-01

Full Text Available Arsenic exposure from drinking water is associated with adverse respiratory outcomes, but it is unknown whether arsenic affects pulmonary microbiota. This exploratory study assessed the effect of exposure to arsenic in drinking water on bacterial diversity in the respiratory tract of non-smokers. Induced sputum was collected from 10 subjects with moderate mean household water arsenic concentration (21.1 ± 6.4 ppb and 10 subjects with low household water arsenic (2.4 ± 0.8 ppb. To assess microbiota in sputum, the V6 hypervariable region amplicons of bacterial 16s rRNA genes were sequenced using the Ion Torrent Personal Genome Machine. Microbial community differences between arsenic exposure groups were evaluated using QIIME and Metastats. A total of 3,920,441 sequence reads, ranging from 37,935 to 508,787 per sample for 316 chips after QIIME quality filtering, were taxonomically classified into 142 individual genera and five phyla. Firmicutes (22%, Proteobacteria (17% and Bacteriodetes (12% were the main phyla in all samples, with Neisseriaceae (15%, Prevotellaceae (12% and Veillonellacea (7% being most common at the genus level. Some genera, including Gemella, Lactobacillales, Streptococcus, Neisseria and Pasteurellaceae were elevated in the moderate arsenic exposure group, while Rothia, Prevotella, Prevotellaceae Fusobacterium and Neisseriaceae were decreased, although none of these differences was statistically significant. Future studies with more participants and a greater range of arsenic exposure are needed to further elucidate the effects of drinking water arsenic consumption on respiratory microbiota.

Arsenic interferes with the signaling transduction pathway of T cell receptor activation by increasing basal and induced phosphorylation of Lck and Fyn in spleen cells

International Nuclear Information System (INIS)

Soto-Pena, Gerson A.; Vega, Libia

2008-01-01

Arsenic is known to produce inhibition as well as induction of immune cells proliferative responses depending on the doses as one of its mechanisms of immunotoxicity. Here we evaluate the effect of arsenic exposure on the activation of splenic mononuclear cells (SMC) in male CD57BL6N mice. Intra-gastric exposure to arsenic (as sodium arsenite) for 30 days (1, 0.1, or 0.01 mg/kg/day), reduced the proportion of CD4+ cells and the CD4+/CD8+ ratio in the spleen, increasing the proportion of CD11b+ cells. Arsenic exposure did not modify the proportion of B cells. SMC showed an increased level of phosphorylation of lck and fyn kinases (first kinases associated to TCR complex when activated). Although normal levels of apoptosis were observed on freshly isolated SMC, an increase in apoptotic cells related with the increase in phosphorylation of lck and fyn was observed when SMC were activated with Concanavalin-A (Con-A). Arsenic exposure reduced the proliferative response of SMC to Con-A, and also reduced secretion of IL-2, IL-6, IL-12 and IFNγ. No effect was observed on IL-4, and IL-10 secretion. The same effects were observed when SMC of exposed animals were activated with anti-CD3/CD28 antibodies for 24 h, but these effects were transitory since a recovery, up to control levels or even higher, were observed after 72 h of stimulation. This study demonstrates that repeated and prolonged exposure to arsenic alters cell populations and produces functional changes depending on the specific activation pathway, and could be related with the phosphorylation status of lck and fyn kinases

Neuroprotective effect of curcumin in arsenic-induced neurotoxicity in rats.

Science.gov (United States)

Yadav, Rajesh S; Shukla, Rajendra K; Sankhwar, Madhu Lata; Patel, Devendra K; Ansari, Reyaz W; Pant, Aditya B; Islam, Fakhrul; Khanna, Vinay K

2010-09-01

Our recent studies have shown that arsenic-induced neurobehavioral toxicity is protected by curcumin by modulating oxidative stress and dopaminergic functions in rats. In addition, the neuroprotective effect of curcumin has been investigated on arsenic-induced alterations in biogenic amines, their metabolites and nitric oxide (NO), which play an important role in neurotransmission process. Decrease in the levels of dopamine (DA, 28%), norepinephrine (NE, 54%), epinephrine (EPN, 46%), serotonin (5-HT, 44%), 3,4-dihydroxyphenylacetic acid (DOPAC, 20%) and homovanillic acid (HVA, 31%) in corpus striatum; DA (51%), NE (22%), EPN (47%), 5-HT (25%), DOPAC (34%) and HVA (41%) in frontal cortex and DA (35%), NE (35%), EPN (29%), 5-HT (54%), DOPAC (37%) and HVA (46%) in hippocampus, observed in arsenic (sodium arsenite, 20 mg/kg body weight, p.o., 28 days) treated rats exhibited a trend of recovery in rats simultaneously treated with arsenic and curcumin (100 mg/kg body weight, p.o., 28 days). Increased levels of NO in corpus striatum (2.4-fold), frontal cortex (6.1-fold) and hippocampus (6.2-fold) in arsenic-treated rats were found decreased in rats simultaneously treated with arsenic and curcumin. It is evident that curcumin modulates levels of brain biogenic amines and NO in arsenic-exposed rats and these results further strengthen its neuroprotective efficacy. Copyright © 2010 Elsevier Inc. All rights reserved.

Urinary total arsenic and 8-hydroxydeoxyguanosine are associated with renal cell carcinoma in an area without obvious arsenic exposure

Energy Technology Data Exchange (ETDEWEB)

Huang, Chao-Yuan [Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan (China); Department of Urology, National Taiwan University Hospital, College of Medicine National Taiwan University, Taipei, Taiwan (China); Su, Chien-Tien [Department of Family Medicine, Taipei Medical University Hospital, Taipei, Taiwan (China); Chung, Chi-Jung [Department of Health Risk Management, College of Public Health, China Medical University, Taichung, Taiwan (China); Department of Medical Research, China Medical University Hospital, Taichung, Taiwan (China); Pu, Yeong-Shiau [Department of Urology, National Taiwan University Hospital, College of Medicine National Taiwan University, Taipei, Taiwan (China); Chu, Jan-Show [Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan (China); Department of Pathology, College of Medicine, Taipei Medical University, Taipei, Taiwan (China); Yang, Hsiu-Yuan [School of Public Health, College of Public Health and Nutrition, Taipei Medical University, Taipei, Taiwan (China); Wu, Chia-Chang [School of Public Health, College of Public Health and Nutrition, Taipei Medical University, Taipei, Taiwan (China); Department of Urology, Taipei Medical Universtiy-Shuang Ho Hospital, Taipei, Taiwan (China); Hsueh, Yu-Mei, E-mail: ymhsueh@tmu.edu.tw [Department of Public Health, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan (China); School of Public Health, College of Public Health and Nutrition, Taipei Medical University, Taipei, Taiwan (China)

2012-08-01

8-Hydroxydeoxyguanosine (8-OHdG) is one of the most reliable and abundant markers of DNA damage. The study was designed to explore the relationship between urinary 8-OHdG and renal cell carcinoma (RCC) and to investigate whether individuals with a high level of 8-OHdG would have a modified odds ratio (OR) of arsenic-related RCC. This case–control study was conducted with 132 RCC patients and 245 age- and sex-matched controls from a hospital-based pool between November 2006 and May 2009. Pathological verification of RCC was completed by image-guided biopsy or surgical resection of renal tumors. Urinary 8-OHdG levels were determined using liquid chromatography with tandem mass spectrometry (LC–MS/MS). Concentrations of urinary arsenic species, including inorganic arsenic, monomethylarsonic acid (MMA) and dimethylarsinic acid (DMA), were determined by a high performance liquid chromatography-linked hydride generator and atomic absorption spectrometry. Level of urinary 8-OHdG was significantly associated with the OR of RCC in a dose–response relationship after multivariate adjustment. Urinary 8-OHdG was significantly related to urinary total arsenic. The greatest OR (3.50) was seen in the individuals with high urinary 8-OHdG and high urinary total arsenic. A trend test indicated that the OR of RCC was increased with one of these factors and was further increased with both (p = 0.002). In conclusion, higher urinary 8-OHdG was a strong predictor of the RCC. High levels of 8-OHdG combined with urinary total arsenic might be indicative of arsenic-induced RCC. -- Highlights: ► Urinary 8-OHdG was significantly related to urinary total arsenic. ► Higher urinary 8-OHdG was a strong predictor of RCC risk. ► Urinary 8-OHdG may modify arsenic related RCC risk.

Perturbations in immune responses induced by concurrent subchronic exposure to arsenic and endosulfan

International Nuclear Information System (INIS)

Aggarwal, Manoj; Naraharisetti, Suresh Babu; Dandapat, S.; Degen, G.H.; Malik, J.K.

2008-01-01

The metalloid arsenic and the chlorinated insecticide endosulfan are common environmental contaminants. Humans, animals, and birds are exposed to these chemicals through water and food. Although health effects due to either arsenic or endosulfan exposure are documented, the toxicological impact of co-exposure to these environmental pollutants is unpredictable and unknown. The present study was undertaken to assess whether concurrent exposure to arsenic and endosulfan induces significant alterations in immunological functions. Day-old chicks were exposed to 3.7 ppm of arsenic via drinking water and to 30 ppm of endosulfan-mixed feed either individually or concurrently for up to 60 days. All the chicks were vaccinated with Ranikhet disease virus (F-strain; RD-F) on days 1 and 30. During the course of study and at term, parameters of cellular and humoral immunity were determined. None of the treatments altered the absolute body weight or body weight gain, except arsenic significantly reduced weight gain on day 60. Absolute, but not the relative, weights of spleen, thymus and bursa of Fabricius were significantly reduced in all the treatment groups. The metalloid and insecticide combination significantly depressed the ability of peripheral blood and splenic lymphocytes to proliferate in response to antigen RD-F and mitogen Con A. The delayed type hypersensitivity response to 2,4-dinitro-1-chlorobenzene or to PHA-P was also significantly decreased. Nitric oxide production by RD-F or lipopolysaccharide-stimulated peripheral blood and splenic mononuclear cells was significantly suppressed following concurrent exposure to arsenic and endosulfan. Furthermore, the combined exposure also decreased the antibody response to RD-F. The suppression of cellular and humoral immune responses was also evident following administration of individual compounds, and it was not exacerbated following concurrent exposure. To our knowledge, this is the first report describing the suppression

Cellular shear stiffness reflects progression of arsenic-induced transformation during G1

DEFF Research Database (Denmark)

Muñoz, Alexandra; Eldridge, Will J; Jakobsen, Nina Munkholt

2017-01-01

epithelial cells were exposed to sodium arsenite to initiate early stages of transformation. Exposed cells were cultured in soft agar to further transformation and select for clonal populations exhibiting anchorage independent growth. Shear stiffness of various cell populations in G1 was assessed using...... reduced stiffness relative to control clonal lines, which were cultured in soft agar but did not receive arsenic treatment. The relative standard deviation of the stiffness of Arsenic clones was reduced compared to control clones, as well as to the arsenic exposed cell population. Cell stiffness...

Comparative investigations of sodium arsenite, arsenic trioxide and cadmium sulphate in combination with gamma-radiation on apoptosis, micronuclei induction and DNA damage in a human lymphoblastoid cell line

International Nuclear Information System (INIS)

Hornhardt, Sabine; Gomolka, Maria; Walsh, Linda; Jung, Thomas

2006-01-01

In the field of radiation protection the combined exposure to radiation and other toxic agents is recognised as an important research area. To elucidate the basic mechanisms of simultaneous exposure, the interaction of the carcinogens and environmental toxicants cadmium and two arsenic compounds, arsenite and arsenic trioxide, in combination with gamma-radiation in human lymphoblastoid cells (TK6) were investigated. Gamma-radiation induced significant genotoxic effects such as micronuclei formation, DNA damage and apoptosis, whereas arsenic and cadmium had no significant effect on these indicators of cellular damage at non-toxic concentrations. However, in combination with gamma-radiation arsenic trioxide induced a more than additive apoptotic rate compared to the sum of the single effects. Here, the level of apoptotic cells was increased, in a dose-dependent way, up to two-fold compared to the irradiated control cells. Arsenite did not induce a significant additive effect at any of the concentrations or radiation doses tested. On the other hand, arsenic trioxide was less effective than arsenite in the induction of DNA protein cross-links. These data indicate that the two arsenic compounds interact through different pathways in the cell. Cadmium sulphate, like arsenite, had no significant effect on apoptosis in combination with gamma-radiation at low concentrations and, at high concentrations, even reduced the radiation-induced apoptosis. An additive effect on micronuclei induction was observed with 1 μM cadmium sulphate with an increase of up to 80% compared to the irradiated control cells. Toxic concentrations of cadmium and arsenic trioxide seemed to reduce micronuclei induction. The results presented here indicate that relatively low concentrations of arsenic and cadmium, close to those occurring in nature, may interfere with radiation effects. Differences in action of the two arsenic compounds were identified

Poly(lactic-co-glycolic) acid loaded nano-insulin has greater potentials of combating arsenic induced hyperglycemia in mice: Some novel findings

International Nuclear Information System (INIS)

Samadder, Asmita; Das, Jayeeta; Das, Sreemanti; De, Arnab; Saha, Santu Kumar; Bhattacharyya, Soumya Sundar; Khuda-Bukhsh, Anisur Rahman

2013-01-01

Diabetes is a menacing problem, particularly to inhabitants of groundwater arsenic contaminated areas needing new medical approaches. This study examines if PLGA loaded nano-insulin (NIn), administered either intraperitoneally (i.p.) or through oral route, has a greater cost-effective anti-hyperglycemic potential than that of insulin in chronically arsenite-fed hyperglycemic mice. The particle size, morphology and zeta potential of nano-insulin were determined using dynamic light scattering method, scanning electronic and atomic force microscopies. The ability of the nano-insulin (NIn) to cross the blood–brain barrier (BBB) was also checked. Circular dichroic spectroscopic (CD) data of insulin and nano-insulin in presence or absence of arsenic were compared. Several diabetic markers in different groups of experimental and control mice were assessed. The mitochondrial functioning through indices like cytochrome c, pyruvate-kinase, glucokinase, ATP/ADP ratio, mitochondrial membrane potential, cell membrane potential and calcium-ion level was also evaluated. Expressions of the relevant marker proteins and mRNAs like insulin, GLUT2, GLUT4, IRS1, IRS2, UCP2, PI3, PPARγ, CYP1A1, Bcl2, caspase3 and p38 for tracking-down the signaling cascade were also analyzed. Results revealed that i.p.-injected nano-encapsulated-insulin showed better results; NIn, due to its smaller size, faster mobility, site-specific release, could cross BBB and showed positive modulation in mitochondrial signaling cascades and other downstream signaling molecules in reducing arsenic-induced-hyperglycemia. CD data indicated that nano-insulin had less distorted secondary structure as compared with that of insulin in presence of arsenic. Thus, overall analyses revealed that PLGA nano-insulin showed better efficacy in combating arsenite-induced-hyperglycemia than that of insulin and therefore, has greater potentials for use in nano-encapsulated form. - Highlights: ► PLGA encapsulated nano

Poly(lactic-co-glycolic) acid loaded nano-insulin has greater potentials of combating arsenic induced hyperglycemia in mice: Some novel findings

Energy Technology Data Exchange (ETDEWEB)

Samadder, Asmita; Das, Jayeeta; Das, Sreemanti; De, Arnab; Saha, Santu Kumar; Bhattacharyya, Soumya Sundar; Khuda-Bukhsh, Anisur Rahman, E-mail: prof_arkb@yahoo.co.in

2013-02-15

Diabetes is a menacing problem, particularly to inhabitants of groundwater arsenic contaminated areas needing new medical approaches. This study examines if PLGA loaded nano-insulin (NIn), administered either intraperitoneally (i.p.) or through oral route, has a greater cost-effective anti-hyperglycemic potential than that of insulin in chronically arsenite-fed hyperglycemic mice. The particle size, morphology and zeta potential of nano-insulin were determined using dynamic light scattering method, scanning electronic and atomic force microscopies. The ability of the nano-insulin (NIn) to cross the blood–brain barrier (BBB) was also checked. Circular dichroic spectroscopic (CD) data of insulin and nano-insulin in presence or absence of arsenic were compared. Several diabetic markers in different groups of experimental and control mice were assessed. The mitochondrial functioning through indices like cytochrome c, pyruvate-kinase, glucokinase, ATP/ADP ratio, mitochondrial membrane potential, cell membrane potential and calcium-ion level was also evaluated. Expressions of the relevant marker proteins and mRNAs like insulin, GLUT2, GLUT4, IRS1, IRS2, UCP2, PI3, PPARγ, CYP1A1, Bcl2, caspase3 and p38 for tracking-down the signaling cascade were also analyzed. Results revealed that i.p.-injected nano-encapsulated-insulin showed better results; NIn, due to its smaller size, faster mobility, site-specific release, could cross BBB and showed positive modulation in mitochondrial signaling cascades and other downstream signaling molecules in reducing arsenic-induced-hyperglycemia. CD data indicated that nano-insulin had less distorted secondary structure as compared with that of insulin in presence of arsenic. Thus, overall analyses revealed that PLGA nano-insulin showed better efficacy in combating arsenite-induced-hyperglycemia than that of insulin and therefore, has greater potentials for use in nano-encapsulated form. - Highlights: ► PLGA encapsulated nano

Polyphenol-rich apple (Malus domestica L.) peel extract attenuates arsenic trioxide induced cardiotoxicity in H9c2 cells via its antioxidant activity.

Science.gov (United States)

Vineetha, Vadavanath Prabhakaran; Girija, Seetharaman; Soumya, Rema Sreenivasan; Raghu, Kozhiparambil Gopalan

2014-03-01

Evidences suggest that apple peel has a wide range of polyphenols having antioxidant activity and its consumption has been linked with improved health benefits. Arsenic trioxide (ATO) is a very effective drug for the treatment of acute promyelocytic leukemia (APL) but it leads to cardiotoxicity mediated through alterations in various cardiac ion channels and by increasing the intracellular calcium level and reactive oxygen species (ROS). The aim of the present investigation was to study the effect of methanolic extract of apple peel (APME) and aqueous extract of apple peel (APAE) on ATO (5 μM) induced toxicity in the H9c2 cardiac myoblast cell line. We estimated the cellular status of innate antioxidant enzymes, level of ROS, mitochondrial superoxide, glutathione and intracellular calcium with ATO and apple peel extracts. Prior to the cell line based study, we had evaluated the antioxidant potential of apple peel extract by 1,1-diphenyl-2-picrylhydrazyl (DPPH), total reducing power (TRP), superoxide anion and hydroxyl radical scavenging activity, in addition to quantifying total phenolic and flavonoid content. Both the extracts showed considerable antioxidant activity in cell-free chemical assays. In addition, both APME and APAE prevented the alteration in antioxidant status induced by ATO in H9c2 cells. Significant differential alterations had been observed in the activity of lactate dehydrogenase, superoxide dismutase, catalase, glutathione, glutathione peroxidase, thioredoxin reductase, xanthine oxidase, calcium overload and caspase 3 activity with ATO. The overall result revealed the protective property of polyphenol-rich apple peel extract against ATO induced cardiac toxicity via its antioxidant activity.

Arsenic induced progesterone production in a caspase-3-dependent manner and changed redox status in preovulatory granulosa cells.

Science.gov (United States)

Yuan, Xiao-Hua; Lu, Cai-Ling; Yao, Nan; An, Li-Sha; Yang, Bai-Qing; Zhang, Chuan-Ling; Ma, Xu

2012-01-01

Arsenic contamination is a principal environmental health threat throughout the world. However, little is known about the effect of arsenic on steroidogenesis in granulosa cells (GCs). We found that the treatment of preovulatory GCs with arsenite stimulated progesterone production. A significant increase in serum level of progesterone was observed in female Sprague-Dawley rats following arsenite treatment at a dose of 10 mg/L/rat/day for 7 days. Further experiments demonstrated that arsenite treatment did not change the level of intracellular cyclic AMP (cAMP) or phosphorylated ERK1/2 in preovulatory GCs; however, progesterone production was significantly decreased when cAMP-dependent protein kinase (PKA) or ERK1/2 pathway was inhibited. This implied that the effect of arsenite on progesterone production may require cAMP/PKA and ERK1/2 signaling but not depend on them. Furthermore, we found that arsenite decreased intracellular reactive oxygen species (ROS) but increased the antioxidant glutathione (GSH) levels and mitochondrial membrane potential (ΔΨm) in parallel to the changes in progesterone production. Progesterone antagonist blocked the arsenic-stimulated increase of GSH levels. Arsenite treatment induced caspase-3 activation, although no apoptosis was observed. Inhibition of caspase-3 activity significantly decreased progesterone production stimulated by arsenite or follicle-stimulating hormone (FSH). GSH depletion with buthionine sulfoximine led to cell apoptosis in response to arsenite treatment. Collectively, this study demonstrated for the first time that arsenite stimulates progesterone production through cleaved/active caspase-3-dependent pathway, and the increase of GSH level promoted by progesterone production may protect GCs against apoptosis and maintain the steroidogenesis of GCs in response to arsenite treatment. Copyright © 2011 Wiley Periodicals, Inc.

Arsenic-induced biochemical and genotoxic effects and distribution in tissues of Sprague-Dawley rats

Science.gov (United States)

Patlolla, Anita K.; Todorov, Todor I.; Tchounwou, Paul B.; van der Voet, Gijsbert; Centeno, Jose A.

2012-01-01

Arsenic (As) is a well documented human carcinogen. However, its mechanisms of toxic action and carcinogenic potential in animals have not been conclusive. In this research, we investigated the biochemical and genotoxic effects of As and studied its distribution in selected tissues of Sprague–Dawley rats. Four groups of six male rats, each weighing approximately 60 ± 2 g, were injected intraperitoneally, once a day for 5 days with doses of 5, 10, 15, 20 mg/kg BW of arsenic trioxide. A control group was also made of 6 animals injected with distilled water. Following anaesthetization, blood was collected and enzyme analysis was performed by spectrophotometry following standard protocols. At the end of experimentation, the animals were sacrificed, and the lung, liver, brain and kidney were collected 24 h after the fifth day treatment. Chromosome and micronuclei preparation was obtained from bone marrow cells. Arsenic exposure significantly increased (p < 0.05) the activities of plasma alanine aminotransferase–glutamate pyruvate transaminase (ALT/GPT), and aspartate aminotransferase–glutamate oxaloacetate transaminase (AST/GOT), as well as the number of structural chromosomal aberrations (SCA) and frequency of micronuclei (MN) in the bone marrow cells. In contrast, the mitotic index in these cells was significantly reduced (p < 0.05). These findings indicate that aminotransferases are candidate biomarkers for arsenic-induced hepatotoxicity. Our results also demonstrate that As has a strong genotoxic potential, as measured by the bone marrow SCA and MN tests in Sprague–Dawley rats. Total arsenic concentrations in tissues were measured by inductively coupled plasma mass spectrometry (ICP-MS). A dynamic reaction cell (DRC) with hydrogen gas was used to eliminate the ArCl interference at mass 75, in the measurement of total As. Total As doses in tissues tended to correlate with specific exposure levels.

Enhanced protective activity of nano formulated andrographolide against arsenic induced liver damage.

Science.gov (United States)

Das, Sujata; Pradhan, Goutam Kumar; Das, Subhadip; Nath, Debjani; Das Saha, Krishna

2015-12-05

Chronic exposure to arsenic over a period of time induces toxicity, primarily in liver but gradually in all systems of the body. Andrographolide (AG), a major diterpene lactone of Andrographis paniculata, shows a wide array of physiological functions including hepatoprotection. Therapeutic applications of AG are however seriously constrained because of its insolubility, poor bioavailability, and short plasma half-life. Nanoparticulation of AG is a possible solution to these problems. In the present study we investigated the effectiveness of polylactide co-glycolide (PLGA) nanocapsulated andrographolide (NA) against arsenic induced liver damage in mice. NA of average diameter 65.8 nm and encapsulation efficiency of 64% were prepared. Sodium arsenite at a dose of 40 mg/L supplied via drinking water in mice significantly raised the serum level of liver function markers such as AST, ALT, and ALP, and caused arsenic deposition in liver and ROS generation, though it did not show any lethality up to 30 days of exposure. However, even liver toxicity was not observed when mice were given AG and NA orally at doses up to 100 mg/kg bwt and 20 mg/kg bwt respectively on alternate days for one month. Treatment of non-toxic doses of AG or NA on alternate days along with arsenic significantly decreased the arsenic induced elevation of the serum level of ALT, AST and ALP, and arsenic deposition in liver. AG and NA increased the level of hepatic antioxidant enzymes such as superoxide dismutase (SOD), and catalase (CAT), and the level of reduced glutathione (GSH). Also, the ROS level was lowered in mice exposed to arsenic but treated with AG or NA. Protective efficiency of NA is about five times more than that of AG. Administration of NA to arsenic-treated mice caused signs of improvement in liver tissue architecture. In conclusion, the results of this study suggest that NA could be beneficial against arsenic-induced liver toxicity. Copyright © 2015 Elsevier Ireland Ltd. All rights

Arsenic-induced toxicity and the protective role of ascorbic acid in mouse testis

International Nuclear Information System (INIS)

Chang, Soo Im; Jin, Bohwan; Youn, Pilju; Park, Changbo; Park, Jung-Duck; Ryu, Doug-Young

2007-01-01

Oxidative stress has been suggested to be a major cause of male reproductive failure. Here, we investigated whether arsenic, which impairs male reproductive functions in rodent models, acts by inducing oxidative stress. Male 8-week-old ICR mice were given drinking water containing 20 or 40 mg/l sodium arsenite with or without 0.75 or 1.5 g/l of the antioxidant ascorbic acid for 5 weeks. The arsenic-treated mice showed decreased epididymidal sperm counts and testicular weights compared to untreated mice. These effects were reversed in mice that were co-treated with ascorbic acid. Similarly, arsenic treatment lowered the activities of testicular 3β-hydroxysteroid dehydrogenase (HSD) and 17β-HSD, which play important roles in steroidogenesis, and this was reversed by co-treatment with ascorbic acid. The testicles of arsenic-treated mice had decreased glutathione (GSH) levels (which correlate inversely with the degree of cellular oxidative stress) and elevated levels of protein carbonyl (a marker of oxidative damage to tissue proteins). Ascorbic acid co-treatment reversed both of these effects. Thus, ascorbic acid blocks both the adverse effects of arsenic on male reproductive functions and the arsenic-induced testicular oxidative changes. These observations support the notion that arsenic impairs male reproductive function by inducing oxidative stress

Low level arsenic promotes progressive inflammatory angiogenesis and liver blood vessel remodeling in mice

International Nuclear Information System (INIS)

Straub, Adam C.; Stolz, Donna B.; Vin, Harina; Ross, Mark A.; Soucy, Nicole V.; Klei, Linda R.; Barchowsky, Aaron

2007-01-01

The vascular effects of arsenic in drinking water are global health concerns contributing to human disease worldwide. Arsenic targets the endothelial cells lining blood vessels, and endothelial cell activation or dysfunction may underlie the pathogenesis of both arsenic-induced vascular diseases and arsenic-enhanced tumorigenesis. The purpose of the current studies was to demonstrate that exposing mice to drinking water containing environmentally relevant levels of arsenic promoted endothelial cell dysfunction and pathologic vascular remodeling. Increased angiogenesis, neovascularization, and inflammatory cell infiltration were observed in Matrigel plugs implanted in C57BL/6 mice following 5-week exposures to 5-500 ppb arsenic [Soucy, N.V., Mayka, D., Klei, L.R., Nemec, A.A., Bauer, J.A., Barchowsky, A., 2005. Neovascularization and angiogenic gene expression following chronic arsenic exposure in mice. Cardiovasc.Toxicol 5, 29-42]. Therefore, functional in vivo effects of arsenic on endothelial cell function and vessel remodeling in an endogenous vascular bed were investigated in the liver. Liver sinusoidal endothelial cells (LSEC) became progressively defenestrated and underwent capillarization to decrease vessel porosity following exposure to 250 ppb arsenic for 2 weeks. Sinusoidal expression of PECAM-1 and laminin-1 proteins, a hallmark of capillarization, was also increased by 2 weeks of exposure. LSEC caveolin-1 protein and caveolae expression were induced after 2 weeks of exposure indicating a compensatory change. Likewise, CD45/CD68-positive inflammatory cells did not accumulate in the livers until after LSEC porosity was decreased, indicating that inflammation is a consequence and not a cause of the arsenic-induced LSEC phenotype. The data demonstrate that the liver vasculature is an early target of pathogenic arsenic effects and that the mouse liver vasculature is a sensitive model for investigating vascular health effects of arsenic

Arsenite induces apoptosis in human mesenchymal stem cells by altering Bcl-2 family proteins and by activating intrinsic pathway

International Nuclear Information System (INIS)

Yadav, Santosh; Shi Yongli; Wang Feng; Wang He

2010-01-01

Purpose: Environmental exposure to arsenic is an important public health issue. The effects of arsenic on different tissues and organs have been intensively studied. However, the effects of arsenic on bone marrow mesenchymal stem cells (MSCs) have not been reported. This study is designed to investigate the cell death process caused by arsenite and its related underlying mechanisms on MSCs. The rationale is that absorbed arsenic in the blood circulation can reach to the bone marrow and may affect the cell survival of MSCs. Methods: MSCs of passage 1 were purchased from Tulane University, grown till 70% confluency level and plated according to the experimental requirements followed by treatment with arsenite at various concentrations and time points. Arsenite (iAs III ) induced cytotoxic effects were confirmed by cell viability and cell cycle analysis. For the presence of canonic apoptosis markers; DNA damage, exposure of intramembrane phosphotidylserine, protein and m-RNA expression levels were analyzed. Results: iAs III induced growth inhibition, G2-M arrest and apoptotic cell death in MSCs, the apoptosis induced by iAs III in the cultured MSCs was, via altering Bcl-2 family proteins and by involving intrinsic pathway. Conclusion: iAs III can induce apoptosis in bone marrow-derived MSCs via Bcl-2 family proteins, regulating intrinsic apoptotic pathway. Due to the multipotency of MSC, acting as progenitor cells for a variety of connective tissues including bone, adipose, cartilage and muscle, these effects of arsenic may be important in assessing the health risk of the arsenic compounds and understanding the mechanisms of arsenic-induced harmful effects.

Arsenic trioxide induced rhabdomyolysis, a rare but severe side effect, in an APL patient: a case report.

Science.gov (United States)

He, Haiyan; An, Ran; Hou, Jian; Fu, Weijun

2017-06-01

Arsenic trioxide (ATO), a component of the traditional Chinese medicine arsenic sublimate, promotes apoptosis and induces leukemic cell differentiation. Combined with all-trans-retinotic acid (ATRA), ATO has become the first-line induction therapy in treating acute promyelocytic leukemia (APL). The most common side effects of ATO include hepatotoxicity, gastrointestinal symptoms, water-sodium retention, and nervous system damage. In this report, we present a rare side effect, rhabdomyolysis, in a 68-year-old female APL patient who was treated with ATO. After taking 10 mg ATO daily for 6 days, she presented shortness of breath, myodynia, elevated creatine kinase, and acute renal insufficiency. This report describes the first case of ATO-induced rhabdomyolysis.

Chronic arsenic exposure increases TGFalpha concentration in bladder urothelial cells of Mexican populations environmentally exposed to inorganic arsenic

International Nuclear Information System (INIS)

Valenzuela, Olga L.; Germolec, Dori R.; Borja-Aburto, Victor H.; Contreras-Ruiz, Jose; Garcia-Vargas, Gonzalo G.; Razo, Luz M. del

2007-01-01

Inorganic arsenic (iAs) is a well-established carcinogen and human exposure has been associated with a variety of cancers including those of skin, lung, and bladder. High expression of transforming growth factor alpha (TGF-α) has associated with local relapses in early stages of urinary bladder cancer. iAs exposures are at least in part determined by the rate of formation and composition of iAs metabolites (MAs III , MAs V , DMAs III , DMAs V ). This study examines the relationship between TGF-α concentration in exfoliated bladder urothelial cells (BUC) separated from urine and urinary arsenic species in 72 resident women (18-51 years old) from areas exposed to different concentrations of iAs in drinking water (2-378 ppb) in central Mexico. Urinary arsenic species, including trivalent methylated metabolites were measured by hydride generation atomic absorption spectrometry method. The concentration of TGF-α in BUC was measured using an ELISA assay. Results show a statistically significant positive correlation between TGF-α concentration in BUC and each of the six arsenic species present in urine. The multivariate linear regression analyses show that the increment of TGF-α levels in BUC was importantly associated with the presence of arsenic species after adjusting by age, and presence of urinary infection. People from areas with high arsenic exposure had a significantly higher TGF-α concentration in BUC than people from areas of low arsenic exposure (128.8 vs. 64.4 pg/mg protein; p < 0.05). Notably, exfoliated cells isolated from individuals with skin lesions contained significantly greater amount of TGF-α than cells from individuals without skin lesions: 157.7 vs. 64.9 pg/mg protein (p = 0.003). These results suggest that TGF-α in exfoliated BUC may serve as a susceptibility marker of adverse health effects on epithelial tissue in arsenic-endemic areas

Atorvastatin ameliorates arsenic-induced hypertension and enhancement of vascular redox signaling in rats

International Nuclear Information System (INIS)

Sarath, Thengumpallil Sasindran; Waghe, Prashantkumar; Gupta, Priyanka; Choudhury, Soumen; Kannan, Kandasamy; Pillai, Ayyappan Harikrishna; Harikumar, Sankaran Kutty; Mishra, Santosh Kumar; Sarkar, Souvendra Nath

2014-01-01

Chronic arsenic exposure has been linked to elevated blood pressure and cardiovascular diseases, while statins reduce the incidence of cardiovascular disease predominantly by their low density lipoprotein-lowering effect. Besides, statins have other beneficial effects, including antioxidant and anti-inflammatory activities. We evaluated whether atorvastatin, a widely used statin, can ameliorate arsenic-induced increase in blood pressure and alteration in lipid profile and also whether the amelioration could relate to altered NO and ROS signaling. Rats were exposed to sodium arsenite (100 ppm) through drinking water for 90 consecutive days. Atorvastatin (10 mg/kg bw, orally) was administered once daily during the last 30 days of arsenic exposure. On the 91st day, blood was collected for lipid profile. Western blot of iNOS and eNOS protein, NO and 3-nitrotyrosine production, Nox-4 and p22Phox mRNA expression, Nox activity, ROS generation, lipid peroxidation and antioxidants were evaluated in thoracic aorta. Arsenic increased systolic, diastolic and mean arterial blood pressure, while it decreased HDL-C and increased LDL-C, total cholesterol and triglycerides in serum. Arsenic down-regulated eNOS and up-regulated iNOS protein expression and increased basal NO and 3-nitrotyrosine level. Arsenic increased aortic Nox-4 and p22Phox mRNA expression, Nox activity, ROS generation and lipid peroxidation. Further, arsenic decreased the activities of superoxide dismutase, catalase, and glutathione peroxidase and depleted aortic GSH content. Atorvastatin regularized blood pressure, improved lipid profile and attenuated arsenic-mediated redox alterations. The results demonstrate that atorvastatin has the potential to ameliorate arsenic-induced hypertension by improving lipid profile, aortic NO signaling and restoring vascular redox homeostasis. - Highlights: • Arsenic increased systolic, diastolic and mean arterial blood pressure and caused dyslipidemia. • Arsenic increased

Atorvastatin ameliorates arsenic-induced hypertension and enhancement of vascular redox signaling in rats

Energy Technology Data Exchange (ETDEWEB)

Sarath, Thengumpallil Sasindran; Waghe, Prashantkumar; Gupta, Priyanka; Choudhury, Soumen; Kannan, Kandasamy [Division of Pharmacology and Toxicology, Indian Veterinary Research Institute, Izatnagar, 243122 Bareilly, Uttar Pradesh (India); Pillai, Ayyappan Harikrishna [Division of Animal Biochemistry, Indian Veterinary Research Institute, Izatnagar, 243122 Bareilly, Uttar Pradesh (India); Harikumar, Sankaran Kutty; Mishra, Santosh Kumar [Division of Pharmacology and Toxicology, Indian Veterinary Research Institute, Izatnagar, 243122 Bareilly, Uttar Pradesh (India); Sarkar, Souvendra Nath, E-mail: snsarkar1911@rediffmail.com [Division of Pharmacology and Toxicology, Indian Veterinary Research Institute, Izatnagar, 243122 Bareilly, Uttar Pradesh (India)

2014-11-01

Chronic arsenic exposure has been linked to elevated blood pressure and cardiovascular diseases, while statins reduce the incidence of cardiovascular disease predominantly by their low density lipoprotein-lowering effect. Besides, statins have other beneficial effects, including antioxidant and anti-inflammatory activities. We evaluated whether atorvastatin, a widely used statin, can ameliorate arsenic-induced increase in blood pressure and alteration in lipid profile and also whether the amelioration could relate to altered NO and ROS signaling. Rats were exposed to sodium arsenite (100 ppm) through drinking water for 90 consecutive days. Atorvastatin (10 mg/kg bw, orally) was administered once daily during the last 30 days of arsenic exposure. On the 91st day, blood was collected for lipid profile. Western blot of iNOS and eNOS protein, NO and 3-nitrotyrosine production, Nox-4 and p22Phox mRNA expression, Nox activity, ROS generation, lipid peroxidation and antioxidants were evaluated in thoracic aorta. Arsenic increased systolic, diastolic and mean arterial blood pressure, while it decreased HDL-C and increased LDL-C, total cholesterol and triglycerides in serum. Arsenic down-regulated eNOS and up-regulated iNOS protein expression and increased basal NO and 3-nitrotyrosine level. Arsenic increased aortic Nox-4 and p22Phox mRNA expression, Nox activity, ROS generation and lipid peroxidation. Further, arsenic decreased the activities of superoxide dismutase, catalase, and glutathione peroxidase and depleted aortic GSH content. Atorvastatin regularized blood pressure, improved lipid profile and attenuated arsenic-mediated redox alterations. The results demonstrate that atorvastatin has the potential to ameliorate arsenic-induced hypertension by improving lipid profile, aortic NO signaling and restoring vascular redox homeostasis. - Highlights: • Arsenic increased systolic, diastolic and mean arterial blood pressure and caused dyslipidemia. • Arsenic increased

Neurotoxicity induced by arsenic in Gallus Gallus: Regulation of oxidative stress and heat shock protein response.

Science.gov (United States)

Zhao, Panpan; Guo, Ying; Zhang, Wen; Chai, Hongliang; Xing, Houjuan; Xing, Mingwei

2017-01-01

Arsenic, a naturally occurring heavy metal pollutant, is one of the functioning risk factors for neurological toxicity in humans. However, little is known about the effects of arsenic on the nervous system of Gallus Gallus. To investigate whether arsenic induce neurotoxicity and influence the oxidative stress and heat shock proteins (Hsps) response in chickens, seventy-two 1-day-old male Hy-line chickens were treated with different doses of arsenic trioxide (As 2 O 3 ). The histological changes, antioxidant enzyme activity, and the expressions of Hsps were detected. Results showed slightly histology changes were obvious in the brain tissues exposure to arsenic. The activities of Glutathione peroxidase (GSH-Px) and catalase (CAT) were decreased compared to the control, whereas the malondialdehyde (MDA) content was increased gradually along with increase in diet-arsenic. The mRNA levels of Hsps and protein expressions of Hsp60 and Hsp70 were up-regulated. These results suggested that sub-chronic exposure to arsenic induced neurotoxicity in chickens. Arsenic exposure disturbed the balance of oxidants and antioxidants. Increased heat shock response tried to protect chicken brain tissues from tissues damage caused by oxidative stress. The mechanisms of neurotoxicity induced by arsenic include oxidative stress and heat shock protein response in chicken brain tissues. Copyright © 2016 Elsevier Ltd. All rights reserved.

Arsenic trioxide mediates HAPI microglia inflammatory response and subsequent neuron apoptosis through p38/JNK MAPK/STAT3 pathway

International Nuclear Information System (INIS)

Mao, Jiamin; Yang, Jianbing; Zhang, Yan; Li, Ting; Wang, Cheng; Xu, Lingfei; Hu, Qiaoyun; Wang, Xiaoke; Jiang, Shengyang; Nie, Xiaoke; Chen, Gang

2016-01-01

Arsenic is a widely distributed toxic metalloid all over the world. Inorganic arsenic species are supposed to affect astrocytic functions and to cause neuron apoptosis in CNS. Microglias are the key cell type involved in innate immune responses in CNS, and microglia activation has been linked to inflammation and neurotoxicity. In this study, using ELISA, we showed that Arsenic trioxide up-regulated the expression and secretion of IL-1β in a dose-dependent manner and a time-dependent manner in cultured HAPI microglia cells. The secretion of IL-1β caused the apoptosis of SH-SY5Y. These pro-inflammatory responses were inhibited by the STAT3 blocker, AG490 and P38/JNK MAPK blockers SB202190, SP600125. Further, Arsenic trioxide exposure could induce phosphorylation and activation of STAT3, and the translocation of STAT3 from the cytosol to the nucleus in this HAPI microglia cell line. Thus, the STAT3 signaling pathway can be activated after Arsenic trioxide treatment. However, P38/JNK MAPK blockers SB202190, SP600125 also obviously attenuated STAT3 activation and transnuclear transport induced by Arsenic trioxide. In concert with these results, we highlighted that the secretion of IL-1β and STAT3 activation induced by Arsenic trioxide can be mediated by elevation of P38/JNK MAPK in HAPI microglia cells and then induced the toxicity of neurons. - Highlights: • Arsenic trioxide exposure induced expression of IL-β in HAPI microglia. • Arsenic trioxide exposure induced activation of MAPK pathways in HAPI microglia. • Arsenic trioxide exposure induced activation of STAT3 pathways in HAPI microglia. • The expression of IL-β though P38/JNK MAPK/STAT3 pathways in HAPI microglia.

Arsenic trioxide mediates HAPI microglia inflammatory response and subsequent neuron apoptosis through p38/JNK MAPK/STAT3 pathway

Energy Technology Data Exchange (ETDEWEB)

Mao, Jiamin [Department of Environmental Health, School of Public Health, Nantong University, Nantong, Jiangsu 226001 (China); Yang, Jianbing [Department of Pediatrics, Affiliated Hospital of Nantong University, Nantong, Jiangsu 226001 (China); Zhang, Yan [Department of Nutrition and Food Hygiene, School of Public Health, Nantong University, Nantong, Jiangsu 226001 (China); Li, Ting [Department of Environmental Health, School of Public Health, Nantong University, Nantong, Jiangsu 226001 (China); Wang, Cheng [Department of Nutrition and Food Hygiene, School of Public Health, Nantong University, Nantong, Jiangsu 226001 (China); Xu, Lingfei; Hu, Qiaoyun; Wang, Xiaoke; Jiang, Shengyang [Department of Environmental Health, School of Public Health, Nantong University, Nantong, Jiangsu 226001 (China); Nie, Xiaoke [Department of Nutrition and Food Hygiene, School of Public Health, Nantong University, Nantong, Jiangsu 226001 (China); Chen, Gang, E-mail: chengang@ntu.edu.cn [Department of Environmental Health, School of Public Health, Nantong University, Nantong, Jiangsu 226001 (China)

2016-07-15

Arsenic is a widely distributed toxic metalloid all over the world. Inorganic arsenic species are supposed to affect astrocytic functions and to cause neuron apoptosis in CNS. Microglias are the key cell type involved in innate immune responses in CNS, and microglia activation has been linked to inflammation and neurotoxicity. In this study, using ELISA, we showed that Arsenic trioxide up-regulated the expression and secretion of IL-1β in a dose-dependent manner and a time-dependent manner in cultured HAPI microglia cells. The secretion of IL-1β caused the apoptosis of SH-SY5Y. These pro-inflammatory responses were inhibited by the STAT3 blocker, AG490 and P38/JNK MAPK blockers SB202190, SP600125. Further, Arsenic trioxide exposure could induce phosphorylation and activation of STAT3, and the translocation of STAT3 from the cytosol to the nucleus in this HAPI microglia cell line. Thus, the STAT3 signaling pathway can be activated after Arsenic trioxide treatment. However, P38/JNK MAPK blockers SB202190, SP600125 also obviously attenuated STAT3 activation and transnuclear transport induced by Arsenic trioxide. In concert with these results, we highlighted that the secretion of IL-1β and STAT3 activation induced by Arsenic trioxide can be mediated by elevation of P38/JNK MAPK in HAPI microglia cells and then induced the toxicity of neurons. - Highlights: • Arsenic trioxide exposure induced expression of IL-β in HAPI microglia. • Arsenic trioxide exposure induced activation of MAPK pathways in HAPI microglia. • Arsenic trioxide exposure induced activation of STAT3 pathways in HAPI microglia. • The expression of IL-β though P38/JNK MAPK/STAT3 pathways in HAPI microglia.

Exercise Prevents Memory Impairment Induced by Arsenic Exposure in Mice: Implication of Hippocampal BDNF and CREB.

Directory of Open Access Journals (Sweden)

Bao-Fei Sun

Full Text Available High concentrations of arsenic, which can be occasionally found in drinking water, have been recognized as a global health problem. Exposure to arsenic can disrupt spatial memory; however, the underlying mechanism remains unclear. In the present study, we tested whether exercise could interfere with the effect of arsenic exposure on the long-term memory (LTM of object recognition in mice. Arsenic (0, 1, 3, and 10 mg/ kg, i.g. was administered daily for 12 weeks. We found that arsenic at dosages of 1, 3, and 10 mg/kg decreased body weight and increased the arsenic content in the brain. The object recognition LTM (tested 24 h after training was disrupted by 3 mg/ kg and 10 mg/ kg, but not 1 mg/ kg arsenic exposure. Swimming exercise also prevented LTM impairment induced by 3 mg/ kg, but not with 10 mg/ kg, of arsenic exposure. The expression of brain-derived neurotrophic factor (BDNF and phosphorylated cAMP-response element binding protein (pCREB in the CA1 and dentate gyrus areas (DG of the dorsal hippocampus were decreased by 3 mg/ kg and 10 mg/ kg, but not by 1 mg/ kg, of arsenic exposure. The decrease in BDNF and pCREB in the CA1 and DG induced by 3 mg/ kg, but not 10 mg/ kg, of arsenic exposure were prevented by swimming exercise. Arsenic exposure did not affect the total CREB expression in the CA1 or DG. Taken together, these results indicated that swimming exercise prevented the impairment of object recognition LTM induced by arsenic exposure, which may be mediated by BDNF and CREB in the dorsal hippocampus.

Cytogenetic insights into DNA damage and repair of lesions induced by a monomethylated trivalent arsenical

Science.gov (United States)

Arsenic is a human carcinogen, and only recently have animal models been developed that are useful in investigating its carcinogenic mode ofaction (MOA). However, how arsenic induces cancer is still an open question. In a previous paper, we proposed a model detailing how arsenic ...

Arsenite induces cell transformation by reactive oxygen species, AKT, ERK1/2, and p70S6K1

International Nuclear Information System (INIS)

Carpenter, Richard L.; Jiang, Yue; Jing, Yi; He, Jun; Rojanasakul, Yon; Liu, Ling-Zhi; Jiang, Bing-Hua

2011-01-01

Highlights: ► Chronic exposure to arsenite induces cell proliferation and transformation. ► Arsenite-induced transformation increases ROS production and downstream signalings. ► Inhibition of ROS levels via catalase reduces arsenite-induced cell transformation. ► Interruption of AKT, ERK, or p70S6K1 inhibits arsenite-induced cell transformation. -- Abstract: Arsenic is naturally occurring element that exists in both organic and inorganic formulations. The inorganic form arsenite has a positive association with development of multiple cancer types. There are significant populations throughout the world with high exposure to arsenite via drinking water. Thus, human exposure to arsenic has become a significant public health problem. Recent evidence suggests that reactive oxygen species (ROS) mediate multiple changes to cell behavior after acute arsenic exposure, including activation of proliferative signaling and angiogenesis. However, the role of ROS in mediating cell transformation by chronic arsenic exposure is unknown. We found that cells chronically exposed to sodium arsenite increased proliferation and gained anchorage-independent growth. This cell transformation phenotype required constitutive activation of AKT, ERK1/2, mTOR, and p70S6K1. We also observed these cells constitutively produce ROS, which was required for the constitutive activation of AKT, ERK1/2, mTOR, and p70S6K1. Suppression of ROS levels by forced expression of catalase also reduced cell proliferation and anchorage-independent growth. These results indicate cell transformation induced by chronic arsenic exposure is mediated by increased cellular levels of ROS, which mediates activation of AKT, ERK1/2, and p70S6K1.

Chronic exposure to low concentration of arsenic is immunotoxic to fish: Role of head kidney macrophages as biomarkers of arsenic toxicity to Clarias batrachus

International Nuclear Information System (INIS)

Datta, Soma; Ghosh, Debabrata; Saha, Dhira Rani; Bhattacharaya, Shelley; Mazumder, Shibnath

2009-01-01

The present study was aimed at elucidating the effect of chronic low-level arsenic exposure on the head kidney (HK) of Clarias batrachus and at determining the changes in head kidney macrophage (HKM) activity in response to arsenic exposure. Chronic exposure (30 days) to arsenic (As 2 O 3 , 0.50 μM) led to significant increase in arsenic content in the HK accompanied by reduction in both HKM number and head kidney somatic index (HKSI). Arsenic induced HK hypertrophy, reduction in melano-macrophage population and increased hemosiderin accumulation. Transmission electron microscopy of 30 days exposed HKM revealed prominent endoplasmic reticulum, chromatin condensation and loss in structural integrity of nuclear membrane. Head kidney macrophages from exposed fish demonstrated significant levels of superoxide anions but on infection with Aeromonas hydrophila were unable to clear the intracellular bacteria and died. Exposure-challenge experiments with A. hydrophila revealed that chronic exposure to micromolar concentration of arsenic interfered with the phagocytic potential of HKM, helped in intracellular survival of the ingested bacteria inside the HKM inducing significant HKM cytotoxicity. The immunosuppressive effect of arsenic was further evident from the ability of A. hydrophila to colonize and disseminate efficiently in exposed fish. Enzyme linked immunosorbent assay indicated that chronic exposure to arsenic suppressed the production of pro-inflammatory 'IL-1β like' factors from HKM. It is concluded that arsenic even at very low concentration is immunotoxic to fish and the changes observed in HKM may provide a useful early biomarker of low-level xenobiotic exposure

Chronic exposure to low concentration of arsenic is immunotoxic to fish: Role of head kidney macrophages as biomarkers of arsenic toxicity to Clarias batrachus

Energy Technology Data Exchange (ETDEWEB)

Datta, Soma; Ghosh, Debabrata [Immunobiology Laboratory, School of Life Sciences, Visva Bharati University, Santiniketan 731 235 (India); Saha, Dhira Rani [Microscopy Laboratory, National Institute of Cholera and Enteric Diseases, P-33, Scheme XM, C.I.T. Road, Beliaghata, Kolkata 700 010 (India); Bhattacharaya, Shelley [Environmental Toxicology Laboratory, School of Life Sciences, Visva Bharati University, Santiniketan 731 235 (India); Mazumder, Shibnath [Immunobiology Laboratory, School of Life Sciences, Visva Bharati University, Santiniketan 731 235 (India)], E-mail: shibnath1@yahoo.co.in

2009-04-09

The present study was aimed at elucidating the effect of chronic low-level arsenic exposure on the head kidney (HK) of Clarias batrachus and at determining the changes in head kidney macrophage (HKM) activity in response to arsenic exposure. Chronic exposure (30 days) to arsenic (As{sub 2}O{sub 3}, 0.50 {mu}M) led to significant increase in arsenic content in the HK accompanied by reduction in both HKM number and head kidney somatic index (HKSI). Arsenic induced HK hypertrophy, reduction in melano-macrophage population and increased hemosiderin accumulation. Transmission electron microscopy of 30 days exposed HKM revealed prominent endoplasmic reticulum, chromatin condensation and loss in structural integrity of nuclear membrane. Head kidney macrophages from exposed fish demonstrated significant levels of superoxide anions but on infection with Aeromonas hydrophila were unable to clear the intracellular bacteria and died. Exposure-challenge experiments with A. hydrophila revealed that chronic exposure to micromolar concentration of arsenic interfered with the phagocytic potential of HKM, helped in intracellular survival of the ingested bacteria inside the HKM inducing significant HKM cytotoxicity. The immunosuppressive effect of arsenic was further evident from the ability of A. hydrophila to colonize and disseminate efficiently in exposed fish. Enzyme linked immunosorbent assay indicated that chronic exposure to arsenic suppressed the production of pro-inflammatory 'IL-1{beta} like' factors from HKM. It is concluded that arsenic even at very low concentration is immunotoxic to fish and the changes observed in HKM may provide a useful early biomarker of low-level xenobiotic exposure.

Atherosclerosis induced by arsenic in drinking water in rats through altering lipid metabolism

International Nuclear Information System (INIS)

Cheng, Tain-Junn; Chuu, Jiunn-Jye; Chang, Chia-Yu; Tsai, Wan-Chen; Chen, Kuan-Jung; Guo, How-Ran

2011-01-01

Arsenic in drinking water is a global environmental health problem, and the exposure may increase cardiovascular and cerebrovascular diseases mortalities, most likely through causing atherosclerosis. However, the mechanism of atherosclerosis formation after arsenic exposure is still unclear. To study the mechanism of atherosclerosis formation after arsenic exposure and explore the role of high cholesterol diet (HCD) in this process, we fed spontaneous hypertensive rats and Wistar Kyoto rats with basal diet or HCD and provided with them drinking water containing arsenic at different ages and orders for 20 consecutive weeks. We measured high density lipoprotein cholesterol (HDL-C), low density lipoprotein cholesterol (LDL-C), total cholesterol, triglycerides, heat shock protein 70 (HSP 70), and high sensitive C-reactive protein (hs-CRP) at predetermined intervals and determined expressions of cholesteryl ester transfer protein-1 (CETP-1) and liver X receptor β (LXRβ) in the liver. Atherosclerosis was determined by examining the aorta with hematoxylin and eosin stain. After 20 weeks, we found arsenic, alone or combined with HCD, may promote atherosclerosis formation with transient increases in HSP 70 and hs-CRP. Early combination exposure decreased the HDL-C/LDL-C ratio without changing the levels of total cholesterol and triglyceride until 30 weeks old. Both CETP-1 and LXRβ activities were suppressed, most significantly in early combination exposure. In conclusion, arsenic exposure may induce atherosclerosis through modifying reverse cholesterol transport in cholesterol metabolism and suppressing LXRβ and CEPT-1 expressions. For decreasing atherosclerosis related mortality associated with arsenic, preventing exposure from environmental sources in early life is an important element. - Highlights: → Arsenic causes cardiovascular and cerebrovascular diseases through atherosclerosis. → Arsenic may promote atherosclerosis with transient increase in HSP 70 and hs

Arsenic activates the expression of 3β-HSD in mouse Leydig cells through repression of histone H3K9 methylation

DEFF Research Database (Denmark)

Alamdar, Ambreen; Xi, Guochen; Huang, Qingyu

2017-01-01

methylation. The results showed that H3K9me2/3 demethylase (JMJD2A) inhibitor, quercetin (Que) significantly attenuated the decrease of H3K9me2/3 and increase of 3β-HSD expression induced by arsenic. To further elucidate the mechanism for the activation of 3β-HSD, we determined the histone H3K9 methylation......Arsenic exposure has been associated with male reproductive dysfunction by disrupting steroidogenesis; however, the roles of epigenetic drivers, especially histone methylation in arsenic-induced steroidogenic toxicity remain not well documented. In this study, we investigated the role of histone H3...... lysine 9 (H3K9) methylation in steroidogenesis disturbance in mouse Leydig cells (MLTC-1) due to arsenic exposure. Our results indicated that mRNA and protein expression levels of 3β-hydroxysteroid dehydrogenase (3β-HSD) were both significantly up-regulated while the rest of key genes involved...

Identification of Arsenic Direct-Binding Proteins in Acute Promyelocytic Leukaemia Cells

Directory of Open Access Journals (Sweden)

Tao Zhang

2015-11-01

Full Text Available The identification of arsenic direct-binding proteins is essential for determining the mechanism by which arsenic trioxide achieves its chemotherapeutic effects. At least two cysteines close together in the amino acid sequence are crucial to the binding of arsenic and essential to the identification of arsenic-binding proteins. In the present study, arsenic binding proteins were pulled down with streptavidin and identified using a liquid chromatograph-mass spectrometer (LC-MS/MS. More than 40 arsenic-binding proteins were separated, and redox-related proteins, glutathione S-transferase P1 (GSTP1, heat shock 70 kDa protein 9 (HSPA9 and pyruvate kinase M2 (PKM2, were further studied using binding assays in vitro. Notably, PKM2 has a high affinity for arsenic. In contrast to PKM2, GSTP1and HSPA9 did not combine with arsenic directly in vitro. These observations suggest that arsenic-mediated acute promyelocytic leukaemia (APL suppressive effects involve PKM2. In summary, we identified several arsenic binding proteins in APL cells and investigated the therapeutic mechanisms of arsenic trioxide for APL. Further investigation into specific signal pathways by which PKM2 mediates APL developments may lead to a better understanding of arsenic effects on APL.

Protective Effects of Hydroalcoholic Extract of Nasturtium officinale on Rat Blood Cells Exposed to Arsenic

Directory of Open Access Journals (Sweden)

Felor Zargari

2015-06-01

Full Text Available Background: Arsenic is one of the most toxic metalloids. Anemia and leukopenia are common results of poisoning with arsenic, which may happen due to a direct hemolytic or cytotoxic effect on blood cells. The aim of this study was to examine the effects of hydroalcoholic extract of Nasturtium officinale on blood cells and antioxidant enzymes in rats exposed to sodium (metaarsenite. Methods: 32 Male Sprague Dawley rats were randomly divided into four groups; Group I (normal healthy rats, Group II (treated with 5.5mg/kg of body weight of NaAsO2, Group III (treated with 500mg/kg of body weight of hydro-alcoholic extract of N. officinale, and Group IV (treated with group II and III supplementations. Blood samples were collected and red blood cell, white blood cell, hematocrit, hemoglobin, platelet, total protein and albumin levels and total antioxidant capacity were measured. Data was analyzed with Mann-Whitney U test. Results: WBC, RBC and Hct were decreased in the rats exposed to NaAsO2 (p<0.05. A significant increase was seen in RBC and Hct after treatment with the plant extract (p<0.05. There was no significant decrease in serum albumin and total protein in the groups exposed to NaAsO2 compared to the group I, but NaAsO2 decreased the total antioxidant capacity, significantly. Conclusion: The Nasturtium officinale extract have protective effect on arsenic-induced damage of blood cells.

Arsenic-induced cutaneous hyperplastic lesions are associated with the dysregulation of Yap, a Hippo signaling-related protein

International Nuclear Information System (INIS)

Li, Changzhao; Srivastava, Ritesh K.; Elmets, Craig A.; Afaq, Farrukh; Athar, Mohammad

2013-01-01

Highlights: •Arsenic activates canonical Hippo signaling pathway and up-regulates αCatenin in the skin. •Arsenic activates transcriptional activity of Yap by its nuclear translocation. •Yap is involved in the disruption of tight/adherens junctions in arsenic-exposed animals. -- Abstract: Arsenic exposure in humans causes a number of toxic manifestations in the skin including cutaneous neoplasm. However, the mechanism of these alterations remains elusive. Here, we provide novel observations that arsenic induced Hippo signaling pathway in the murine skin. This pathway plays crucial roles in determining organ size during the embryonic development and if aberrantly activated in adults, contributes to the pathogenesis of epithelial neoplasm. Arsenic treatment enhanced phosphorylation-dependent activation of LATS1 kinase and other Hippo signaling regulatory proteins Sav1 and MOB1. Phospho-LATS kinase is known to catalyze the inactivation of a transcriptional co-activator, Yap. However, in arsenic-treated epidermis, we did not observed its inactivation. Thus, as expected, unphosphorylated-Yap was translocated to the nucleus in arsenic-treated epidermis. Yap by binding to the transcription factors TEADs induces transcription of its target genes. Consistently, an up-regulation of Yap-dependent target genes Cyr61, Gli2, Ankrd1 and Ctgf was observed in the skin of arsenic-treated mice. Phosphorylated Yap is important in regulating tight and adherens junctions through its binding to αCatenin. We found disruption of these junctions in the arsenic-treated mouse skin despite an increase in αCatenin. These data provide evidence that arsenic-induced canonical Hippo signaling pathway and Yap-mediated disruption of tight and adherens junctions are independently regulated. These effects together may contribute to the carcinogenic effects of arsenic in the skin

Is it possible to avert arsenic effects on cells and tissues bypassing its toxicity and suppressive consequences of energy production? A hypothesis

Directory of Open Access Journals (Sweden)

Biplab Giri

2017-01-01

Full Text Available Arsenic, a sulfhydryl reactive metalloid, found primarily in two forms: arsenite and arsenate, causing several human health problems, is considered as a dreaded agent against public health. It mainly spreads through groundwater contamination and affects human mainly through drinking water. Arsenic contaminated groundwater is now a major threat in some parts of India (the river basin of Ganga and Brahmaputra and Bangladesh. The current authors belong to the region where arsenic poisoning and its consequences are spreading in an uncontrolled way. We are helpless to stop the spreading of geogenic groundwater arsenic contamination at present. Although most of the research on arsenic removal from drinking water and on toxicity profile has been carried out, very few preventive measures have been reported till date to balance the arsenic-induced cellular energy deficiency and oxidative stress-mediated cell death and cellular senescence. And, therefore, we need to think about alternative remedial to address such problems, which propel us to propose the current hypothesis that the adverse effects of energy imbalance due to arsenic toxicity in cells could be dodged by intake of moderate amount of alcohol. While pyruvate dehydrogenase complex is blocked by arsenic, glucose cannot be utilized through Kreb's cycle. However, alcohol can produce energy by bypassing the aerobic adenosine triphosphate (ATP production machinery. In addition, arsenic poisoning incurs cellular oxidative stress which needs to be scavenged further. So to meet this secondary problem, we also suggest consuming red grape juice (a potent antioxidant and cytoprotective agent in addition to alcohol (as per International Center for Alcohol Policies (ICAP Drinking Guidelines in our second part of the hypothesis. In conclusion, it can be suggested that the red wine which contains moderate amount of alcohol and high levels of red grape polyphenols, galic acid, resveratrol, and other

Ground water pollution by arsenic and its effects on health. Involvement of metabolic methylation in arsenic-induced genetic damage and tumorigenesis; Muki hiso no mechiru ka taisha to idenshi shogaisei narabini shuyo yuhatsusei

Energy Technology Data Exchange (ETDEWEB)

Yamanaka, K. [Nihon Univ., Tokyo (Japan)] Okada, S. [Shizuoka Prefecture (Japan)

1997-07-10

Drinking water contamination has become a worldwide problem. It is pointed out that re-evaluation of genetic damage with carcinogen is considered as an important problem particularly arsenic`s effects on health. To explain the genetic damage development mechanism of arsenic compound, results of the research conducted on the action of arsenic compound which develops during metabolic methylation process and inorganic arsenic are explained in this paper. The results of the study are summarized as follows. Arsenic genetic damage mutation is caused by dimethyl arsenic in main metabolism than inorganic arsenic. Lung DNA damage is induced by the interaction of O2 and arsenic peroxide radical. Dimethyl arsenic shows very important effect on lung cancer formation process which is induced based on 4-nitroquinoline-1-oxide (4NQO). It not only promotes lung cancer but it also plays an important role in malignant tumor`s mutation. 25 refs., 2 figs.

Arsenic-induced alteration in the expression of genes related to type 2 diabetes mellitus

International Nuclear Information System (INIS)

Diaz-Villasenor, Andrea; Burns, Anna L.; Hiriart, Marcia; Cebrian, Mariano E.; Ostrosky-Wegman, Patricia

2007-01-01

Chronic exposure to high concentrations of arsenic in drinking water is associated with an increased risk for developing type 2 diabetes. The present revision focuses on the effect of arsenic on tissues that participate directly in glucose homeostasis, integrating the most important published information about the impairment of the expression of genes related to type 2 diabetes by arsenic as one of the possible mechanisms by which it leads to the disease. Many factors are involved in the manner in which arsenic contributes to the occurrence of diabetes. The reviewed studies suggest that arsenic might increase the risk for type 2 diabetes via multiple mechanisms, affecting a cluster of regulated events, which in conjunction trigger the disease. Arsenic affects insulin sensitivity in peripheral tissue by modifying the expression of genes involved in insulin resistance and shifting away cells from differentiation to the proliferation pathway. In the liver arsenic disturbs glucose production, whereas in pancreatic beta-cells arsenic decreases insulin synthesis and secretion and reduces the expression of antioxidant enzymes. The consequences of these changes in gene expression include the reduction of insulin secretion, induction of oxidative stress in the pancreas, alteration of gluconeogenesis, abnormal proliferation and differentiation pattern of muscle and adipocytes as well as peripheral insulin resistance

Subchronic Arsenic Exposure Induces Anxiety-Like Behaviors in Normal Mice and Enhances Depression-Like Behaviors in the Chemically Induced Mouse Model of Depression

Directory of Open Access Journals (Sweden)

Chia-Yu Chang

2015-01-01

Full Text Available Accumulating evidence implicates that subchronic arsenic exposure causes cerebral neurodegeneration leading to behavioral disturbances relevant to psychiatric disorders. However, there is still little information regarding the influence of subchronic exposure to arsenic-contaminated drinking water on mood disorders and its underlying mechanisms in the cerebral prefrontal cortex. The aim of this study is to assess the effects of subchronic arsenic exposure (10 mg/LAs2O3 in drinking water on the anxiety- and depression-like behaviors in normal mice and in the chemically induced mouse model of depression by reserpine pretreatment. Our findings demonstrated that 4 weeks of arsenic exposure enhance anxiety-like behaviors on elevated plus maze (EPM and open field test (OFT in normal mice, and 8 weeks of arsenic exposure augment depression-like behaviors on tail suspension test (TST and forced swimming test (FST in the reserpine pretreated mice. In summary, in this present study, we demonstrated that subchronic arsenic exposure induces only the anxiety-like behaviors in normal mice and enhances the depression-like behaviors in the reserpine induced mouse model of depression, in which the cerebral prefrontal cortex BDNF-TrkB signaling pathway is involved. We also found that eight weeks of subchronic arsenic exposure are needed to enhance the depression-like behaviors in the mouse model of depression. These findings imply that arsenic could be an enhancer of depressive symptoms for those patients who already had the attribute of depression.

Arsenic augments the uptake of oxidized LDL by upregulating the expression of lectin-like oxidized LDL receptor in mouse aortic endothelial cells

Energy Technology Data Exchange (ETDEWEB)

Hossain, Ekhtear [Department of Biochemistry, Aichi Medical University School of Medicine, Nagakute, Aichi (Japan); Ota, Akinobu, E-mail: aota@aichi-med-u.ac.jp [Department of Biochemistry, Aichi Medical University School of Medicine, Nagakute, Aichi (Japan); Karnan, Sivasundaram; Damdindorj, Lkhagvasuren [Department of Biochemistry, Aichi Medical University School of Medicine, Nagakute, Aichi (Japan); Takahashi, Miyuki [Department of Biochemistry, Aichi Medical University School of Medicine, Nagakute, Aichi (Japan); Division of Hematology, Department of Internal Medicine, Aichi Medical University School of Medicine, Nagakute, Aichi (Japan); Konishi, Yuko; Konishi, Hiroyuki; Hosokawa, Yoshitaka [Department of Biochemistry, Aichi Medical University School of Medicine, Nagakute, Aichi (Japan)

2013-12-15

Although chronic arsenic exposure is a well-known risk factor for cardiovascular diseases, including atherosclerosis, the molecular mechanism underlying arsenic-induced atherosclerosis remains obscure. Therefore, this study aimed to elucidate this molecular mechanism. We examined changes in the mRNA level of the lectin-like oxidized LDL (oxLDL) receptor (LOX-1) in a mouse aortic endothelial cell line, END-D, after sodium arsenite (SA) treatment. SA treatment significantly upregulated LOX-1 mRNA expression; this finding was also verified at the protein expression level. Flow cytometry and fluorescence microscopy analyses showed that the cellular uptake of fluorescence (Dil)-labeled oxLDL was significantly augmented with SA treatment. In addition, an anti-LOX-1 antibody completely abrogated the augmented uptake of Dil-oxLDL. We observed that SA increased the levels of the phosphorylated forms of nuclear factor of kappa light polypeptide gene enhancer in B cells (NF-κB)/p65. SA-induced upregulation of LOX-1 protein expression was clearly prevented by treatment with an antioxidant, N-acetylcysteine (NAC), or an NF-κB inhibitor, caffeic acid phenethylester (CAPE). Furthermore, SA-augmented uptake of Dil-oxLDL was also prevented by treatment with NAC or CAPE. Taken together, our results indicate that arsenic upregulates LOX-1 expression through the reactive oxygen species-mediated NF-κB signaling pathway, followed by augmented cellular oxLDL uptake, thus highlighting a critical role of the aberrant LOX-1 signaling pathway in the pathogenesis of arsenic-induced atherosclerosis. - Highlights: • Sodium arsenite (SA) increases LOX-1 expression in mouse aortic endothelial cells. • SA enhances cellular uptake of oxidized LDL in dose-dependent manner. • SA-induced ROS generation enhances phosphorylation of NF-κB. • SA upregulates LOX-1 expression through ROS-activated NF-κB signaling pathway.

Characterization of intracellular inclusions in the urothelium of mice exposed to inorganic arsenic.

Science.gov (United States)

Dodmane, Puttappa R; Arnold, Lora L; Muirhead, David E; Suzuki, Shugo; Yokohira, Masanao; Pennington, Karen L; Dave, Bhavana J; Lu, Xiufen; Le, X Chris; Cohen, Samuel M

2014-01-01

Inorganic arsenic (iAs) is a known human carcinogen at high exposures, increasing the incidences of urinary bladder, skin, and lung cancers. In most mammalian species, ingested iAs is excreted mainly through urine primarily as dimethylarsinic acid (DMA(V)). In wild-type (WT) mice, iAs, DMA(V), and dimethylarsinous acid (DMA(III)) exposures induce formation of intramitochondrial urothelial inclusions. Arsenite (iAs(III)) also induced intranuclear inclusions in arsenic (+3 oxidation state) methyltransferase knockout (As3mt KO) mice. The arsenic-induced formation of inclusions in the mouse urothelium was dose and time dependent. The inclusions do not occur in iAs-treated rats and do not appear to be related to arsenic-induced urothelial cytotoxicity. Similar inclusions in exfoliated urothelial cells from humans exposed to iAs have been incorrectly identified as micronuclei. We have characterized the urothelial inclusions using transmission electron microscopy (TEM), DNA-specific 4',6-diamidino-2-phenylindole (DAPI), and non-DNA-specific Giemsa staining and determined the arsenical content. The mouse inclusions stained with Giemsa but not with the DAPI stain. Analysis of urothelial mitochondrial- and nuclear-enriched fractions isolated from WT (C57BL/6) and As3mt KO mice exposed to arsenate (iAs(V)) for 4 weeks showed higher levels of iAs(V) in the treated groups. iAs(III) was the major arsenical present in the enriched nuclear fraction from iAs(V)-treated As3mt KO mice. In conclusion, the urothelial cell inclusions induced by arsenicals appear to serve as a detoxifying sequestration mechanism similar to other metals, and they do not represent micronuclei.

Use of the fluorescent micronucleus assay to detect the genotoxic effects of radiation and arsenic exposure in exfoliated human epithelial cells

International Nuclear Information System (INIS)

Moore, L.E.; Warner, M.L.; Smith, A.H.

1996-01-01

The exfoliated cell micronucleus (MN) assay using fluorescent in situ hybridization (FISH) with a centromeric probe is a rapid method for determining the mechanism of MN formation in epithelial tissues exposed to carcinogenic agents. Here, we describe the use of this assay to detect the presence or absence of centromeric DNA in MN induced in vivo by radiation therapy and chronic arsenic (As) ingestion. We examined the buccal cells of an individual receiving 6,500 rads of photon radiation to the head and neck. Exfoliated cells were collected before, during, and after treatment. After radiation exposure a 16.6-fold increase in buccal cell MN frequency was seen. All induced MN were centromere negative (MN-) resulting from chromosome breakage. This finding is consistent with the clastogenic action of radiation and confirmed the reliability of the method. Three weeks post-therapy, MN frequencies returned to baseline. The assay was used on 18 people chronically exposed to high levels of inorganic arsenic (In-As) in drinking water (average level, 1,312 μg As/L) and 18 matched controls (average level, 16 μg As/L). The combined increase in MN frequency was 1.8-fold (P = 0.001, Fisher's exact test). Frequencies of micronuclei containing acentric fragments (MN-) and those containing whole chromosomes (MN+) both increased, suggesting that arsenic may have both clastogenic and weak aneuploidogenic properties in vivo. After stratification on sex, the effect was stronger in male than in female bladder cells. In males the MN-frequency increased 2.06-fold (P =0.07) while the frequency of MN+ increased 1.86-fold (P = 0.08). In addition, the frequencies of MN and MN+ were positively associated with urinary arsenic and its metabolites. The association was stronger for micronuclei containing acentric fragments. By using FISH with centromeric probes, the mechanism of chemically induced genotoxicity can not be determined in epithelial tissues. 35 refs., 4 tabs

Arsenic trioxide sensitizes glioblastoma to a myc inhibitor.

Directory of Open Access Journals (Sweden)

Yayoi Yoshimura

Full Text Available Glioblastoma multiforme (GBM is associated with high mortality due to infiltrative growth and recurrence. Median survival of the patients is less than 15 months, increasing requirements for new therapies. We found that both arsenic trioxide and 10058F4, an inhibitor of Myc, induced differentiation of cancer stem-like cells (CSC of GBM and that arsenic trioxide drastically enhanced the anti-proliferative effect of 10058F4 but not apoptotic effects. EGFR-driven genetically engineered GBM mouse model showed that this cooperative effect is higher in EGFRvIII-expressing INK4a/Arf-/- neural stem cells (NSCs than in control wild type NSCs. In addition, treatment of GBM CSC xenografts with arsenic trioxide and 10058F4 resulted in significant decrease in tumor growth and increased differentiation with concomitant decrease of proneural and mesenchymal GBM CSCs in vivo. Our study was the first to evaluate arsenic trioxide and 10058F4 interaction in GBM CSC differentiation and to assess new opportunities for arsenic trioxide and 10058F4 combination as a promising approach for future differentiation therapy of GBM.

Arsenic compound-induced increases in glutathione levels in cultured Chinese hamster V79 cells and mechanisms associated with changes in {gamma}-glutamylcysteine synthetase activity, cystine uptake and utilization of cysteine

Energy Technology Data Exchange (ETDEWEB)

Ochi, Takafumi [Department of Environmental Toxicology, Faculty of Pharmaceutical Sciences, Teikyo University, Sagamiko, Kanagawa 199-01 (Japan)

1997-11-01

Increases in the glutathione (GSH) level in cultured Chinese hamster V79 cells incubated with arsenic compounds were investigated in terms of changes in the activity of {gamma}-glutamylcysteine synthetase ({gamma}-GCS), rate of cystine uptake, and utilization of cysteine. Arsenite at subtoxic concentrations caused a marked increase of the GSH level at 8 h after addition and then declined. Increase in the GSH level caused by arsenite was associated with an increase in the rate of cystine uptake, but not in {gamma}-GCS activity. Increase in the rate of uptake of cystine was attributed mainly to an increase in the utilization of cysteine in the synthesis of GSH. Dimethylarsinic acid (DMAA) also caused an increase in the GSH level in a time- and concentration-dependent manner. Increase in the GSH level was accompanied by increases in {gamma}-GCS activity and in the uptake of cystine. DMAA caused a reduction in the rate of utilization of cysteine for protein synthesis while enhancing the rate of cysteine utilization for GSH synthesis. Cycloheximide inhibited increases in {gamma}-GCS activity caused by DMAA and in the rate of cystine uptake caused by arsenite and DMAA. The cystine transport system is suggested to be induced by arsenite and DMAA with {gamma}-GCS induced in cells incubated with DMAA. Among the arsenic compounds, methylarsonic acid (MAA) was not effective in causing an increase in the GSH level. Accordingly, increases in the GSH level caused by arsenite and DMAA may be specific phenomena in which the cells responded to the arsenicals by increasing the GSH level. (orig.) With 13 figs., 1 tab., 47 refs.

Expression of cyclin A in A549 cell line after treatment with arsenic trioxide

Directory of Open Access Journals (Sweden)

Agnieszka Żuryń

2015-12-01

Full Text Available Background: Arsenic trioxide (ATO is an effective drug used in acute promyelocytic leukemia (AML. Many reports suggest that ATO can also be applied as an anticancer agent for solid tumors in the future. The influence of arsenic trioxide on the expression of different cell cycle regulators is poorly recognized. The purpose of the current study is to investigate how arsenic trioxide affects cyclin A expression and localization in the A549 cell line.Materials and methods: Morphological and ultrastructural changes in A549 cells were observed using light and transmission electron microscopes. Cyclin A localization was determined by immunofluorescence. Image-based cytometry was applied to evaluate the effect of arsenic trioxide on apoptosis and the cell cycle. Expression of cyclin A mRNA was quantified by real-time PCR.Results: After treatment with arsenic trioxide, increased numbers of cells with cytoplasmic localization of cyclin A were observed. The doses of 10 and 15 μM ATO slightly reduced expression of cyclin A mRNA. The apoptotic phenotype of cells was poorly represented, and the Tali imagebased cytometry analysis showed low percentages of apoptotic cells. The A549 population displayed an enriched fraction of cells in G0/G1 phase in the presence of 5μM ATO, whereas starting from the higher concentrations of the drug, i.e. 10 and 15 μM ATO, the G2/M fraction was on the increase.Discussion: Low expression of cyclin A in the A549 cell line may constitute a potential factor determining arsenic trioxide resistance. It could be hypothesized that the observed alterations in cyclin A expression/distribution may correlate well with changes in cell cycle regulation in our model, which in turn determines the outcome of the treatment.

Redistribution of cell cycle by arsenic trioxide is associated with demethylation and expression changes of cell cycle related genes in acute promyelocytic leukemia cell line (NB4).

Science.gov (United States)

Hassani, Saeed; Khaleghian, Ali; Ahmadian, Shahin; Alizadeh, Shaban; Alimoghaddam, Kamran; Ghavamzadeh, Ardeshir; Ghaffari, Seyed H

2018-01-01

PML-RARα perturbs the normal epigenetic setting, which is essential to oncogenic transformation in acute promyelocytic leukemia (APL). Transcription induction and recruitment of DNA methyltransferases (DNMTs) by PML-RARα and subsequent hypermethylation are components of this perturbation. Arsenic trioxide (ATO), an important drug in APL therapy, concurrent with degradation of PML-RARα induces cell cycle change and apoptosis. How ATO causes cell cycle alteration has remained largely unexplained. Here, we investigated DNA methylation patterns of cell cycle regulatory genes promoters, the effects of ATO on the methylated genes and cell cycle distribution in an APL cell line, NB4. Analysis of promoter methylation status of 22 cell cycle related genes in NB4 revealed that CCND1, CCNE1, CCNF, CDKN1A, GADD45α, and RBL1 genes were methylated 60.7, 84.6, 58.6, 8.7, 33.4, and 73.7%, respectively, that after treatment with 2 μM ATO for 48 h, turn into 0.6, 13.8, 0.1, 6.6, 10.7, and 54.5% methylated. ATO significantly reduced the expression of DNMT1, 3A, and 3B. ATO induced the expression of CCND1, CCNE1, and GADD45α genes, suppressed the expression of CCNF and CDKN1A genes, which were consistent with decreased number of cells in G1 and S phases and increased number of cells in G2/M phase. In conclusion, demethylation and alteration in the expression level of the cell cycle related genes may be possible mechanisms in ATO-induced cell cycle arrest in APL cells. It may suggest that ATO by demethylation of CCND1 and CCNE1 and their transcriptional activation accelerates G1 and S transition into the G2/M cell cycle arrest.

High fat diet aggravates arsenic induced oxidative stress in rat heart and liver.

Science.gov (United States)

Dutta, Mousumi; Ghosh, Debosree; Ghosh, Arnab Kumar; Bose, Gargi; Chattopadhyay, Aindrila; Rudra, Smita; Dey, Monalisa; Bandyopadhyay, Arkita; Pattari, Sanjib K; Mallick, Sanjaya; Bandyopadhyay, Debasish

2014-04-01

Arsenic is a well known global groundwater contaminant. Exposure of human body to arsenic causes various hazardous effects via oxidative stress. Nutrition is an important susceptible factor which can affect arsenic toxicity by several plausible mechanisms. Development of modern civilization led to alteration in the lifestyle as well as food habits of the people both in urban and rural areas which led to increased use of junk food containing high level of fat. The present study was aimed at investigating the effect of high fat diet on heart and liver tissues of rats when they were co-treated with arsenic. This study was established by elucidating heart weight to body weight ratio as well as analysis of the various functional markers, oxidative stress biomarkers and also the activity of the antioxidant enzymes. Histological analysis confirmed the biochemical investigations. From this study it can be concluded that high fat diet increased arsenic induced oxidative stress. Copyright © 2014 Elsevier Ltd. All rights reserved.

Combined Administration of Taurine and Monoisoamyl Dmsa Protects Arsenic Induced Oxidative Injury in Rats

Directory of Open Access Journals (Sweden)

Swaran J. S. Flora

2008-01-01

Full Text Available Arsenic is a naturally occurring element that is ubiquitously present in the environment. High concentration of naturally occurring arsenic in drinking water is a major health problem in different parts of the world. Despite arsenic being a health hazard and a well documented carcinogen, no safe, effective and specific preventive or therapeutic measures are available. Among various recent strategies adopted, administration of an antioxidant has been reported to be the most effective. The present study was designed to evaluate the therapeutic efficacy of monoisoamyl dimercaptosuccinic acid (MiADMSA, administered either individually or in combination with taurine post chronic arsenic exposure in rats. Arsenic exposed male rats (25 ppm, sodium arsenite in drinking water for 24 weeks were treated with taurine (100 mg/kg, i.p., once daily, monoisoamyl dimercaptosuccinic acid (MiADMSA (50 mg/kg, oral, once daily either individually or in combination for 5 consecutive days. Biochemical variables indicative of oxidative stress along-with arsenic concentration in blood, liver and kidney were measured. Arsenic exposure significantly reduced blood δ-aminolevulinic acid dehydratase (ALAD activity, a key enzyme involved in the heme biosynthesis and enhanced zinc protoporphyrin (ZPP level. Clinical hematological variables like white blood cells (WBC, mean cell hemoglobin (MCH, and mean cell hemoglobin concentration (MCHC showed significant decrease with a significant elevation in platelet (PLT count. These changes were accompanied by significant decrease in superoxide dismutase (SOD activity and increased catalase activity. Arsenic exposure caused a significant decrease in hepatic and renal glutathione (GSH level and an increase in oxidized glutathione (GSSG. These biochemical changes were correlated with an increased uptake of arsenic in blood, liver and kidney. Administration of taurine significantly reduced hepatic oxidative stress however co

Genetic polymorphisms in glutathione S-transferase (GST superfamily and risk of arsenic-induced urothelial carcinoma in residents of southwestern Taiwan

Directory of Open Access Journals (Sweden)

Hsueh Yu-Mei

2011-07-01

Full Text Available Abstract Background Arsenic exposure is an important public health issue worldwide. Dose-response relationship between arsenic exposure and risk of urothelial carcinoma (UC is consistently observed. Inorganic arsenic is methylated to form the metabolites monomethylarsonic acid and dimethylarsinic acid while ingested. Variations in capacity of xenobiotic detoxification and arsenic methylation might explain individual variation in susceptibility to arsenic-induced cancers. Methods To estimate individual susceptibility to arsenic-induced UC, 764 DNA specimens from our long-term follow-up cohort in Southwestern Taiwan were used and the genetic polymorphisms in GSTM1, GSTT1, GSTP1 and arsenic methylation enzymes including GSTO1 and GSTO2 were genotyped. Results The GSTT1 null was marginally associated with increased urothelial carcinoma (UC risk (HR, 1.91, 95% CI, 1.00-3.65, while the association was not observed for other GSTs. Among the subjects with cumulative arsenic exposure (CAE ≥ 20 mg/L*year, the GSTT1 null genotype conferred a significantly increased cancer risk (RR, 3.25, 95% CI, 1.20-8.80. The gene-environment interaction between the GSTT1 and high arsenic exposure with respect to cancer risk was statistically significant (multiplicative model, p = 0.0151 and etiologic fraction was as high as 0.86 (95% CI, 0.51-1.22. The genetic effects of GSTO1/GSTO2 were largely confined to high arsenic level (CAE ≥ 20. Diplotype analysis showed that among subjects exposed to high levels of arsenic, the AGG/AGG variant of GSTO1 Ala140Asp, GSTO2 5'UTR (-183A/G, and GSTO2 Asn142Asp was associated with an increased cancer risk (HRs, 4.91, 95% CI, 1.02-23.74 when compared to the all-wildtype reference, respectively. Conclusions The GSTs do not play a critical role in arsenic-induced urothelial carcinogenesis. The genetic effects of GSTT1 and GSTO1 on arsenic-induced urothelial carcinogenesis are largely confined to very high exposure level.

Ameliorative potential of Psidium guajava in induced arsenic toxicity in Wistar rats

Directory of Open Access Journals (Sweden)

Manju Roy and Sushovan Roy

2011-04-01

Full Text Available The study was undertaken to determine the effect of Psidium.guajava leaf extract on arsenic induced biochemical alterations in Wistar rats. Significant (P<0.05 increased glucose serum urea nitrogen and serum creatinine was observed whereas non significant decrease in total protein, calcium and phosphorus was observed. It is concluded that kidney damage caused by arsenic can be repaired up to some extent by AEPG50. [Veterinary World 2011; 4(2.000: 82-83

Epigenetic mediated transcriptional activation of WNT5A participates in arsenical-associated malignant transformation

International Nuclear Information System (INIS)

Jensen, Taylor J.; Wozniak, Ryan J.; Eblin, Kylee E.; Wnek, Sean M.; Gandolfi, A. Jay; Futscher, Bernard W.

2009-01-01

Arsenic is a human carcinogen with exposure associated with cancer of the lung, skin, and bladder. Many potential mechanisms have been implicated as playing a role in the process of arsenical-induced malignancy including the perturbation of signaling pathways and aberrant epigenetic regulation. We initiated studies to examine the role of a member of the non-canonical WNT signaling pathway, WNT5A, in UROtsa cells and arsenite [URO-ASSC] and monomethylarsonous acid [URO-MSC] malignantly transformed variants. We present data herein that suggest that WNT5A is transcriptionally activated during arsenical-induced malignant transformation. This WNT5A transcriptional activation is correlated with the enrichment of permissive histone modifications and the reduction of repressive modifications in the WNT5A promoter region. The epigenetic activation of WNT5A expression and acetylation of its promoter remain after the removal of the arsenical, consistent with the maintenance of an anchorage independent growth phenotype in these cells. Additionally, treatment with epigenetic modifying drugs supports a functional role for these epigenetic marks in controlling gene expression. Reduction of WNT5A using lentiviral shRNA greatly attenuated the ability of these cells to grow in an anchorage independent fashion. Extension of our model into human bladder cancer cell lines indicates that each of the cell lines examined also express WNT5A. Taken together, these data suggest that the epigenetic remodeling of the WNT5A promoter is correlated with its transcriptional activation and this upregulation likely participates in arsenical-induced malignant transformation

Identification of arsenite-and arsenic diglutathione-binding proteins in human hepatocarcinoma cells

Energy Technology Data Exchange (ETDEWEB)

Mizumura, Ayano; Watanabe, Takayuki [Graduate School of Pharmaceutical Sciences, Chiba University, Yayoi, Inage, Chiba 263-8522 (Japan); Kobayashi, Yayoi [Graduate School of Pharmaceutical Sciences, Chiba University, Yayoi, Inage, Chiba 263-8522 (Japan); Environmental Health Sciences Division, National Institute for Environmental Studies, 16-2 Onogawa, Tsukuba, Ibaraki 305-8506 (Japan); Hirano, Seishiro [Graduate School of Pharmaceutical Sciences, Chiba University, Yayoi, Inage, Chiba 263-8522 (Japan); Research Center for Environmental Risk, National Institute for Environmental Studies, 16-2 Onogawa, Tsukuba, Ibaraki 305-8506 (Japan)

2010-01-15

-conjugated arsenicals can still react with some proteins in hepatic cells.

Arsenic speciation in saliva of acute promyelocytic leukemia patients undergoing arsenic trioxide treatment

OpenAIRE

Chen, Baowei; Cao, Fenglin; Yuan, Chungang; Lu, Xiufen; Shen, Shengwen; Zhou, Jin; Le, X. Chris

2013-01-01

Arsenic trioxide has been successfully used as a therapeutic in the treatment of acute promyelocytic leukemia (APL). Detailed monitoring of the therapeutic arsenic and its metabolites in various accessible specimens of APL patients can contribute to improving treatment efficacy and minimizing arsenic-induced side effects. This article focuses on the determination of arsenic species in saliva samples from APL patients undergoing arsenic treatment. Saliva samples were collected from nine APL pa...

Leukemia-associated gene MLAA-34 reduces arsenic trioxide-induced apoptosis in HeLa cells via activation of the Wnt/β-catenin signaling pathway.

Science.gov (United States)

Zhang, Pengyu; Zhao, Xuan; Zhang, Wenjuan; He, Aili; Lei, Bo; Zhang, Wanggang; Chen, Yinxia

2017-01-01

Our laboratory previously used the SEREX method in U937 cells and identified a novel leukemia-associated gene MLAA-34, a novel splice variant of CAB39L associated with acute monocytic leukemia, that exhibited anti-apoptotic activities in U937 cells. Whether MLAA-34 has an anti-apoptotic role in other tumor cells has not yet been reported. We explored whether MLAA-34 exhibited anti-apoptotic effects in HeLa cervical cancer cells and the possible mechanism of action. We generated a HeLa cell line stably expressing MLAA-34 and found that MLAA-34 overexpression had no effect on the growth, apoptosis and cell cycle of HeLa cells. However, upon treatment with arsenic trioxide (ATO) to induce apoptosis, the cell viability and colony formation ability of ATO-treated MLAA-34 stable HeLa cells were significantly higher than that of ATO-treated controls, and the apoptosis rate and proportion of G2/M cells also decreased. We found that ATO treatment of HeLa cells resulted in significant decreases in the expression of β-catenin mRNA and protein and the downstream target factors c-Myc, cyclin B1, and cyclin D1 in the Wnt signaling pathway. Notably, ATO-treated MLAA-34 stable HeLa cells showed a significant reduction in the ATO-mediated downregulation of these factors. In addition, MLAA-34 overexpression significantly increased the expression of nuclear β-catenin protein in ATO-treated cells compared with HeLa cells treated only with ATO. Thus, here we have found that the Wnt/β-catenin signaling pathway is involved in ATO-induced apoptosis in HeLa cells. MLAA-34 reduces ATO-induced apoptosis and G2/M arrest, and the anti-apoptotic effect may be achieved by activating the Wnt/β-catenin signaling pathway in HeLa cells.

Association of oxidative stress with arsenic methylation in chronic arsenic-exposed children and adults

International Nuclear Information System (INIS)

Xu Yuanyuan; Wang Yi; Zheng Quanmei; Li Xin; Li Bing; Jin Yaping; Sun Xiance; Sun Guifan

2008-01-01

Though oxidative stress is recognized as an important pathogenic mechanism of arsenic, and arsenic methylation capacity is suggested to be highly involved in arsenic-related diseases, the association of arsenic methylation capacity with arsenic-induced oxidative stress remains unclear. To explore oxidative stress and its association with arsenic methylation, cross-sectional studies were conducted among 208 high and 59 low arsenic-exposed subjects. Levels of urinary arsenic species [inorganic arsenic (iAs), monomethylated arsenic (MMA) and dimethylated arsenic (DMA)] were determined by hydride generation atomic absorption spectrometry. Proportions of urinary arsenic species, the first methylation ratio (FMR) and the secondary methylation ratio (SMR) were used as indicators for arsenic methylation capacity. Urinary 8-hydroxy-2'-deoxyguanosine (8-OHdG) concentrations were analyzed by enzyme-linked immunosorbent assay kits. Reduced glutathione (GSH) levels and superoxide dismutase (SOD) activity in whole blood were determined to reflect anti-oxidative status. The high arsenic-exposed children and adults were significantly increased in urinary 8-OHdG concentrations but decreased in blood GSH levels compared with the low exposed children and adults. In multiple linear regression models, blood GSH levels and urinary 8-OHdG concentrations of arsenic-exposed children and adults showed strong associations with the levels of urinary arsenic species. Arsenic-exposed subjects in the lower and the upper quartiles of proportions of urinary arsenic species, FMR or SMR were significantly different in urinary 8-OHdG, blood GSH and SOD. The associations of arsenic methylation capacity with 8-OHdG, GSH and SOD were also observed in multivariate regression analyses. These results may provide linkage between arsenic methylation capacity and oxidative stress in humans and suggest that adverse health effects induced by arsenic are related to arsenic methylation through oxidative stress

In Vivo and In Vitro Arsenic Exposition Induces Oxidative Stress in Anterior Pituitary Gland.

Science.gov (United States)

Ronchetti, Sonia A; Bianchi, María S; Duvilanski, Beatriz H; Cabilla, Jimena P

2016-07-01

Inorganic arsenic (iAs) is at the top of toxic metalloids. Inorganic arsenic-contaminated water consumption is one of the greatest environmental health threats worldwide. Human iAs exposure has been associated with cancers of several organs, neurological disorders, and reproductive problems. Nevertheless, there are no reports describing how iAs affects the anterior pituitary gland. The aim of this study was to investigate the mechanisms involved in iAs-mediated anterior pituitary toxicity both in vivo and in vitro. We showed that iAs administration (from 5 to 100 ppm) to male rats through drinking water increased messenger RNA expression of several oxidative stress-responsive genes in the anterior pituitary gland. Serum prolactin levels diminished, whereas luteinizing hormone (LH) levels were only affected at the higher dose tested. In anterior pituitary cells in culture, 25 µmol/L iAs significantly decreased prolactin release in a time-dependent fashion, whereas LH levels remained unaltered. Cell viability was significantly reduced mainly by apoptosis evidenced by morphological and phosphatidylserine externalization studies. This process is characterized by early depolarization of mitochondrial membrane potential and increased levels of reactive oxygen species. Expression of some key oxidative stress-responsive genes, such as heme oxygenase-1 and metallothionein-1, was also stimulated by iAs exposure. The antioxidant N-acetyl cysteine prevented iAs-induced effects on the expression of oxidative stress markers, prolactin release, and apoptosis. In summary, the present work demonstrates for the first time that iAs reduces prolactin release both in vivo and in vitro and induces apoptosis in anterior pituitary cells, possibly resulting from imbalanced cellular redox status. © The Author(s) 2016.

Curcumin and turmeric attenuate arsenic-induced angiogenesis in ovo.

Science.gov (United States)

Pantazis, Panayotis; Varman, Aarthi; Simpson-Durand, Cindy; Thorpe, Jessica; Ramalingam, Satish; Subramaniam, Dharmalingam; Houchen, Courtney; Ihnat, Michael; Anant, Shrikant; Ramanujam, Rama P

2010-01-01

Trivalent arsenic [As(III)] is currently approved by the FDA for the treatment of chronic and acute leukemias. However, As(III) has also demonstrated damaging effects on human health, including development of cardiovascular disease, diabetes, and cancer. Further, As(III) is a potent angiogenic agent. In this context, curcumin, an active ingredient in the dietary agent turmeric, has demonstrated potent antiproliferative, antiinflammatory, and antiangiogenic properties. In this report, we have shown that both curcumin and turmeric inhibit expression of vascular endothelial growth factor in HCT-116 human colon cancer cells exposed to As(III). Further, in the chicken chorioallantoic membrane assay model, treatment with low As(III) concentrations results in extensive increase in blood vessel density, which, however, is reduced in the presence of curcumin or turmeric. Collectively, the findings reported here strongly suggest that turmeric and curcumin can dramatically attenuate the process of angiogenesis induced by low As(III) concentrations.

Arsenic induced clinico-hemato-pathological alterations in broilers and its attenuation by vitamin e and selenium

International Nuclear Information System (INIS)

Mashkoor, J.; Khan, A.; Khan, M.Z.; Saleemi, M.K.; Mahmood, F.

2012-01-01

Present study was carried out to know the arsenic (As) induced toxico-pathological alterations in broiler chicks and their attenuation with vitamin E (Vit E) and selenium (Se). A total of 90 day-old broiler chicks were equally distributed into 5 groups. Groups 1-4 were administered As at 50 mg/kg BW daily through feed for 30 days. In addition to A , groups 2 to 4 received Vitamin E at 150 mg/kg BW, selenium at 0.25 mg/kg BW and Vitamin E plus selenium, respectively. Group 5 (Control) received normal drinking water for 30 days. Dullness, depression, open mouth breathing, increased thirst; ruffled feathers, pale comb, skin irritation and watery diarrhea were the most striking clinical signs. The body weight and feed intake was significantly decreased in treated birds. The erythrocyte counts, hemoglobin concentration and packed cell volume decreased (P<0.05) in treated broilers with As or As with Se and Vit E. Grossly pale and hemorrhagic liver and swollen kidneys were observed in As treated birds. Arsenic treated groups showed significant decrease in serum. Histopathologically, liver exhibited congestion and cytoplasmic vacuolation. In kidneys, condensation of tubular epithelium nuclei, epithelial cell necrosis, increased urinary spaces, sloughing of tubules from basement membrane and cast deposition were observed. In conclusion As induced toxico-pathological alterations and vitamin E and selenium partially ameliorate the toxic effects in broilers chicks. (author)

ETME, a novel β-elemene derivative, synergizes with arsenic trioxide in inducing apoptosis and cell cycle arrest in hepatocarcinoma cells via a p53-dependent pathway

Directory of Open Access Journals (Sweden)

Zhiying Yu

2014-12-01

Full Text Available Arsenic trioxide (ATO has been identified as an effective treatment for acute promyelocytic leukemia (APL but is much less effective against solid tumors such as hepatocellular carcinoma (HCC. In the search for ways to enhance its therapeutic efficacy against solid tumors, we have examined its use in combination with a novel derivative of β-elemene, N-(β-elemene-13-yltryptophan methyl ester (ETME. Here we report the effects of the combination on cell viability, apoptosis, the cell cycle and mitochondria membrane potential (MMP in HCC SMMC-7721 cells. We found that the two compounds acted synergistically to enhance antiproliferative activity and apoptosis. The combination also decreased the MMP, down-regulated Bcl-2 and pro-proteins of the caspase family, and up-regulated Bax and BID, all of which were reversed by the p53 inhibitor, pifithrin-α. In addition, the combination induced cell cycle arrest at the G2/M phase and reduced tumor volume and weight in an xenograft model of nude mice. Overall, the results suggest that ETME in combination with ATO may be useful in the treatment of HCC patients particularly those unresponsive to ATO alone.

Establishment and characterization of arsenic trioxide resistant KB/ATO cells.

Science.gov (United States)

Zhang, Yun-Kai; Dai, Chunling; Yuan, Chun-Gang; Wu, Hsiang-Chun; Xiao, Zhijie; Lei, Zi-Ning; Yang, Dong-Hua; Le, X Chris; Fu, Liwu; Chen, Zhe-Sheng

2017-09-01

Arsenic trioxide (ATO) is used as a chemotherapeutic agent for the treatment of acute promyelocytic leukemia. However, increasing drug resistance is reducing its efficacy. Therefore, a better understanding of ATO resistance mechanism is required. In this study, we established an ATO-resistant human epidermoid carcinoma cell line, KB/ATO, from its parental KB-3-1 cells. In addition to ATO, KB/ATO cells also exhibited cross-resistance to other anticancer drugs such as cisplatin, antimony potassium tartrate, and 6-mercaptopurine. The arsenic accumulation in KB/ATO cells was significantly lower than that in KB-3-1 cells. Further analysis indicated that neither application of P-glycoprotein inhibitor, breast cancer resistant protein (BCRP) inhibitor, or multidrug resistance protein 1 (MRP1) inhibitor could eliminate ATO resistance. We found that the expression level of ABCB6 was increased in KB/ATO cells. In conclusion, ABCB6 could be an important factor for ATO resistance in KB/ATO cells. The ABCB6 level may serve as a predictive biomarker for the effectiveness of ATO therapy.

Low-dose synergistic immunosuppression of T-dependent antibody responses by polycyclic aromatic hydrocarbons and arsenic in C57BL/6J murine spleen cells

International Nuclear Information System (INIS)

Li Qian; Lauer, Fredine T.; Liu Kejian; Hudson, Laurie G.; Burchiel, Scott W.

2010-01-01

Polycyclic aromatic hydrocarbons (PAHs) and arsenic are both environmental agents that are known to have significant immunotoxicity. Previous studies have shown that PAH exposure of spleen cells in vitro produces significant immune suppression of humoral immunity, especially when P450 activation products are examined. Exposure to arsenic, particularly sodium arsenite, has also been found to be suppressive to antibody responses in vitro and in vivo. The purpose of the present studies was to examine the immunotoxicity of PAHs and arsenite following coexposures with the theory being that the agents may exert synergistic actions, which might be based on their different mechanisms of action. Spleen cells were isolated from male C57BL/6J wild-type mice and treated with PAHs and/or arsenic (arsenite or arsenate). Immunotoxicity assays were used to assess the T-dependent antibody response (TDAR) to sheep red blood cells (SRBCs), measured by a direct plaque-forming cell (PFC) assay. Cell viability was measured by trypan blue staining. Spleen cell viability was not altered following 4 days of PAH and/or arsenic treatment. However, the TDAR demonstrated suppression by both PAHs and arsenic in a concentration-dependent manner. p53 was also induced by NaAsO 2 (As 3+ ) and PAHs alone or in combination. The PAHs and their metabolites investigated included benzo[a]pyrene (BaP), BaP-7,8-diol, BaP-7,8-diol-9,10-epoxide (BPDE), 7,12-dimethylbenz[a]anthracene (DMBA), DMBA-3,4-diol, dibenzo[a,l]pyrene (DB[a,l]P). PAH metabolites were found to be more potent than parent compounds in producing immunosuppression and inducing p53 expression. Interestingly, DB[a,l]P, a potent carcinogenic PAH not previously characterized for immunotoxicity, was also found to be strongly immunosuppressive. Arsenite (NaAsO 2 , As 3+ ) was found to produce immunosuppression at concentrations as low as 0.5 μM and was immunosuppressive at a 10-fold lower concentration than sodium arsenate (Na 2 HAsO 4 , As 5

Urinary Arsenic Metabolites of Subjects Exposed to Elevated Arsenic Present in Coal in Shaanxi Province, China

Directory of Open Access Journals (Sweden)

Linsheng Yang

2011-06-01

Full Text Available In contrast to arsenic (As poisoning caused by naturally occurring inorganic arsenic-contaminated water consumption, coal arsenic poisoning (CAP induced by elevated arsenic exposure from coal combustion has rarely been reported. In this study, the concentrations and distributions of urinary arsenic metabolites in 57 volunteers (36 subjects with skin lesions and 21 subjects without skin lesions, who had been exposed to elevated levels of arsenic present in coal in Changshapu village in the south of Shaanxi Province (China, were reported. The urinary arsenic species, including inorganic arsenic (iAs [arsenite (iAsIII and arsenate (iAsV], monomethylarsonic acid (MMAV and dimethylarsinic acid (DMAV, were determined by high-performance liquid chromatography (HPLC combined with inductively coupled plasma mass spectroscopy (ICP-MS. The relative distributions of arsenic species, the primary methylation index (PMI = MMAV/iAs and the secondary methylation index (SMI = DMAV/MMAV were calculated to assess the metabolism of arsenic. Subjects with skin lesions had a higher concentration of urinary arsenic and a lower arsenic methylation capability than subjects without skin lesions. Women had a significantly higher methylation capability of arsenic than men, as defined by a higher percent DMAV and SMI in urine among women, which was the one possible interpretation of women with a higher concentration of urinary arsenic but lower susceptibility to skin lesions. The findings suggested that not only the dose of arsenic exposure but also the arsenic methylation capability have an impact on the individual susceptibility to skin lesions induced by coal arsenic exposure.

Arsenic trioxide: impact on the growth and differentiation of cancer cells and possible use in cancer therapy

Directory of Open Access Journals (Sweden)

Ewelina Hoffman

2013-08-01

Full Text Available Arsenic trioxide (As2O3 has recently been identified as an effective drug in different types of cancer therapy. It is a useful pharmacological agent in acute promyelocytic leukemia (APL treatment, especially the form that is resistant to conventional chemotherapy with all-trans retinoic acid (ATRA. What is more, laboratory data suggest that As2O3 is also active when it comes to several solid tumor cell lines. However, the mechanism of action is not fully understood. As2O3 in high doses triggers apoptosis, while in lower concentrations it induces partial differentiation. The As2O3 mechanism of action involves effects on mitochondrial transmembrane potential which lead to apoptosis. It also acts on the activity of JNK kinase, glutathione, caspases, NF-ĸB nuclear factor or pro- and antiapoptotic proteins. This publication presents the current knowledge about the influence of arsenic trioxide in cancer cells.

Arsenic silences hepatic PDK4 expression through activation of histone H3K9 methylatransferase G9a

Energy Technology Data Exchange (ETDEWEB)

Zhang, Xi; Wu, Jianguo; Choiniere, Jonathan [Department of Physiology and Neurobiology and The Institute for Systems Genomics, University of Connecticut, Storrs, CT 062696 (United States); Yang, Zhihong [Department of Physiology and Neurobiology and The Institute for Systems Genomics, University of Connecticut, Storrs, CT 062696 (United States); Veterans Affairs Connecticut Healthcare System, West Haven, CT 06516 (United States); Huang, Yi [Department of Physiology and Neurobiology and The Institute for Systems Genomics, University of Connecticut, Storrs, CT 062696 (United States); School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035 (China); Bennett, Jason [Department of Physiology and Neurobiology and The Institute for Systems Genomics, University of Connecticut, Storrs, CT 062696 (United States); Wang, Li, E-mail: li.wang@uconn.edu [Department of Physiology and Neurobiology and The Institute for Systems Genomics, University of Connecticut, Storrs, CT 062696 (United States); Veterans Affairs Connecticut Healthcare System, West Haven, CT 06516 (United States); School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035 (China); Department of Internal Medicine, Section of Digestive Diseases, Yale University, New Haven, CT 06520 (United States)

2016-08-01

It is well established that increased liver cancer incidence is strongly associated with epigenetic silencing of tumor suppressor genes; the latter is contributed by the environmental exposure to arsenic. Pyruvate dehydrogenase kinase 4 (PDK4) is a mitochondrial protein that regulates the TCA cycle. However, the epigenetic mechanisms mediated by arsenic to control PDK4 expression remain elusive. In the present study, we showed that histone methyltransferase G9a- and Suv39H-mediated histone H3 lysine 9 (H3K9) methylations contributed to PDK4 silencing in hepatic cells. The PDK4 expression was induced by G9a inhibitor BRD4770 (BRD) and Suv39H inhibitor Chaetocin (CHA). In contrast, arsenic exposure decreased PDK4 expression by inducing G9a and increasing H3K9 di- and tri-methylations levels (H3K9me2/3). In addition, arsenic exposure antagonizes the effect of BRD by enhancing the enrichment of H3K9me2/3 in the PKD4 promoter. Moreover, knockdown of G9a using siRNA induced PDK4 expression in HCC cells. Furthermore, arsenic decreased hepatic PDK4 expression as well as diminished the induction of PDK4 by BRD in mouse liver and hepatocytes. Overall, the results suggest that arsenic causes aberrant repressive histone modification to silence PDK4 in both HCC cells and in mouse liver. - Graphical abstract: Schematic showing arsenic-mediated epigenetic pathway that inhibits PDK4 expression. (A) BRD induces PDK4 expression by decreasing G9a protein and histone H3K9me2 and H3K9me3 levels as well as diminishing their recruitment to the PDK4 promoter. (B) Arsenic counteracts the effect of BRD by increasing histone H3K9me2 and H3K9me3 levels as well as enhancing their enrichment to the PDK4 promoter. Display Omitted - Highlights: • Histone methyltrasferase G9a inhibitor BRD induces PDK4 expression. • Arsenic decreases PDK4 expression and increases H3K9me2 and me3 levels. • Arsenic enhances H3K9me2/me3 enrichment in the PDK4 promoter. • Arsenic antagonizes the activation of

Arsenic silences hepatic PDK4 expression through activation of histone H3K9 methylatransferase G9a

International Nuclear Information System (INIS)

Zhang, Xi; Wu, Jianguo; Choiniere, Jonathan; Yang, Zhihong; Huang, Yi; Bennett, Jason; Wang, Li

2016-01-01

It is well established that increased liver cancer incidence is strongly associated with epigenetic silencing of tumor suppressor genes; the latter is contributed by the environmental exposure to arsenic. Pyruvate dehydrogenase kinase 4 (PDK4) is a mitochondrial protein that regulates the TCA cycle. However, the epigenetic mechanisms mediated by arsenic to control PDK4 expression remain elusive. In the present study, we showed that histone methyltransferase G9a- and Suv39H-mediated histone H3 lysine 9 (H3K9) methylations contributed to PDK4 silencing in hepatic cells. The PDK4 expression was induced by G9a inhibitor BRD4770 (BRD) and Suv39H inhibitor Chaetocin (CHA). In contrast, arsenic exposure decreased PDK4 expression by inducing G9a and increasing H3K9 di- and tri-methylations levels (H3K9me2/3). In addition, arsenic exposure antagonizes the effect of BRD by enhancing the enrichment of H3K9me2/3 in the PKD4 promoter. Moreover, knockdown of G9a using siRNA induced PDK4 expression in HCC cells. Furthermore, arsenic decreased hepatic PDK4 expression as well as diminished the induction of PDK4 by BRD in mouse liver and hepatocytes. Overall, the results suggest that arsenic causes aberrant repressive histone modification to silence PDK4 in both HCC cells and in mouse liver. - Graphical abstract: Schematic showing arsenic-mediated epigenetic pathway that inhibits PDK4 expression. (A) BRD induces PDK4 expression by decreasing G9a protein and histone H3K9me2 and H3K9me3 levels as well as diminishing their recruitment to the PDK4 promoter. (B) Arsenic counteracts the effect of BRD by increasing histone H3K9me2 and H3K9me3 levels as well as enhancing their enrichment to the PDK4 promoter. Display Omitted - Highlights: • Histone methyltrasferase G9a inhibitor BRD induces PDK4 expression. • Arsenic decreases PDK4 expression and increases H3K9me2 and me3 levels. • Arsenic enhances H3K9me2/me3 enrichment in the PDK4 promoter. • Arsenic antagonizes the activation of

Sulfate and glutathione enhanced arsenic accumulation by arsenic hyperaccumulator Pteris vittata L

International Nuclear Information System (INIS)

Wei Shuhe; Ma, Lena Q.; Saha, Uttam; Mathews, Shiny; Sundaram, Sabarinath; Rathinasabapathi, Bala; Zhou Qixing

2010-01-01

This experiment examined the effects of sulfate (S) and reduced glutathione (GSH) on arsenic uptake by arsenic hyperaccumulator Pteris vittata after exposing to arsenate (0, 15 or 30 mg As L -1 ) with sulfate (6.4, 12.8 or 25.6 mg S L -1 ) or GSH (0, 0.4 or 0.8 mM) for 2-wk. Total arsenic, S and GSH concentrations in plant biomass and arsenic speciation in the growth media and plant biomass were determined. While both S (18-85%) and GSH (77-89%) significantly increased arsenic uptake in P. vittata, GSH also increased arsenic translocation by 61-85% at 0.4 mM (p < 0.05). Sulfate and GSH did not impact plant biomass or arsenic speciation in the media and biomass. The S-induced arsenic accumulation by P. vittata was partially attributed to increased plant GSH (21-31%), an important non-enzymatic antioxidant countering oxidative stress. This experiment demonstrated that S and GSH can effectively enhance arsenic uptake and translocation by P. vittata. - Sulfate and glutathione increased arsenic uptake and translocation in Pteris vittata.

MicroRNA-200b Suppresses Arsenic-transformed Cell Migration by Targeting Protein Kinase Cα and Wnt5b-Protein Kinase Cα Positive Feedback Loop and Inhibiting Rac1 Activation*

Science.gov (United States)

Wang, Zhishan; Humphries, Brock; Xiao, Hua; Jiang, Yiguo; Yang, Chengfeng

2014-01-01

MicroRNA-200b (miR-200b) is a member of miR-200 family that has been found to inhibit cell migration and cancer metastasis; however, the underlying mechanism is not well understood. We previously reported that miR-200 expression is depleted in arsenic-transformed human bronchial epithelial cells with highly migratory and invasive characteristics, whereas stably re-expressing miR-200b strongly suppresses arsenic-transformed cell migration. This study was performed to investigate how miR-200b inhibits arsenic-transformed cell migration. We found that protein kinase Cα (PKCα) is significantly up-regulated in arsenic-transformed cells. Combining bioinformatics analysis with PKCα 3′-untranslated region vector luciferase reporter assays, we showed that PKCα is a direct target of miR-200b. Inhibiting PKCα activity or knocking down PKCα expression drastically reduced cell migration, phenocoping the inhibitory effect of overexpressing miR-200b. In contrast, forced expression of PKCα in miR-200b overexpressing cells impaired the inhibitory effect of miR-200b on cell migration. In addition, we also found a positive feedback loop between Wnt5b and PKCα in arsenic-transformed cells. Knocking down Wnt5b expression reduced phospho-PKC levels and cell migration; and knocking down PKCα expression decreased Wnt5b level and cell migration. Moreover, forced expression of PKCα increased Wnt5b and phospho-PKC levels and cell migration. Further mechanistic studies revealed that Rac1 is highly activated in arsenic-transformed cells and stably expressing miR-200b abolishes Rac1 activation changing actin cytoskeleton organization. Manipulating PKCα or Wnt5b expression levels significantly altered the level of active Rac1. Together, these findings indicate that miR-200b suppresses arsenic-transformed cell migration by targeting PKCα and Wnt5b-PKCα positive feedback loop and subsequently inhibiting Rac1 activation. PMID:24841200

MicroRNA-200b suppresses arsenic-transformed cell migration by targeting protein kinase Cα and Wnt5b-protein kinase Cα positive feedback loop and inhibiting Rac1 activation.

Science.gov (United States)

Wang, Zhishan; Humphries, Brock; Xiao, Hua; Jiang, Yiguo; Yang, Chengfeng

2014-06-27

MicroRNA-200b (miR-200b) is a member of miR-200 family that has been found to inhibit cell migration and cancer metastasis; however, the underlying mechanism is not well understood. We previously reported that miR-200 expression is depleted in arsenic-transformed human bronchial epithelial cells with highly migratory and invasive characteristics, whereas stably re-expressing miR-200b strongly suppresses arsenic-transformed cell migration. This study was performed to investigate how miR-200b inhibits arsenic-transformed cell migration. We found that protein kinase Cα (PKCα) is significantly up-regulated in arsenic-transformed cells. Combining bioinformatics analysis with PKCα 3'-untranslated region vector luciferase reporter assays, we showed that PKCα is a direct target of miR-200b. Inhibiting PKCα activity or knocking down PKCα expression drastically reduced cell migration, phenocoping the inhibitory effect of overexpressing miR-200b. In contrast, forced expression of PKCα in miR-200b overexpressing cells impaired the inhibitory effect of miR-200b on cell migration. In addition, we also found a positive feedback loop between Wnt5b and PKCα in arsenic-transformed cells. Knocking down Wnt5b expression reduced phospho-PKC levels and cell migration; and knocking down PKCα expression decreased Wnt5b level and cell migration. Moreover, forced expression of PKCα increased Wnt5b and phospho-PKC levels and cell migration. Further mechanistic studies revealed that Rac1 is highly activated in arsenic-transformed cells and stably expressing miR-200b abolishes Rac1 activation changing actin cytoskeleton organization. Manipulating PKCα or Wnt5b expression levels significantly altered the level of active Rac1. Together, these findings indicate that miR-200b suppresses arsenic-transformed cell migration by targeting PKCα and Wnt5b-PKCα positive feedback loop and subsequently inhibiting Rac1 activation. © 2014 by The American Society for Biochemistry and Molecular

α-Lipoic Acid Mitigates Arsenic-Induced Hematological Abnormalities in Adult Male Rats

Directory of Open Access Journals (Sweden)

Sonali Ghosh

2017-05-01

Full Text Available Background: Arsenic toxicity is a major global health problem and exposure via contaminated drinking water has been associated with hematological and other systemic disorders. The present investigation has been conducted in adult male rats to evaluate the protective ability of α-lipoic acid (ALA against such hematological disorders. Methods: Twenty-four adult male Wister rats (b.wt.130±10g were grouped and accordingly group I (control received the normal diet, group II (treated was given arsenic orally for 28 consecutive days as arsenic trioxide (3 mg/kgbw/rat/day whereas group III (supplemented received the same dose of arsenic along with ALA (25 mg/kgbw/rat/day as oral supplement. Hematological profile, plasma oxidant/antioxidant status, and erythrocyte morphology were assessed. Statistical analysis was done by one-way ANOVA using SPSS software (version 16.0. Results: Arsenic exposure caused reduction of erythrocyte (P=0.021, leucocyte (P<0.001, and hemoglobin (P=0.031 associated with echinocytic transformation as evidenced by light and scanning electron microscopic studies. The other significantly altered parameters include increased mean corpuscular volume (P=0.041 and lymphocytopenia (P<0.001 with insignificant neutropenia and eosinophilia. Altered serum oxidative balance as evidenced by decreased TAS (P<0.001 and increased TOS (P<0.001 with OSI (P<0.001 was also noted. The dietary supplementation of ALA has a beneficial effect against the observed (P<0.05 arsenic toxicities. It brings about the protection by restoring the hematological redox and inflammatory status near normal in treated rats. Arsenic-induced morphological alteration of erythrocytes was also partially attenuated by ALA supplementation. Conclusion: It is concluded that arsenicosis is associated with hematological alterations and ALA co-supplementation can partially alleviate these changes in an experimental male rat model.

HPLC-HG-AFS determination of arsenic species in acute promyelocytic leukemia (APL) plasma and blood cells.

Science.gov (United States)

Guo, Meihua; Wang, Wenjing; Hai, Xin; Zhou, Jin

2017-10-25

Arsenic trioxide (ATO) has been successfully used in the treatment of acute promyelocytic leukemia (APL). To clarify the arsenic species in APL patients, high performance liquid chromatography-hydride generation-atomic fluorescence spectrometry (HPLC-HG-AFS) and HG-AFS methods were developed and validated to quantify the plasma concentrations of inorganic arsenic (As(III) and As(V)) and methylated metabolites (MMA and DMA), and the total amounts of arsenic in blood cells and plasma. Blood cells and plasma were digested with mixtures of HNO 3 H 2 O 2 and analyzed by HG-AFS. For arsenic speciation, plasma samples were prepared with perchloric acid to precipitate protein. The supernatant was separated on an anion-exchange column within 6min with isocratic elution using 13mM CH 3 COONa, 3mM NaH 2 PO 4 , 4mM KNO 3 and 0.2mM EDTA-2Na. The methods provided linearity range of 0.2-20ng/mL for total arsenic and 2.0-50ng/mL for four arsenic species. The developed methods for total arsenic and arsenic species determination were precise and accurate. The spiked recoveries ranged from 81.2%-108.6% and the coefficients of variation for intra- and inter-batch precision were less than 9.3% and 12.5%, respectively. The developed methods were applied successfully for the assay of total arsenic and arsenic species in 5 APL patients. The HPLC-HG-AFS may be a good alternative for arsenic species determination in APL patients with its simplicity and low-cost in comparison with HPLC-ICP-MS. Copyright © 2017 Elsevier B.V. All rights reserved.

A cross sectional study of anemia and iron deficiency as risk factors for arsenic-induced skin lesions in Bangladeshi women

Directory of Open Access Journals (Sweden)

Molly L. Kile

2016-02-01

Full Text Available Abstract Background In the Ganges Delta, chronic arsenic poisoning is a health concern affecting millions of people who rely on groundwater as their potable water source. The prevalence of anemia is also high in this region, particularly among women. Moreover, arsenic is known to affect heme synthesis and erythrocytes and the risk of arsenic-induced skin lesions appears to differ by sex. Methods We conducted a case-control study in 147 arsenic-exposed Bangladeshi women to assess the association between anemia and arsenic-induced skin lesions. Results We observed that the odds of arsenic-related skin lesions were approximately three times higher among women who were anemic (hemoglobin < 120 g/L compared to women with normal hemoglobin levels [Odds Ratio (OR = 3.32, 95 % Confidence Intervals (CI: 1.29, 8.52] after adjusting for arsenic levels in drinking water and other covariates. Furthermore, 75 % of the women with anemia had adequate iron stores (serum ferritin ≥12 μg/L, suggesting that the majority of anemia detected in this population was unrelated to iron depletion. Conclusions Considering the magnitude of arsenic exposure and prevalence of anemia in Bangladeshi women, additional research is warranted that identifies the causes of anemia so that effective interventions can be implemented while arsenic remediation efforts continue.

Radiation-induced physical ageing in network arsenic-sulfide/selenide glasses

International Nuclear Information System (INIS)

Shpotyuk, M; Golovchak, R; Kozdras, A; Shpotyuk, O

2010-01-01

Effect of radiation-induced physical ageing is investigated by differential scanning calorimetry method in As x Se 100-x (10 ≤ x ≤ 42) and As x S 100-x (30 ≤ x ≤ 42) glasses. Obtained results are compared with conventional physical ageing at normal conditions. Significant radiation-induced physical ageing is recorded for glassy As x S 100-x within 30 ≤ x x Se 100-x glasses from the same compositional interval do not show any measurable changes in DSC curves after γ-irradiation. Observed difference in radiation-induced physical ageing in arsenic-sulfide/selenide glasses is explained by a greater lifetime of γ-induced excitations within sulfur-based network in comparison with selenium-based one.

Arsenic may be involved in fluoride-induced bone toxicity through PTH/PKA/AP1 signaling pathway.

Science.gov (United States)

Zeng, Qi-bing; Xu, Yu-yan; Yu, Xian; Yang, Jun; Hong, Feng; Zhang, Ai-hua

2014-01-01

Chronic exposure to combined fluoride and arsenic continues to be a major public health problem worldwide, affecting thousands of people. In recent years, more and more researchers began to focus on the interaction between the fluorine and the arsenic. In this study, the selected investigation site was located in China. The study group was selected from people living in fluoride-arsenic polluted areas due to burning coal. The total number of participants was 196; including the fluoride-arsenic anomaly group (130) and the fluoride-arsenic normal group (63). By observing the changes in gene and protein expression of PTH/PKA/AP1 signaling pathway, the results show that fluoride can increase the expression levels of PTH, PKA, and AP1, but arsenic can only affect the expression of AP1; fluoride and arsenic have an interaction on the expression of AP1. Further study found that fluoride and arsenic can affect the mRNA expression level of c-fos gene (AP1 family members), and have an interaction on the expression of c-fos, but not c-jun. The results indicate that PTH/PKA/AP1 signaling pathway may play an important role in bone toxicity of fluoride. Arsenic can affect the expression of c-fos, thereby affecting the expression of transcription factor AP1, indirectly involved in fluoride-induced bone toxicity. Copyright © 2013. Published by Elsevier B.V.

Activating transcription factor 4 underlies the pathogenesis of arsenic trioxide-mediated impairment of macrophage innate immune functions

Energy Technology Data Exchange (ETDEWEB)

Srivastava, Ritesh K.; Li, Changzhao [Department of Dermatology and Skin Diseases Research Center, University of Alabama at Birmingham, Birmingham, AL (United States); Wang, Yong [Department of Medicine, University of Alabama at Birmingham, Birmingham, AL (United States); Weng, Zhiping; Elmets, Craig A. [Department of Dermatology and Skin Diseases Research Center, University of Alabama at Birmingham, Birmingham, AL (United States); Harrod, Kevin S. [Department of Anesthesiology and Perioperative Medicine, University of Alabama at Birmingham, Birmingham, AL (United States); Deshane, Jessy S., E-mail: treena@uab.edu [Department of Medicine, University of Alabama at Birmingham, Birmingham, AL (United States); Athar, Mohammad, E-mail: mathar@uab.edu [Department of Dermatology and Skin Diseases Research Center, University of Alabama at Birmingham, Birmingham, AL (United States)

2016-10-01

Chronic arsenic exposure to humans is considered immunosuppressive with augmented susceptibility to several infectious diseases. The exact molecular mechanisms, however, remain unknown. Earlier, we showed the involvement of unfolded protein response (UPR) signaling in arsenic-mediated impairment of macrophage functions. Here, we show that activating transcription factor 4 (ATF4), a UPR transcription factor, regulates arsenic trioxide (ATO)-mediated dysregulation of macrophage functions. In ATO-treated ATF4{sup +/+} wild-type mice, a significant down-regulation of CD11b expression was associated with the reduced phagocytic functions of peritoneal and lung macrophages. This severe immuno-toxicity phenotype was not observed in ATO-treated ATF4{sup +/−} heterozygous mice. To confirm these observations, we demonstrated in Raw 264.7 cells that ATF4 knock-down rescues ATO-mediated impairment of macrophage functions including cytokine production, bacterial engulfment and clearance of engulfed bacteria. Sustained activation of ATF4 by ATO in macrophages induces apoptosis, while diminution of ATF4 expression protects against ATO-induced apoptotic cell death. Raw 264.7 cells treated with ATO also manifest dysregulated Ca{sup ++} homeostasis. ATO induces Ca{sup ++}-dependent calpain-1 and caspase-12 expression which together regulated macrophage apoptosis. Additionally, apoptosis was also induced by mitochondria-regulated pathway. Restoring ATO-impaired Ca{sup ++} homeostasis in ER/mitochondria by treatments with the inhibitors of inositol 1,4,5-trisphosphate receptor (IP3R) and voltage-dependent anion channel (VDAC) attenuate innate immune functions of macrophages. These studies identify a novel role for ATF4 in underlying pathogenesis of macrophage dysregulation and immuno-toxicity of arsenic. - Highlights: • ATF4 regulates arsenic-mediated impairment in macrophage functions. • Arsenic-mediated alterations in pulmonary macrophage are diminished in ATF4{sup +/−} mice

Activating transcription factor 4 underlies the pathogenesis of arsenic trioxide-mediated impairment of macrophage innate immune functions

International Nuclear Information System (INIS)

Srivastava, Ritesh K.; Li, Changzhao; Wang, Yong; Weng, Zhiping; Elmets, Craig A.; Harrod, Kevin S.; Deshane, Jessy S.; Athar, Mohammad

2016-01-01

Chronic arsenic exposure to humans is considered immunosuppressive with augmented susceptibility to several infectious diseases. The exact molecular mechanisms, however, remain unknown. Earlier, we showed the involvement of unfolded protein response (UPR) signaling in arsenic-mediated impairment of macrophage functions. Here, we show that activating transcription factor 4 (ATF4), a UPR transcription factor, regulates arsenic trioxide (ATO)-mediated dysregulation of macrophage functions. In ATO-treated ATF4 +/+ wild-type mice, a significant down-regulation of CD11b expression was associated with the reduced phagocytic functions of peritoneal and lung macrophages. This severe immuno-toxicity phenotype was not observed in ATO-treated ATF4 +/− heterozygous mice. To confirm these observations, we demonstrated in Raw 264.7 cells that ATF4 knock-down rescues ATO-mediated impairment of macrophage functions including cytokine production, bacterial engulfment and clearance of engulfed bacteria. Sustained activation of ATF4 by ATO in macrophages induces apoptosis, while diminution of ATF4 expression protects against ATO-induced apoptotic cell death. Raw 264.7 cells treated with ATO also manifest dysregulated Ca ++ homeostasis. ATO induces Ca ++ -dependent calpain-1 and caspase-12 expression which together regulated macrophage apoptosis. Additionally, apoptosis was also induced by mitochondria-regulated pathway. Restoring ATO-impaired Ca ++ homeostasis in ER/mitochondria by treatments with the inhibitors of inositol 1,4,5-trisphosphate receptor (IP3R) and voltage-dependent anion channel (VDAC) attenuate innate immune functions of macrophages. These studies identify a novel role for ATF4 in underlying pathogenesis of macrophage dysregulation and immuno-toxicity of arsenic. - Highlights: • ATF4 regulates arsenic-mediated impairment in macrophage functions. • Arsenic-mediated alterations in pulmonary macrophage are diminished in ATF4 +/− mice. • Changes in macrophage

Examination of the effects of arsenic on glucose homeostasis in cell culture and animal studies: Development of a mouse model for arsenic-induced diabetes

International Nuclear Information System (INIS)

Paul, David S.; Hernandez-Zavala, Araceli; Walton, Felecia S.; Adair, Blakely M.; Dedina, Jiri; Matousek, Tomas; Styblo, Miroslav

2007-01-01

Previous epidemiologic studies found increased prevalences of type 2 diabetes mellitus in populations exposed to high levels of inorganic arsenic (iAs) in drinking water. Although results of epidemiologic studies in low-exposure areas or occupational settings have been inconclusive, laboratory research has shown that exposures to iAs can produce effects that are consistent with type 2 diabetes. The current paper reviews the results of laboratory studies that examined the effects of iAs on glucose metabolism and describes new experiments in which the diabetogenic effects of iAs exposure were reproduced in a mouse model. Here, weanling male C57BL/6 mice drank deionized water with or without the addition of arsenite (25 or 50 ppm As) for 8 weeks. Intraperitoneal glucose tolerance tests revealed impaired glucose tolerance in mice exposed to 50 ppm As, but not to 25 ppm As. Exposure to 25 and 50 ppm As in drinking-water resulted in proportional increases in the concentration of iAs and its metabolites in the liver and in organs targeted by type 2 diabetes, including pancreas, skeletal muscle and adipose tissue. Dimethylarsenic was the predominant form of As in the tissues of mice in both 25 and 50 ppm groups. Notably, the average concentration of total speciated arsenic in livers from mice in the 50 ppm group was comparable to the highest concentration of total arsenic reported in the livers of Bangladeshi residents who had consumed water with an order of magnitude lower level of iAs. These data suggest that mice are less susceptible than humans to the diabetogenic effects of chronic exposure to iAs due to a more efficient clearance of iAs or its metabolites from target tissues

Arsenic exposure disrupts epigenetic regulation of SIRT1 in human keratinocytes

Energy Technology Data Exchange (ETDEWEB)

Herbert, Katharine J. [School of Health Sciences, University of Tasmania, Launceston, TAS 7250 (Australia); Holloway, Adele [Menzies Research Institute Tasmania, University of Tasmania, Hobart, TAS 7000 (Australia); Cook, Anthony L. [School of Health Sciences, University of Tasmania, Launceston, TAS 7250 (Australia); Chin, Suyin P. [Menzies Research Institute Tasmania, University of Tasmania, Hobart, TAS 7000 (Australia); Snow, Elizabeth T., E-mail: elizabeth.snow@utas.edu.au [School of Health Sciences, University of Tasmania, Launceston, TAS 7250 (Australia)

2014-11-15

Arsenic is an environmental toxin which increases skin cancer risk for exposed populations worldwide; however the underlying biomolecular mechanism for arsenic-induced carcinogenesis is complex and poorly defined. Recent investigations show that histone deacetylase and DNA methyltransferase activity is impaired, and epigenetic patterns of gene regulation are consistently altered in cancers associated with arsenic exposure. Expression of the histone deacetylase SIRT1 is altered in solid tumours and haematological malignancies; however its role in arsenic-induced pathology is unknown. In this study we investigated the effect of arsenic on epigenetic regulation of SIRT1 and its targeting microRNA, miR-34a in primary human keratinocytes. Acetylation of histone H4 at lysine 16 (H4K16) increased in keratinocytes exposed to 0.5 μM arsenite [As(III)]; and this was associated with chromatin remodelling at the miR-34a promoter. Moreover, although SIRT1 protein initially increased in these As(III)-exposed cells, after 24 days expression was not significantly different from untreated controls. Extended exposure to low-dose As(III) (0.5 μM; > 5 weeks) compromised the pattern of CpG methylation at SIRT1 and miR-34a gene promoters, and this was associated with altered expression for both genes. We have found that arsenic alters epigenetic regulation of SIRT1 expression via structural reorganisation of chromatin at the miR-34a gene promoter in the initial 24 h of exposure; and over time, through shifts in miR-34a and SIRT1 gene methylation. Taken together, this investigation demonstrates that arsenic produces cumulative disruptions to epigenetic regulation of miR-34a expression, and this is associated with impaired coordination of SIRT1 functional activity. - Highlights: • Submicromolar arsenic concentrations disrupt SIRT1 activity and expression in human keratinocytes. • Arsenic-induced chromatin remodelling at the miR-34a gene promoter is associated with hyperacetylation

Arsenic exposure disrupts epigenetic regulation of SIRT1 in human keratinocytes

International Nuclear Information System (INIS)

Herbert, Katharine J.; Holloway, Adele; Cook, Anthony L.; Chin, Suyin P.; Snow, Elizabeth T.

2014-01-01

Arsenic is an environmental toxin which increases skin cancer risk for exposed populations worldwide; however the underlying biomolecular mechanism for arsenic-induced carcinogenesis is complex and poorly defined. Recent investigations show that histone deacetylase and DNA methyltransferase activity is impaired, and epigenetic patterns of gene regulation are consistently altered in cancers associated with arsenic exposure. Expression of the histone deacetylase SIRT1 is altered in solid tumours and haematological malignancies; however its role in arsenic-induced pathology is unknown. In this study we investigated the effect of arsenic on epigenetic regulation of SIRT1 and its targeting microRNA, miR-34a in primary human keratinocytes. Acetylation of histone H4 at lysine 16 (H4K16) increased in keratinocytes exposed to 0.5 μM arsenite [As(III)]; and this was associated with chromatin remodelling at the miR-34a promoter. Moreover, although SIRT1 protein initially increased in these As(III)-exposed cells, after 24 days expression was not significantly different from untreated controls. Extended exposure to low-dose As(III) (0.5 μM; > 5 weeks) compromised the pattern of CpG methylation at SIRT1 and miR-34a gene promoters, and this was associated with altered expression for both genes. We have found that arsenic alters epigenetic regulation of SIRT1 expression via structural reorganisation of chromatin at the miR-34a gene promoter in the initial 24 h of exposure; and over time, through shifts in miR-34a and SIRT1 gene methylation. Taken together, this investigation demonstrates that arsenic produces cumulative disruptions to epigenetic regulation of miR-34a expression, and this is associated with impaired coordination of SIRT1 functional activity. - Highlights: • Submicromolar arsenic concentrations disrupt SIRT1 activity and expression in human keratinocytes. • Arsenic-induced chromatin remodelling at the miR-34a gene promoter is associated with hyperacetylation

Combination of Bifunctional Alkylating Agent and Arsenic Trioxide Synergistically Suppresses the Growth of Drug-Resistant Tumor Cells

Directory of Open Access Journals (Sweden)

Pei-Chih Lee

2010-05-01

Full Text Available Drug resistance is a crucial factor in the failure of cancer chemotherapy. In this study, we explored the effect of combining alkylating agents and arsenic trioxide (ATO on the suppression of tumor cells with inherited or acquired resistance to therapeutic agents. Our results showed that combining ATO and a synthetic derivative of 3a-aza-cyclopenta[a]indenes (BO-1012, a bifunctional alkylating agent causing DNA interstrand cross-links, was more effective in killing human cancer cell lines (H460, H1299, and PC3 than combining ATO and melphalan or thiotepa. We further demonstrated that the combination treatment of H460 cells with BO-1012 and ATO resulted in severe G2/M arrest and apoptosis. In a xenograft mouse model, the combination treatment with BO-1012 and ATO synergistically reduced tumor volumes in nude mice inoculated with H460 cells. Similarly, the combination of BO-1012 and ATO effectively reduced the growth of cisplatin-resistant NTUB1/P human bladder carcinoma cells. Furthermore, the repair of BO-1012-induced DNA interstrand cross-links was significantly inhibited by ATO, and consequently, γH2AX was remarkably increased and formed nuclear foci in H460 cells treated with this drug combination. In addition, Rad51 was activated by translocating and forming foci in nuclei on treatment with BO-1012, whereas its activation was significantly suppressed by ATO. We further revealed that ATO might mediate through the suppression of AKT activity to inactivate Rad51. Taken together, the present study reveals that a combination of bifunctional alkylating agents and ATO may be a rational strategy for treating cancers with inherited or acquired drug resistance.

Induction of glutathione synthesis in human hepatocytes by acute and chronic arsenic exposure: Differential roles of mitogen-activated protein kinases

International Nuclear Information System (INIS)

Hou, Yongyong; Wang, Yi; Wang, Huihui; Xu, Yuanyuan

2014-01-01

Highlights: • Arsenic exposure increased intracellular levels of glutathione. • Mitogen-activated protein kinases were involved in glutathione homeostasis. • ERK contributed to glutathione synthesis during acute arsenic exposure. • Glutathione synthesis was regulated by p38 at least in part independent of NRF2 during chronic arsenic exposure. - Abstract: Glutathione (GSH) is a vital component of antioxidant defense which protects cells from toxic insults. Previously we found intracellular GSH was involved in cell resistance against arsenic-induced cytotoxicity. However, molecular mechanisms of GSH homeostasis during arsenic exposure are largely undefined. Here, we investigated roles of mitogen-activated protein kinases (MAPKs) in GSH synthesis pathway with two arsenic exposure strategies by using Chang human hepatocytes. In one strategy, acute arsenic exposure (20 μM, 24 h) was applied, as MAPK signaling is generally considered to be transient. In the other one, chronic arsenic exposure (500 nM, 20 weeks) was applied, which mimicked the general human exposure to arsenic. We found that acute arsenic exposure activated extracellular signal-regulated 1/2 kinases (ERK1/2) and c-Jun N-terminal kinase (JNK) in parallel with increased transcription and nuclear translocation of factor-erythroid 2-related factor 2 (NRF2) and enhanced expression of γ-glutamyl cysteine ligase catalytic subunit (GCLC), resulting in elevated intracellular GSH levels. Specific ERK inhibitor abolished arsenic-induced NRF2 nuclear translocation and GSH synthesis. During chronic arsenic exposure which induced a malignant cellular phenotype, continuous p38 activation and NRF2 nuclear translocation were observed with enhanced GSH synthesis. Specific p38 inhibitor attenuated arsenic-enhanced GSH synthesis without changing NRF2 nuclear translocation. Taken together, our results indicate MAPK pathways play an important role in cellular GSH homeostasis in response to arsenic. However, the

Radiation-induced physical ageing in network arsenic-sulfide/selenide glasses

Energy Technology Data Exchange (ETDEWEB)

Shpotyuk, M; Golovchak, R; Kozdras, A; Shpotyuk, O, E-mail: shpotyuk@novas.lviv.ua

2010-11-15

Effect of radiation-induced physical ageing is investigated by differential scanning calorimetry method in As{sub x}Se{sub 100-x} (10 {<=} x {<=} 42) and As{sub x}S{sub 100-x} (30 {<=} x {<=} 42) glasses. Obtained results are compared with conventional physical ageing at normal conditions. Significant radiation-induced physical ageing is recorded for glassy As{sub x}S{sub 100-x} within 30 {<=} x < 40 range, while As{sub x}Se{sub 100-x} glasses from the same compositional interval do not show any measurable changes in DSC curves after {gamma}-irradiation. Observed difference in radiation-induced physical ageing in arsenic-sulfide/selenide glasses is explained by a greater lifetime of {gamma}-induced excitations within sulfur-based network in comparison with selenium-based one.

Unfolded protein response (UPR) signaling regulates arsenic trioxide-mediated macrophage innate immune function disruption

International Nuclear Information System (INIS)

Srivastava, Ritesh K.; Li, Changzhao; Chaudhary, Sandeep C.; Ballestas, Mary E.; Elmets, Craig A.; Robbins, David J.; Matalon, Sadis; Deshane, Jessy S.; Afaq, Farrukh; Bickers, David R.; Athar, Mohammad

2013-01-01

Arsenic exposure is known to disrupt innate immune functions in humans and in experimental animals. In this study, we provide a mechanism by which arsenic trioxide (ATO) disrupts macrophage functions. ATO treatment of murine macrophage cells diminished internalization of FITC-labeled latex beads, impaired clearance of phagocytosed fluorescent bacteria and reduced secretion of pro-inflammatory cytokines. These impairments in macrophage functions are associated with ATO-induced unfolded protein response (UPR) signaling pathway characterized by the enhancement in proteins such as GRP78, p-PERK, p-eIF2α, ATF4 and CHOP. The expression of these proteins is altered both at transcriptional and translational levels. Pretreatment with chemical chaperon, 4-phenylbutyric acid (PBA) attenuated the ATO-induced activation in UPR signaling and afforded protection against ATO-induced disruption of macrophage functions. This treatment also reduced ATO-mediated reactive oxygen species (ROS) generation. Interestingly, treatment with antioxidant N-acetylcysteine (NAC) prior to ATO exposure, not only reduced ROS production and UPR signaling but also improved macrophage functions. These data demonstrate that UPR signaling and ROS generation are interdependent and are involved in the arsenic-induced pathobiology of macrophage. These data also provide a novel strategy to block the ATO-dependent impairment in innate immune responses. - Highlights: • Inorganic arsenic to humans and experimental animals disrupt innate immune responses. • The mechanism underlying arsenic impaired macrophage functions involves UPR signaling. • Chemical chaperon attenuates arsenic-mediated macrophage function impairment. • Antioxidant, NAC blocks impairment in arsenic-treated macrophage functions

Unfolded protein response (UPR) signaling regulates arsenic trioxide-mediated macrophage innate immune function disruption

Energy Technology Data Exchange (ETDEWEB)

Srivastava, Ritesh K.; Li, Changzhao; Chaudhary, Sandeep C. [Department of Dermatology and Skin Diseases Research Center, University of Alabama at Birmingham, Birmingham, AL (United States); Ballestas, Mary E. [Department of Pediatrics Infectious Disease, Children' s of Alabama, School of Medicine, University of Alabama at Birmingham, AL (United States); Elmets, Craig A. [Department of Dermatology and Skin Diseases Research Center, University of Alabama at Birmingham, Birmingham, AL (United States); Robbins, David J. [Department of Surgery, Molecular Oncology Program, Miller School of Medicine, University of Miami, Miami (United States); Matalon, Sadis [Department of Anesthesiology, University of Alabama at Birmingham, Birmingham, AL (United States); Deshane, Jessy S. [Department of Medicine, Division of Pulmonary, Allergy and Critical Care Medicine, University of Alabama at Birmingham, Birmingham, AL (United States); Afaq, Farrukh [Department of Dermatology and Skin Diseases Research Center, University of Alabama at Birmingham, Birmingham, AL (United States); Bickers, David R. [Department of Dermatology, Columbia University Medical Center, New York (United States); Athar, Mohammad, E-mail: mathar@uab.edu [Department of Dermatology and Skin Diseases Research Center, University of Alabama at Birmingham, Birmingham, AL (United States)

2013-11-01

Arsenic exposure is known to disrupt innate immune functions in humans and in experimental animals. In this study, we provide a mechanism by which arsenic trioxide (ATO) disrupts macrophage functions. ATO treatment of murine macrophage cells diminished internalization of FITC-labeled latex beads, impaired clearance of phagocytosed fluorescent bacteria and reduced secretion of pro-inflammatory cytokines. These impairments in macrophage functions are associated with ATO-induced unfolded protein response (UPR) signaling pathway characterized by the enhancement in proteins such as GRP78, p-PERK, p-eIF2α, ATF4 and CHOP. The expression of these proteins is altered both at transcriptional and translational levels. Pretreatment with chemical chaperon, 4-phenylbutyric acid (PBA) attenuated the ATO-induced activation in UPR signaling and afforded protection against ATO-induced disruption of macrophage functions. This treatment also reduced ATO-mediated reactive oxygen species (ROS) generation. Interestingly, treatment with antioxidant N-acetylcysteine (NAC) prior to ATO exposure, not only reduced ROS production and UPR signaling but also improved macrophage functions. These data demonstrate that UPR signaling and ROS generation are interdependent and are involved in the arsenic-induced pathobiology of macrophage. These data also provide a novel strategy to block the ATO-dependent impairment in innate immune responses. - Highlights: • Inorganic arsenic to humans and experimental animals disrupt innate immune responses. • The mechanism underlying arsenic impaired macrophage functions involves UPR signaling. • Chemical chaperon attenuates arsenic-mediated macrophage function impairment. • Antioxidant, NAC blocks impairment in arsenic-treated macrophage functions.

Arsenic trioxide inhibits cell proliferation and human papillomavirus oncogene expression in cervical cancer cells

International Nuclear Information System (INIS)

Wang, Hongtao; Gao, Peng; Zheng, Jie

2014-01-01

Highlights: • As 2 O 3 inhibits growth of cervical cancer cells and expression of HPV oncogenes in these cells. • HPV-negative cervical cancer cells are more sensitive to As 2 O 3 than HPV-positive cervical cancer cells. • HPV-18 positive cervical cancer cells are more sensitive to As 2 O 3 than HPV-16 positive cancer cells. • Down-regulation of HPV oncogenes by As 2 O 3 is partially due to the diminished AP-1 binding. - Abstract: Arsenic trioxide (As 2 O 3 ) has shown therapeutic effects in some leukemias and solid cancers. However, the molecular mechanisms of its anticancer efficacy have not been clearly elucidated, particularly in solid cancers. Our previous data showed that As 2 O 3 induced apoptosis of human papillomavirus (HPV) 16 DNA-immortalized human cervical epithelial cells and cervical cancer cells and inhibited the expression of HPV oncogenes in these cells. In the present study, we systemically examined the effects of As 2 O 3 on five human cervical cancer cell lines and explored the possible molecular mechanisms. MTT assay showed that HPV-negative C33A cells were more sensitive to growth inhibition induced by As 2 O 3 than HPV-positive cervical cancer cells, and HPV 18-positive HeLa and C4-I cells were more sensitive to As 2 O 3 than HPV 16-positive CaSki and SiHa cells. After As 2 O 3 treatment, both mRNA and protein levels of HPV E6 and E7 obviously decreased in all HPV positive cell lines. In contrast, p53 and Rb protein levels increased in all tested cell lines. Transcription factor AP-1 protein expression decreased significantly in HeLa, CaSki and C33A cells with ELISA method. These results suggest that As 2 O 3 is a potential anticancer drug for cervical cancer

Arsenic trioxide inhibits cell proliferation and human papillomavirus oncogene expression in cervical cancer cells

Energy Technology Data Exchange (ETDEWEB)

Wang, Hongtao [Department of Pathology, School of Medicine, Southeast University, Nanjing 210009 (China); Gao, Peng [Department of Internal Medicine, University of Iowa, Iowa City, IA 52242 (United States); Zheng, Jie, E-mail: jiezheng54@126.com [Department of Pathology, School of Medicine, Southeast University, Nanjing 210009 (China)

2014-09-05

Highlights: • As{sub 2}O{sub 3} inhibits growth of cervical cancer cells and expression of HPV oncogenes in these cells. • HPV-negative cervical cancer cells are more sensitive to As{sub 2}O{sub 3} than HPV-positive cervical cancer cells. • HPV-18 positive cervical cancer cells are more sensitive to As{sub 2}O{sub 3} than HPV-16 positive cancer cells. • Down-regulation of HPV oncogenes by As{sub 2}O{sub 3} is partially due to the diminished AP-1 binding. - Abstract: Arsenic trioxide (As{sub 2}O{sub 3}) has shown therapeutic effects in some leukemias and solid cancers. However, the molecular mechanisms of its anticancer efficacy have not been clearly elucidated, particularly in solid cancers. Our previous data showed that As{sub 2}O{sub 3} induced apoptosis of human papillomavirus (HPV) 16 DNA-immortalized human cervical epithelial cells and cervical cancer cells and inhibited the expression of HPV oncogenes in these cells. In the present study, we systemically examined the effects of As{sub 2}O{sub 3} on five human cervical cancer cell lines and explored the possible molecular mechanisms. MTT assay showed that HPV-negative C33A cells were more sensitive to growth inhibition induced by As{sub 2}O{sub 3} than HPV-positive cervical cancer cells, and HPV 18-positive HeLa and C4-I cells were more sensitive to As{sub 2}O{sub 3} than HPV 16-positive CaSki and SiHa cells. After As{sub 2}O{sub 3} treatment, both mRNA and protein levels of HPV E6 and E7 obviously decreased in all HPV positive cell lines. In contrast, p53 and Rb protein levels increased in all tested cell lines. Transcription factor AP-1 protein expression decreased significantly in HeLa, CaSki and C33A cells with ELISA method. These results suggest that As{sub 2}O{sub 3} is a potential anticancer drug for cervical cancer.

Transplacental arsenic carcinogenesis in mice

International Nuclear Information System (INIS)

Waalkes, Michael P.; Liu, Jie; Diwan, Bhalchandra A.

2007-01-01

Our work has focused on the carcinogenic effects of in utero arsenic exposure in mice. Our data show that a short period of maternal exposure to inorganic arsenic in the drinking water is an effective, multi-tissue carcinogen in the adult offspring. These studies have been reproduced in three temporally separate studies using two different mouse strains. In these studies pregnant mice were treated with drinking water containing sodium arsenite at up to 85 ppm arsenic from days 8 to 18 of gestation, and the offspring were observed for up to 2 years. The doses used in all these studies were well tolerated by both the dam and offspring. In C3H mice, two separate studies show male offspring exposed to arsenic in utero developed liver carcinoma and adrenal cortical adenoma in a dose-related fashion during adulthood. Prenatally exposed female C3H offspring show dose-related increases in ovarian tumors and lung carcinoma and in proliferative lesions (tumors plus preneoplastic hyperplasia) of the uterus and oviduct. In addition, prenatal arsenic plus postnatal exposure to the tumor promoter, 12-O-tetradecanoyl phorbol-13-acetate (TPA) in C3H mice produces excess lung tumors in both sexes and liver tumors in females. Male CD1 mice treated with arsenic in utero develop tumors of the liver and adrenal and renal hyperplasia while females develop tumors of urogenital system, ovary, uterus and adrenal and hyperplasia of the oviduct. Additional postnatal treatment with diethylstilbestrol or tamoxifen after prenatal arsenic in CD1 mice induces urinary bladder transitional cell proliferative lesions, including carcinoma and papilloma, and enhances the carcinogenic response in the liver of both sexes. Overall this model has provided convincing evidence that arsenic is a transplacental carcinogen in mice with the ability to target tissues of potential human relevance, such as the urinary bladder, lung and liver. Transplacental carcinogenesis clearly occurs with other agents in humans

Vascular Hyperpermeability Response in Animals Systemically Exposed to Arsenic.

Science.gov (United States)

Chen, Shih-Chieh; Chang, Chao-Yuah; Lin, Ming-Lu

2018-01-01

The mechanisms underlying cardiovascular diseases induced by chronic exposure to arsenic remain unclarified. The objectives of this study were to investigate whether increased vascular leakage is induced by inflammatory mustard oil in mice systemically exposed to various doses of arsenic and whether an increased vascular leakage response is still present in arsenic-fed mice after arsenic discontinuation for 2 or 6 months. ICR mice were fed water or various doses of sodium arsenite (10, 15, or 20 mg/kg/day; 5 days/week) for 8 weeks. In separate experiments, the mice were treated with sodium arsenite (20 mg/kg) for 2 or 8 weeks, followed by arsenic discontinuation for 2 or 6 months. Vascular permeability to inflammatory mustard oil was quantified using Evans blue (EB) techniques. Both arsenic-exposed and water-fed (control) mice displayed similar basal levels of EB leakage in the ears brushed with mineral oil, a vehicle of mustard oil. The levels of EB leakage induced by mustard oil in the arsenic groups fed with sodium arsenite (10 or 15 mg/kg) were similar to those of water-fed mice. However, increased levels of EB leakage in response to mustard oil stimulation were significantly higher in mice treated with sodium arsenite (20 mg/kg; high dose) than in arsenic-fed (10 or 15 mg/kg; low and middle doses) or control mice. After arsenic discontinuation for 2 or 6 months, mustard oil-induced vascular EB leakage in arsenic-fed (20 mg/kg) mice was similar to that in control mice. Dramatic increases in mustard oil-induced vascular leakage were only present in mice systemically exposed to the high arsenic dose, indicating the synergistic effects of the high arsenic dose and mustard oil.

Life Redefined: Microbes Built with Arsenic

Energy Technology Data Exchange (ETDEWEB)

Webb, Sam (SLAC and Felisa Wolfe-Simon, NASA and U.S. Geological Survey)

2011-03-22

Life can survive in many harsh environments, from extreme heat to the presence of deadly chemicals. However, life as we know it has always been based on the same six elements -- carbon, oxygen, nitrogen, hydrogen, sulfur and phosphorus. Now it appears that even this rule has an exception. In the saline and poisonous environment of Mono Lake, researchers have found a bacterium that can grow by incorporating arsenic into its structure in place of phosphorus. X-ray images taken at SLAC's synchrotron light source reveal that this microbe may even use arsenic as a building block for DNA. Please join us as we describe this discovery, which rewrites the textbook description of how living cells work.

Arsenic trioxide (As2O3) induced calcium signals and cytotoxicity in two human cell lines: SY-5Y neuroblastoma and 293 embryonic kidney (HEK)

International Nuclear Information System (INIS)

Florea, Ana-Maria; Splettstoesser, Frank; Buesselberg, Dietrich

2007-01-01

Arsenic trioxide (As 2 O 3 ) has anticancer properties; however, its use also leads to neuro-, hepato- or nephro-toxicity, and therefore, it is important to understand the mechanism of As 2 O 3 toxicity. We studied As 2 O 3 influence on intracellular calcium ([Ca 2+ ] i ) homeostasis of human neuroblastoma SY-5Y and embryonic kidney cells (HEK 293).We also relate the As 2 O 3 induced [Ca 2+ ] i modifications with cytotoxicity. We used Ca 2+ sensitive dyes (fluo-4 and rhod-2) combined with laser scanning microscopy or fluorescence activated cell sorting to measure Ca 2+ changes during the application of As 2 O 3 and we approach evaluation of cytotoxicity. As 2 O 3 (1 μM) increased [Ca 2+ ] i in SY-5Y and HEK 293 cells. Three forms of [Ca 2+ ] i -elevations were found: (1) steady-state increases (2) transient [Ca 2+ ] i -elevations and (3) Ca 2+ -spikes. [Ca 2+ ] i modifications were independent from extracellular Ca 2+ but dependent on internal calcium stores. The effect was not reversible. Inositol triphosphate (IP 3 ) and ryanodine (Ry) receptors are involved in regulation of signals induced by As 2 O 3 . 2-APB and dantrolene significantly reduced the [Ca 2+ ] i -rise (p 2+ ] i -elevation or spiking. This indicates that other Ca 2+ regulating mechanisms are involved. In cytotoxicity tests As 2 O 3 significantly reduced cell viability in both cell types. Staining with Hoechst 33342 showed occurrence of apoptosis and DNA damage. Our data suggest that [Ca 2+ ] i is an important messenger in As 2 O 3 induced cell death

Molecular basis for arsenic-Induced alteration in nitric oxide production and oxidative stress: implication of endothelial dysfunction

International Nuclear Information System (INIS)

Kumagai, Yoshito; Pi Jingbo

2004-01-01

Accumulated epidemiological studies have suggested that prolonged exposure of humans to arsenic in drinking water is associated with vascular diseases. The exact mechanism of how this occurs currently unknown. Nitric oxide (NO), formed by endothelial NO synthase (eNOS), plays a crucial role in the vascular system. Decreased availability of biologically active NO in the endothelium is implicated in the pathophysiology of several vascular diseases and inhibition of eNOS by arsenic is one of the proposed mechanism s for arsenic-induced vascular diseases. In addition, during exposure to arsenic, overproduction of reactive oxygen species (ROS) can occur, resulting in oxidative stress, which is another major risk factor for vascular dysfunction. The molecular basis for decreased NO levels and increased oxidative stress during arsenic exposure is poorly understood. In this article, evidence for arsenic-mediated alteration in NO production and oxidative stress is reviewed. The results of a cross-sectional study in an endemic area of chronic arsenic poisoning and experimental animal studies to elucidate a potential mechanism for the impairment of NO formation and oxidative stress caused by prolonged exposure to arsenate in the drinking water are also reviewed

Arsenic and human health effects: A review.

Science.gov (United States)

Abdul, Khaja Shameem Mohammed; Jayasinghe, Sudheera Sammanthi; Chandana, Ediriweera P S; Jayasumana, Channa; De Silva, P Mangala C S

2015-11-01

Arsenic (As) is ubiquitous in nature and humans being exposed to arsenic via atmospheric air, ground water and food sources are certain. Major sources of arsenic contamination could be either through geological or via anthropogenic activities. In physiological individuals, organ system is described as group of organs that transact collectively and associate with other systems for conventional body functions. Arsenic has been associated with persuading a variety of complications in body organ systems: integumentary, nervous, respiratory, cardiovascular, hematopoietic, immune, endocrine, hepatic, renal, reproductive system and development. In this review, we outline the effects of arsenic on the human body with a main focus on assorted organ systems with respective disease conditions. Additionally, underlying mechanisms of disease development in each organ system due to arsenic have also been explored. Strikingly, arsenic has been able to induce epigenetic changes (in utero) and genetic mutations (a leading cause of cancer) in the body. Occurrence of various arsenic induced health effects involving emerging areas such as epigenetics and cancer along with their respective mechanisms are also briefly discussed. Copyright © 2015 Elsevier B.V. All rights reserved.

PIXE study on absorption of arsenate and arsenite by arsenic hyperaccumulating fern (Pteris vittata)

International Nuclear Information System (INIS)

Yamazaki, H.; Ishii, K.; Matsuyama, S.

2008-01-01

Pytoremediation using an arsenic hyperaccumulator, Petris vittata L., has generated an increasing interest worldwide due to both environmentally sound and cost effectiveness. However the mechanism of arsenic accumulation by this fern is not clear at this time. This study examined the uptake of arsenate (As(V)) and arsenite (As(III)) by a hydroponic culture of Pteris vittata using both in-air submilli-PIXE for different parts of the fern and in-air micro-PIXE for the tissue cells. These PIXE analysis systems used 3 MeV proton beams from a 4.5-MV single-ended Dynamitron accelerator at Tohoku University, Japan. The fern took up both arsenate and arsenite from hydroponic solutions which were spiked with 50 mg of arsenic per litter. Final amount of arsenic accumulation in the fern is 1,500 mg per kg (wet weight) of the plant biomass in arsenite treatment and 1,100 mg per kg in arsenate treatment. Arsenic accumulation was not observed at the root parts of the ferns. The in-vivo mapping of elements by submilli-PIXE analyses on the fern laminas showed the arsenic accumulation in the edges of a pinna. The micro-PIXE analyses revealed arsenic maps homogeneously distributed in cells of the lamina, stem and rhizome of the fern. These results indicate that arsenic, both arsenate and arsenite in a contaminated medium are translocated quickly from roots to fronds of Pteris vittata, and distributes homogeneously into tissue cells of the fern laminas. (author)

Interactions between arsenic species and marine algae

Energy Technology Data Exchange (ETDEWEB)

Sanders, J.G.

1978-01-01

The arsenic concentration and speciation of marine algae varies widely, from 0.4 to 23 ng.mg/sup -1/, with significant differences in both total arsenic content and arsenic speciation occurring between algal classes. The Phaeophyceae contain more arsenic than other algal classes, and a greater proportion of the arsenic is organic. The concentration of inorganic arsenic is fairly constant in macro-algae, and may indicate a maximum level, with the excess being reduced and methylated. Phytoplankton take up As(V) readily, and incorporate a small percentage of it into the cell. The majority of the As(V) is reduced, methylated, and released to the surrounding media. The arsenic speciation in phytoplankton and Valonia also changes when As(V) is added to cultures. Arsenate and phosphate compete for uptake by algal cells. Arsenate inhibits primary production at concentrations as low as 5 ..mu..g.1/sup -1/ when the phosphate concentration is low. The inhibition is competitive. A phosphate enrichment of > 0.3 ..mu..M alleviates this inhibition; however, the As(V) stress causes an increase in the cell's phosphorus requirement. Arsenite is also toxic to phytoplankton at similar concentrations. Methylated arsenic species did not affect cell productivity, even at concentrations of 25 ..mu..g.1/sup -1/. Thus, the methylation of As(V) by the cell produces a stable, non-reactive compound which is nontoxic. The uptake and subsequent reduction and methylation of As(V) is a significant factor in determining the arsenic biogeochemistry of productive systems, and also the effect that the arsenic may have on algal productivity. Therefore, the role of marine algae in determining the arsenic speciation of marine systems cannot be ignored. (ERB)

Dose- and Time-Dependent Response of Human Leukemia (HL-60 Cells to Arsenic Trioxide Treatment

Directory of Open Access Journals (Sweden)

Paul B. Tchounwou

2006-06-01

Full Text Available The treatment of acute promyelocytic leukemia (APL has been based on the administration of all-trans retinoic acid plus anthracycline chemotherapy, which is very effective as first line therapy; however 25 to 30% of patients will relapse with their disease becoming refractory to conventional therapy. Recently, studies have shown arsenic trioxide to be effective in the treatment of acute promyelocytic leukemia. In this study, we used the human leukemia (HL-60 cell line as a model to evaluate the cytoxicity of arsenic trioxide based on the MTT assay. Data obtained from this assay indicated that arsenic trioxide significantly reduced the viability of HL-60 cells, showing LD50 values of 14.26 + 0.5μg/mL, 12.54 + 0.3μg/mL, and 6.4 + 0.6μg/mL upon 6, 12, and 24 hours of exposure, respectively; indicating a dose- and time-dependent response relationship. Findings from the present study indicate that arsenic trioxide is highly cytotoxic to human leukemia (HL-60 cells, supporting its use as an effective therapeutic agent in the management of acute promyelocytic leukemia.

Serum Acetyl Cholinesterase as a Biomarker of Arsenic Induced Neurotoxicity in Sprague-Dawley Rats

Directory of Open Access Journals (Sweden)

Paul B. Tchounwou

2005-04-01

cholinesterase is a candidate biomarker for arsenic-induced neurotoxicity in Sprague-Dawley rats.

Tungsten-induced carcinogenesis in human bronchial epithelial cells

Energy Technology Data Exchange (ETDEWEB)

Laulicht, Freda; Brocato, Jason; Cartularo, Laura; Vaughan, Joshua; Wu, Feng; Kluz, Thomas; Sun, Hong [Department of Environmental Medicine, New York University Langone Medical Center, Tuxedo, NY 10987 (United States); Oksuz, Betul Akgol [Genome Technology Center, New York University Langone Medical Center, New York, NY 10016 (United States); Shen, Steven [Center for Health Informatics and Bioinformatics, New York University Langone Medical Center, New York, NY 10016 (United States); Peana, Massimiliano; Medici, Serenella; Zoroddu, Maria Antonietta [Department of Chemistry and Pharmacy, University of Sassari, Sassari (Italy); Costa, Max, E-mail: Max.Costa@nyumc.org [Department of Environmental Medicine, New York University Langone Medical Center, Tuxedo, NY 10987 (United States)

2015-10-01

Metals such as arsenic, cadmium, beryllium, and nickel are known human carcinogens; however, other transition metals, such as tungsten (W), remain relatively uninvestigated with regard to their potential carcinogenic activity. Tungsten production for industrial and military applications has almost doubled over the past decade and continues to increase. Here, for the first time, we demonstrate tungsten's ability to induce carcinogenic related endpoints including cell transformation, increased migration, xenograft growth in nude mice, and the activation of multiple cancer-related pathways in transformed clones as determined by RNA sequencing. Human bronchial epithelial cell line (Beas-2B) exposed to tungsten developed carcinogenic properties. In a soft agar assay, tungsten-treated cells formed more colonies than controls and the tungsten-transformed clones formed tumors in nude mice. RNA-sequencing data revealed that the tungsten-transformed clones altered the expression of many cancer-associated genes when compared to control clones. Genes involved in lung cancer, leukemia, and general cancer genes were deregulated by tungsten. Taken together, our data show the carcinogenic potential of tungsten. Further tests are needed, including in vivo and human studies, in order to validate tungsten as a carcinogen to humans. - Highlights: • Tungsten (W) induces cell transformation and increases migration in vitro. • W increases xenograft growth in nude mice. • W altered the expression of cancer-related genes such as those involved in leukemia. • Some of the dysregulated leukemia genes include, CD74, CTGF, MST4, and HOXB5. • For the first time, data is presented that demonstrates tungsten's carcinogenic potential.

c-Jun/AP-1 pathway-mediated cyclin D1 expression participates in low dose arsenite-induced transformation in mouse epidermal JB6 Cl41 cells

International Nuclear Information System (INIS)

Zhang Dongyun; Li Jingxia; Gao Jimin; Huang Chuanshu

2009-01-01

Arsenic is a well-documented human carcinogen associated with skin carcinogenesis. Our previous work reveals that arsenite exposure is able to induce cell transformation in mouse epidermal cell JB6 Cl41 through the activation of ERK, rather than JNK pathway. Our current studies further evaluate downstream pathway in low dose arsenite-induced cell transformation in JB6 Cl41 cells. Our results showed that treatment of cells with low dose arsenite induced activation of c-Jun/AP-1 pathway, and ectopic expression of dominant negative mutant of c-Jun (TAM67) blocked arsenite-induced transformation. Furthermore, our data indicated that cyclin D1 was an important downstream molecule involved in c-Jun/AP-1-mediated cell transformation upon low dose arsenite exposure, because inhibition of cyclin D1 expression by its specific siRNA in the JB6 Cl41 cells resulted in impairment of anchorage-independent growth of cells induced by low dose arsenite. Collectively, our results demonstrate that c-Jun/AP-1-mediated cyclin D1 expression is at least one of the key events implicated in cell transformation upon low dose arsenite exposure

Atorvastatin acts synergistically with N-acetyl cysteine to provide therapeutic advantage against Fas-activated erythrocyte apoptosis during chronic arsenic exposure in rats

Energy Technology Data Exchange (ETDEWEB)

Biswas, Debabrata; Sen, Gargi; Sarkar, Avik; Biswas, Tuli

2011-01-01

Arsenic is an environmental toxicant that reduces the lifespan of circulating erythrocytes during chronic exposure. Our previous studies had indicated involvement of hypercholesterolemia and reactive oxygen species (ROS) in arsenic-induced apoptotic death of erythrocytes. In this study, we have shown an effective recovery from arsenic-induced death signaling in erythrocytes in response to treatment with atorvastatin (ATV) and N-acetyl cysteine (NAC) in rats. Our results emphasized on the importance of cholesterol in the promotion of ROS-mediated Fas signaling in red cells. Arsenic-induced activation of caspase 3 was associated with phosphatidylserine exposure on the cell surface and microvesiculation of erythrocyte membrane. Administration of NAC in combination with ATV, proved to be more effective than either of the drugs alone towards the rectification of arsenic-mediated disorganization of membrane structural integrity, and this could be linked with decreased ROS accumulation through reduced glutathione (GSH) repletion along with cholesterol depletion. Moreover, activation of caspase 3 was capable of promoting aggregation of band 3 with subsequent binding of autologous IgG and opsonization by C3b that led to phagocytosis of the exposed cells by the macrophages. NAC-ATV treatment successfully amended these events and restored lifespan of erythrocytes from the exposed animals almost to the control level. This work helped us to identify intracellular membrane cholesterol enrichment and GSH depletion as the key regulatory points in arsenic-mediated erythrocyte destruction and suggested a therapeutic strategy against Fas-activated cell death related to enhanced cholesterol and accumulation of ROS.

Long-term exposure to arsenic affects head kidney and impairs humoral immune responses of Clarias batrachus

Energy Technology Data Exchange (ETDEWEB)

Ghosh, Debabrata [Immunobiology Laboratory, School of Life Sciences, Visva-Bharati University, Santiniketan 731235 (India); Datta, Soma [Immunobiology Laboratory, School of Life Sciences, Visva-Bharati University, Santiniketan 731235 (India); Bhattacharya, Shelley [Environmental Toxicology Laboratory, School of Life Sciences, Visva-Bharati University, Santiniketan 731235 (India); Mazumder, Shibnath [Immunobiology Laboratory, School of Life Sciences, Visva-Bharati University, Santiniketan 731235 (India)]. E-mail: shibnath1@yahoo.co.in

2007-02-15

The present study was aimed at determining the effects of long-term arsenic exposure on the head kidney (HK) and ensuing humoral immune responses in Clarias batrachus L. Long-term exposure (150 days) to non-lethal concentrations of arsenic (42.42 {mu}M) resulted in significant time-dependent alterations in HK cell number eventually affecting the HK somatic index. Prolonged exposure to arsenic also suppressed HK-B cell proliferation and led to significant reduction in serum immunoglobulin levels and antigen-specific serum bacterial agglutinin titers. A decline in the number of antigen-specific plaque-forming cells with duration of arsenic exposure was noted in the HK. Enzyme linked immunosorbent assays further revealed that arsenic exposure inhibited the release of 'IL-4 like factors' from HK-T cells. Histological studies documented time-dependent changes in the structure and cellular composition of HK characterized by extensive lymphocytopenia, decrease in melano-macrophage population and hemosiderin accumulation. From exposure-challenge studies with Aeromonas hydrophila it was evident that pathogens could efficiently disseminate and colonize distant host tissues in the exposed fish. Moreover, the ability to decrease the pathogen load was also significantly reduced in the arsenic-exposed fish. Thus long-term exposure to non-lethal concentrations of arsenic affects HK and interferes with the humoral immune system of C. batrachus rendering them immunocompromised and susceptible to pathogenic challenge.

Long-term exposure to arsenic affects head kidney and impairs humoral immune responses of Clarias batrachus

International Nuclear Information System (INIS)

Ghosh, Debabrata; Datta, Soma; Bhattacharya, Shelley; Mazumder, Shibnath

2007-01-01

The present study was aimed at determining the effects of long-term arsenic exposure on the head kidney (HK) and ensuing humoral immune responses in Clarias batrachus L. Long-term exposure (150 days) to non-lethal concentrations of arsenic (42.42 μM) resulted in significant time-dependent alterations in HK cell number eventually affecting the HK somatic index. Prolonged exposure to arsenic also suppressed HK-B cell proliferation and led to significant reduction in serum immunoglobulin levels and antigen-specific serum bacterial agglutinin titers. A decline in the number of antigen-specific plaque-forming cells with duration of arsenic exposure was noted in the HK. Enzyme linked immunosorbent assays further revealed that arsenic exposure inhibited the release of 'IL-4 like factors' from HK-T cells. Histological studies documented time-dependent changes in the structure and cellular composition of HK characterized by extensive lymphocytopenia, decrease in melano-macrophage population and hemosiderin accumulation. From exposure-challenge studies with Aeromonas hydrophila it was evident that pathogens could efficiently disseminate and colonize distant host tissues in the exposed fish. Moreover, the ability to decrease the pathogen load was also significantly reduced in the arsenic-exposed fish. Thus long-term exposure to non-lethal concentrations of arsenic affects HK and interferes with the humoral immune system of C. batrachus rendering them immunocompromised and susceptible to pathogenic challenge

Speciation of arsenic in exfoliated urinary bladder epithelial cells from individuals exposed to arsenic in drinking water

Czech Academy of Sciences Publication Activity Database

Hernández-Zavala, A.; Valenzuela, O.L.; Matoušek, Tomáš; Drobná, Z.; Dědina, Jiří; Garcia-Vargas, G.G.; Thomas, D. J.; Del Razo, L.M.; Stýblo, M.

2008-01-01

Roč. 116, č. 12 (2008), s. 1656-1660 ISSN 0091-6765 R&D Projects: GA AV ČR IAA400310507 Institutional research plan: CEZ:AV0Z40310501 Keywords : arsenic species * drinking water * exfoliated human urinary bladder epithelial cells Subject RIV: CB - Analytical Chemistry, Separation Impact factor: 6.123, year: 2008

Arsenic-induced skin lesions among Atacameño people in Northern Chile despite good nutrition and centuries of exposure.

Science.gov (United States)

Smith, A H; Arroyo, A P; Mazumder, D N; Kosnett, M J; Hernandez, A L; Beeris, M; Smith, M M; Moore, L E

2000-07-01

It has been suggested that the indigenous Atacameño people in Northern Chile might be protected from the health effects of arsenic in drinking water because of many centuries of exposure. Here we report on the first intensive investigation of arsenic-induced skin lesions in this population. We selected 11 families (44 participants) from the village of Chiu Chiu, which is supplied with water containing between 750 and 800 microg/L inorganic arsenic. For comparison, 8 families (31 participants) were also selected from a village where the water contains approximately 10 microg/L inorganic arsenic. After being transported to the nearest city for blind assessment, participants were examined by four physicians with experience in studying arsenic-induced lesions. Four of the six men from the exposed village, who had been drinking the contaminated water for more than 20 years, were diagnosed with skin lesions due to arsenic, but none of the women had definite lesions. A 13-year-old girl had definite skin pigmentation changes due to arsenic, and a 19-year-old boy had both pigmentation changes and keratoses on the palms of his hands and the soles of his feet. Family interviews identified a wide range of fruits and vegetables consumed daily by the affected participants, as well as the weekly intake of red meat and chicken. However, the prevalence of skin lesions among men and children in the small population studied was similar to that reported with corresponding arsenic drinking water concentrations in both Taiwan and West Bengal, India--populations in which extensive malnutrition has been thought to increase susceptibility.

Evaluation of the ability of arsenic species to traverse cell membranes by simple diffusion using octanol-water and liposome-water partition coefficients.

Science.gov (United States)

Chávez-Capilla, Teresa; Maher, William; Kelly, Tamsin; Foster, Simon

2016-11-01

Arsenic metabolism in living organisms is dependent on the ability of different arsenic species to traverse biological membranes. Simple diffusion provides an alternative influx and efflux route to mediated transport mechanisms that can increase the amount of arsenic available for metabolism in cells. Using octanol-water and liposome-water partition coefficients, the ability of arsenous acid, arsenate, methylarsonate, dimethylarsinate, thio-methylarsonate, thio-dimethylarsinic acid, arsenotriglutathione and monomethylarsonic diglutathione to diffuse through the lipid bilayer of cell membranes was investigated. Molecular modelling of arsenic species was used to explain the results. All arsenic species with the exception of arsenate, methylarsonate and thio-methylarsonate were able to diffuse through the lipid bilayer of liposomes, with liposome-water partition coefficients between 0.04 and 0.13. Trivalent arsenic species and thio-pentavalent arsenic species showed higher partition coefficients, suggesting that they can easily traverse cell membranes by passive simple diffusion. Given the higher toxicity of these species compared to oxo-pentavalent arsenic species, this study provides evidence supporting the risk associated with human exposure to trivalent and thio-arsenic species. Copyright © 2016. Published by Elsevier B.V.

Combined Efficacy of Gallic Acid and MiADMSA with Limited Beneficial Effects Over MiADMSA Against Arsenic-induced Oxidative Stress in Mouse.

Science.gov (United States)

Pachauri, Vidhu; Flora, Sjs

2015-01-01

Gallic acid is an organic acid known for its antioxidant and anticancer properties. The present study is focused on evaluating the role of gallic acid in providing better therapeutic outcomes against arsenic-induced toxicity. Animals pre-exposed to arsenic were treated with monoisoamyl meso-2,3-dimercaptosuccinic acid (MiADMSA), a new chelating drug, alone and in combination with gallic acid, consecutively for 10 days. The study suggests that (1) gallic acid in presence of MiADMSA is only moderately beneficial against arsenic, (2) monotherapy with gallic acid is more effective than in combination with MiADMSA after arsenic exposure in reducing oxidative injury, and (3) MiADMSA monotherapy as reported previously provides significant therapeutic efficacy against arsenic. Thus, based on the present results, we conclude that gallic acid is effective against arsenic-induced oxidative stress but provides limited additional beneficial effects when administered in combination with MiADMSA. We still recommend that lower doses of gallic acid be evaluated both individually and in combination with MiADMSA, as it might not exhibit the shortcomings we observed with higher doses in this study.

Reduced cellular DNA repair capacity after environmentally relevant arsenic exposure. Influence of Ogg1 deficiency

International Nuclear Information System (INIS)

Bach, Jordi; Peremartí, Jana; Annangi, Balasubramnayam; Marcos, Ricard; Hernández, Alba

2015-01-01

Highlights: • Repair ability under long-term exposure to arsenic was tested using the comet assay. • Effects were measured under Ogg1 wild-type and deficient backgrounds. • Exposed cells repair less efficiency the DNA damage induced by SA, KBrO 3 , MMA III or UVC radiation. • Oxidative damage and Ogg1 deficient background exacerbate repair deficiencies. • Overexpression of the arsenic metabolizing enzyme As3mt acts as adaptive mechanism. - Abstract: Inorganic arsenic (i-As) is a genotoxic and carcinogenic environmental contaminant known to affect millions of people worldwide. Our previous work demonstrated that chronic sub-toxic i-As concentrations were able to induce biologically significant levels of genotoxic and oxidative DNA damage that were strongly influenced by the Ogg1 genotype. In order to study the nature of the observed levels of damage and the observed differences between MEF Ogg1 +/+ and Ogg1 −/− genetic backgrounds, the genotoxic and oxidative DNA repair kinetics of 18-weeks exposed MEF cells were evaluated by the comet assay. Results indicate that MEF Ogg1 +/+ and Ogg1 −/− cells chronically exposed to i-As repair the DNA damage induced by arsenite, potassium bromide and UVC radiation less efficiently than control cells, being that observation clearly more pronounced in MEF Ogg1 −/− cells. Consequently, exposed cells accumulate a higher percentage of unrepaired DNA damage at the end of the repair period. As an attempt to eliminate i-As associated toxicity, chronically exposed MEF Ogg1 −/− cells overexpress the arsenic metabolizing enzyme As3mt. This adaptive response confers cells a significant resistance to i-As-induced cell death, but at expenses of accumulating high levels of DNA damage due to their repair impairment. Overall, the work presented here evidences that i-As chronic exposure disrupts the normal cellular repair function, and that oxidative DNA damage—and Ogg1 deficiency—exacerbates this phenomenon. The

Reduced cellular DNA repair capacity after environmentally relevant arsenic exposure. Influence of Ogg1 deficiency

Energy Technology Data Exchange (ETDEWEB)

Bach, Jordi; Peremartí, Jana; Annangi, Balasubramnayam [Grup de Mutagènesi, Departament de Genètica i de Microbiologia, Facultat de Biociències, Universitat Autònoma de Barcelona, Cerdanyola del Vallès, Barcelona (Spain); Marcos, Ricard, E-mail: ricard.marcos@uab.es [Grup de Mutagènesi, Departament de Genètica i de Microbiologia, Facultat de Biociències, Universitat Autònoma de Barcelona, Cerdanyola del Vallès, Barcelona (Spain); CIBER Epidemiología y Salud Pública, ISCIII, Madrid (Spain); Hernández, Alba, E-mail: alba.hernandez@uab.es [Grup de Mutagènesi, Departament de Genètica i de Microbiologia, Facultat de Biociències, Universitat Autònoma de Barcelona, Cerdanyola del Vallès, Barcelona (Spain); CIBER Epidemiología y Salud Pública, ISCIII, Madrid (Spain)

2015-09-15

Highlights: • Repair ability under long-term exposure to arsenic was tested using the comet assay. • Effects were measured under Ogg1 wild-type and deficient backgrounds. • Exposed cells repair less efficiency the DNA damage induced by SA, KBrO{sub 3}, MMA{sup III} or UVC radiation. • Oxidative damage and Ogg1 deficient background exacerbate repair deficiencies. • Overexpression of the arsenic metabolizing enzyme As3mt acts as adaptive mechanism. - Abstract: Inorganic arsenic (i-As) is a genotoxic and carcinogenic environmental contaminant known to affect millions of people worldwide. Our previous work demonstrated that chronic sub-toxic i-As concentrations were able to induce biologically significant levels of genotoxic and oxidative DNA damage that were strongly influenced by the Ogg1 genotype. In order to study the nature of the observed levels of damage and the observed differences between MEF Ogg1{sup +/+} and Ogg1{sup −/−} genetic backgrounds, the genotoxic and oxidative DNA repair kinetics of 18-weeks exposed MEF cells were evaluated by the comet assay. Results indicate that MEF Ogg1{sup +/+} and Ogg1{sup −/−} cells chronically exposed to i-As repair the DNA damage induced by arsenite, potassium bromide and UVC radiation less efficiently than control cells, being that observation clearly more pronounced in MEF Ogg1{sup −/−} cells. Consequently, exposed cells accumulate a higher percentage of unrepaired DNA damage at the end of the repair period. As an attempt to eliminate i-As associated toxicity, chronically exposed MEF Ogg1{sup −/−} cells overexpress the arsenic metabolizing enzyme As3mt. This adaptive response confers cells a significant resistance to i-As-induced cell death, but at expenses of accumulating high levels of DNA damage due to their repair impairment. Overall, the work presented here evidences that i-As chronic exposure disrupts the normal cellular repair function, and that oxidative DNA damage—and Ogg1 deficiency�

Arsenic in Ground Water of the United States

Science.gov (United States)

... Team More Information Arsenic in groundwater of the United States Arsenic in groundwater is largely the result of ... Gronberg (2011) for updated arsenic map. Featured publications United States Effects of human-induced alteration of groundwater flow ...

Arsenic tolerant Trichoderma sp. reduces arsenic induced stress in chickpea (Cicer arietinum).

Science.gov (United States)

Tripathi, Pratibha; Singh, Poonam C; Mishra, Aradhana; Srivastava, Suchi; Chauhan, Reshu; Awasthi, Surabhi; Mishra, Seema; Dwivedi, Sanjay; Tripathi, Preeti; Kalra, Alok; Tripathi, Rudra D; Nautiyal, Chandra S

2017-04-01

Toxic metalloids including arsenic (As) can neither be eliminated nor destroyed from environment; however, they can be converted from toxic to less/non-toxic forms. The form of As species and their concentration determines its toxicity in plants. Therefore, the microbe mediated biotransformation of As is crucial for its plant uptake and toxicity. In the present study the role of As tolerant Trichoderma in modulating As toxicity in chickpea plants was explored. Chickpea plants grown in arsenate spiked soil under green house conditions were inoculated with two plant growth promoting Trichoderma strains, M-35 (As tolerant) and PPLF-28 (As sensitive). Total As concentration in chickpea tissue was comparable in both the Trichoderma treatments, however, differences in levels of organic and inorganic As (iAs) species were observed. The shift in iAs to organic As species ratio in tolerant Trichoderma treatment correlated with enhanced plant growth and nutrient content. Arsenic stress amelioration in tolerant Trichoderma treatment was also evident through rhizospheric microbial community and anatomical studies of the stem morphology. Down regulation of abiotic stress responsive genes (MIPS, PGIP, CGG) in tolerant Trichoderma + As treatment as compared to As alone and sensitive Trichoderma + As treatment also revealed that tolerant strain enhanced the plant's potential to cope with As stress as compared to sensitive one. Considering the bioremediation and plant growth promotion potential, the tolerant Trichoderma may appear promising for its utilization in As affected fields for enhancing agricultural productivity. Copyright © 2017 Elsevier Ltd. All rights reserved.

Effects of Nrf2 deficiency on arsenic metabolism in mice.

Science.gov (United States)

Wang, Huihui; Zhu, Jiayu; Li, Lu; Li, Yongfang; Lv, Hang; Xu, Yuanyuan; Sun, Guifan; Pi, Jingbo

2017-12-15

Inorganic arsenic (iAs) is a known toxicant and carcinogen. Worldwide arsenic exposure has become a threat to human health. The severity of arsenic toxicity is strongly correlated with the speed of arsenic metabolism (methylation) and clearance. Furthermore, oxidative stress is recognized as a major mechanism for arsenic-induced toxicity. Nuclear factor-E2-related factor 2 (Nrf2), a key regulator in cellular adaptive antioxidant response, is clearly involved in alleviation of arsenic-induced oxidative damage. Multiple studies demonstrate that Nrf2 deficiency mice are more vulnerable to arsenic-induced intoxication. However, what effect Nrf2 deficiency might have on arsenic metabolism in mice is still unknown. In the present study, we measured the key enzymes involved in arsenic metabolism in Nrf2-WT and Nrf2-KO mice. Our results showed that basal transcript levels of glutathione S-transferase omega 2 (Gsto2) were significantly higher and GST mu 1 (Gstm1) lower in Nrf2-KO mice compared to Nrf2-WT control. Arsenic speciation and methylation rate in liver and urine was then studied in mice treated with 5mg/kg sodium arsenite for 12h. Although there were some alterations in arsenic metabolism enzymes between Nrf2-WT and Nrf2-KO mice, the Nrf2 deficiency had no significant effect on arsenic methylation. These results suggest that the Nrf2-KO mice are more sensitive to arsenic than Nrf2-WT mainly because of differences in adaptive antioxidant detoxification capacity rather than arsenic methylation capacity. Copyright © 2017. Published by Elsevier Inc.

In silico analysis of bacterial arsenic islands reveals remarkable synteny and functional relatedness between arsenate and phosphate

DEFF Research Database (Denmark)

Li, Hang; Li, Mingshun; Huang, Yinyan

2013-01-01

In order to construct a more universal model for understanding the genetic requirements for bacterial AsIII oxidation, an in silico examination of the available sequences in the GenBank was assessed and revealed 21 conserved 5-71 kb arsenic islands within phylogenetically diverse bacterial genomes....... The arsenic islands included the AsIII oxidase structural genes aioBA, ars operons (e.g., arsRCB) which code for arsenic resistance, and pho, pst, and phn genes known to be part of the classical phosphate stress response and that encode functions associated with regulating and acquiring organic and inorganic...... phosphorus. The regulatory genes aioXSR were also an island component, but only in Proteobacteria and orientated differently depending on whether they were in a-Proteobacteria or β-/γ-Proteobacteria. Curiously though, while these regulatory genes have been shown to be essential to AsIII oxidation...

Arsenic Removal from Groundwater by Solar Driven Inline-Electrolytic Induced Co-Precipitation and Filtration—A Long Term Field Test Conducted in West Bengal

OpenAIRE

Otter, Philipp; Malakar, Pradyut; Jana, Bana Bihari; Grischek, Thomas; Benz, Florian; Goldmaier, Alexander; Feistel, Ulrike; Jana, Joydev; Lahiri, Susmita; Alvarez, Juan Antonio

2017-01-01

Arsenic contamination in drinking water resources is of major concern in the Ganga delta plains of West Bengal in India and Bangladesh. Here, several laboratory and field studies on arsenic removal from drinking water resources were conducted in the past and the application of strong-oxidant-induced co-precipitation of arsenic on iron hydroxides is still considered as the most promising mechanism. This paper suggests an autonomous, solar driven arsenic removal setting and presents the finding...

Arsenic in North Carolina: public health implications.

Science.gov (United States)

Sanders, Alison P; Messier, Kyle P; Shehee, Mina; Rudo, Kenneth; Serre, Marc L; Fry, Rebecca C

2012-01-01

Arsenic is a known human carcinogen and relevant environmental contaminant in drinking water systems. We set out to comprehensively examine statewide arsenic trends and identify areas of public health concern. Specifically, arsenic trends in North Carolina private wells were evaluated over an eleven-year period using the North Carolina Department of Health and Human Services database for private domestic well waters. We geocoded over 63,000 domestic well measurements by applying a novel geocoding algorithm and error validation scheme. Arsenic measurements and geographical coordinates for database entries were mapped using Geographic Information System techniques. Furthermore, we employed a Bayesian Maximum Entropy (BME) geostatistical framework, which accounts for geocoding error to better estimate arsenic values across the state and identify trends for unmonitored locations. Of the approximately 63,000 monitored wells, 7712 showed detectable arsenic concentrations that ranged between 1 and 806μg/L. Additionally, 1436 well samples exceeded the EPA drinking water standard. We reveal counties of concern and demonstrate a historical pattern of elevated arsenic in some counties, particularly those located along the Carolina terrane (Carolina slate belt). We analyzed these data in the context of populations using private well water and identify counties for targeted monitoring, such as Stanly and Union Counties. By spatiotemporally mapping these data, our BME estimate revealed arsenic trends at unmonitored locations within counties and better predicted well concentrations when compared to the classical kriging method. This study reveals relevant information on the location of arsenic-contaminated private domestic wells in North Carolina and indicates potential areas at increased risk for adverse health outcomes. Copyright © 2011 Elsevier Ltd. All rights reserved.

Developmental and genetic modulation of arsenic biotransformation: A gene by environment interaction?

International Nuclear Information System (INIS)

Meza, Mercedes; Gandolfi, A. Jay; Klimecki, Walter T.

2007-01-01

The complexity of arsenic toxicology has confounded the identification of specific pathways of disease causation. One focal point of arsenic research is aimed at fully characterizing arsenic biotransformation in humans, a process that appears to be quite variable, producing a mixture of several arsenic species with greatly differing toxic potencies. In an effort to characterize genetic determinants of variability in arsenic biotransformation, a genetic association study of 135 subjects in western Sonora, Mexico was performed by testing 23 polymorphic sites in three arsenic biotransformation candidate genes. One gene, arsenic 3 methyltransferase (AS3MT), was strongly associated with the ratio of urinary dimethylarsinic acid to monomethylarsonic acid (D/M) in children (7-11 years) but not in adults (18-79 years). Subsequent analyses revealed that the high D/M values associated with variant AS3MT alleles were primarily due to lower levels of monomethylarsonic acid as percent of total urinary arsenic (%MMA5). In light of several reports of arsenic-induced disease being associated with relatively high %MMA5 levels, these findings raise the possibility that variant AS3MT individuals may suffer less risk from arsenic exposure than non-variant individuals. These analyses also provide evidence that, in this population, regardless of AS3MT variant status, children tend to have lower %MMA5 values than adults, suggesting that the global developmental regulation of arsenic biotransformation may interact with genetic variants in metabolic genes to result in novel genetic effects such as those in this report

Absorption of foliar-applied arsenic by the arsenic hyperaccumulating fern (Pteris vittata L.)

Energy Technology Data Exchange (ETDEWEB)

Bondada, Bhaskar R.; Tu, Shuxin; Ma, Lena Q

2004-10-01

The fact that heavy metals can enter various domains of the plant system through foliar pathways spurred us to explore if the fronds of the Chinese brake fern (Pteris vittata L.), a hyperaccumulator of arsenic, a carcinogenic metalloid, was proficient in absorbing arsenic in the form of sprays. The specific objective of this study was to investigate the impact of frond age, form of arsenic, and time of application on the absorption of foliar-applied arsenic by the brake fern; also examined were the effects of foliar sprays on surface ultrastructure and arsenic speciation in the frond following absorption. Foliar sprays of different arsenic concentrations (0, 50, 100, 200, and 400 ppm) were applied to young and fertile fronds. A positive linear relationship existed between arsenic concentration and absorption; the arsenic concentration of fronds increased from 50 to 200 ppm. Time-course analysis with excised pinnae indicated an initial linear increase followed by a plateau at 48 h. The young fronds with immature sori absorbed more arsenic (3100 ppm) than the fertile mature fronds (890 ppm). In the frond, the arsenic absorption was greatest in the lamina of the pinnae followed by the sori and the rachis. Applying arsenic during night (20:00-22:00 h) or afternoon (12:00-14:00 h) resulted in greater absorption of arsenic than the application in the morning (08:00-10:00 h). The arsenic absorption was greater through abaxial surfaces than through adaxial surfaces. The brake fern absorbed more arsenic when it was applied in the form of arsenite. Regardless of the form of arsenic and the surface it was applied to, arsenic occurred as arsenite, the reduced and the most toxic form of arsenic, after having been absorbed by the fronds. Scanning electron microscopy revealed no surface morphological alterations following all arsenic sprays. The study unequivocally illustrated that the Chinese brake fern absorbed foliar-applied arsenic with great efficiency. Consequently, the

Absorption of foliar-applied arsenic by the arsenic hyperaccumulating fern (Pteris vittata L.)

International Nuclear Information System (INIS)

Bondada, Bhaskar R.; Tu, Shuxin; Ma, Lena Q.

2004-01-01

The fact that heavy metals can enter various domains of the plant system through foliar pathways spurred us to explore if the fronds of the Chinese brake fern (Pteris vittata L.), a hyperaccumulator of arsenic, a carcinogenic metalloid, was proficient in absorbing arsenic in the form of sprays. The specific objective of this study was to investigate the impact of frond age, form of arsenic, and time of application on the absorption of foliar-applied arsenic by the brake fern; also examined were the effects of foliar sprays on surface ultrastructure and arsenic speciation in the frond following absorption. Foliar sprays of different arsenic concentrations (0, 50, 100, 200, and 400 ppm) were applied to young and fertile fronds. A positive linear relationship existed between arsenic concentration and absorption; the arsenic concentration of fronds increased from 50 to 200 ppm. Time-course analysis with excised pinnae indicated an initial linear increase followed by a plateau at 48 h. The young fronds with immature sori absorbed more arsenic (3100 ppm) than the fertile mature fronds (890 ppm). In the frond, the arsenic absorption was greatest in the lamina of the pinnae followed by the sori and the rachis. Applying arsenic during night (20:00-22:00 h) or afternoon (12:00-14:00 h) resulted in greater absorption of arsenic than the application in the morning (08:00-10:00 h). The arsenic absorption was greater through abaxial surfaces than through adaxial surfaces. The brake fern absorbed more arsenic when it was applied in the form of arsenite. Regardless of the form of arsenic and the surface it was applied to, arsenic occurred as arsenite, the reduced and the most toxic form of arsenic, after having been absorbed by the fronds. Scanning electron microscopy revealed no surface morphological alterations following all arsenic sprays. The study unequivocally illustrated that the Chinese brake fern absorbed foliar-applied arsenic with great efficiency. Consequently, the

Screening and characterization of useful microorganisms to arsenic removal

OpenAIRE

宮武, 宗利; 林, 幸男

2007-01-01

Microorganisms were isolated from soil and their arsenic removal abilities were evaluated. Seven out of the 100 isolated strains showed more than 20% arsenic removal. Time courses of arsenic removal and cell growth were investigated in three of these isolated strains. Although the growth rates were different, the dependence of arsenic removal on cell growth was similar in three strains (A-84, 88, 89). Strain A-89 showed highest arsenic removal rate of 63% after first day. Strain A-88 was best...

Beam-induced redox transformation of arsenic during As K-edge XAS measurements: availability of reducing or oxidizing agents and As speciation.

Science.gov (United States)

Han, Young Soo; Jeong, Hoon Young; Hyun, Sung Pil; Hayes, Kim F; Chon, Chul Min

2018-05-01

During X-ray absorption spectroscopy (XAS) measurements of arsenic (As), beam-induced redox transformation is often observed. In this study, the As species immobilized by poorly crystallized mackinawite (FeS) was assessed for the susceptibility to beam-induced redox reactions as a function of sample properties including the redox state of FeS and the solid-phase As speciation. The beam-induced oxidation of reduced As species was found to be mediated by the atmospheric O 2 and the oxidation products of FeS [e.g. Fe(III) (oxyhydr)oxides and intermediate sulfurs]. Regardless of the redox state of FeS, both arsenic sulfide and surface-complexed As(III) readily underwent the photo-oxidation upon exposure to the atmospheric O 2 during XAS measurements. With strict O 2 exclusion, however, both As(0) and arsenic sulfide were less prone to the photo-oxidation by Fe(III) (oxyhydr)oxides than NaAsO 2 and/or surface-complexed As(III). In case of unaerated As(V)-reacted FeS samples, surface-complexed As(V) was photocatalytically reduced during XAS measurements, but arsenic sulfide did not undergo the photo-reduction.

Understanding arsenic carcinogenicity by the use of animal models

International Nuclear Information System (INIS)

Wanibuchi, Hideki; Salim, Elsayed I.; Kinoshita, Anna; Shen Jun; Wei Min; Morimura, Keiichirou; Yoshida, Kaoru; Kuroda, Koichi; Endo, Ginji; Fukushima, Shoji

2004-01-01

Although numerous epidemiological studies have indicated that human arsenic exposure is associated with increased incidences of bladder, liver, skin, and lung cancers, limited attempts have been made to understand mechanisms of carcinogenicity using animal models. Dimethylarsinic acid (DMA), an organic arsenic compound, is a major metabolite of ingested inorganic arsenics in mammals. Recent in vitro studies have proven DMA to be a potent clastogenic agent, capable of inducing DNA damage including double strand breaks and cross-link formation. In our attempts to clarify DMA carcinogenicity, we have recently shown carcinogenic effects of DMA and its related metabolites using various experimental protocols in rats and mice: (1) a multi-organ promotion bioassay in rats; (2) a two-stage promotion bioassay by DMA of rat urinary bladder and liver carcinogenesis; (3) a 2-year carcinogenicity test of DMA in rats; (4) studies on the effects of DMA on lung carcinogenesis in rats; (5) promotion of skin carcinogenesis by DMA in keratin (K6)/ornithine decarboxylase (ODC) transgenic mice; (6) carcinogenicity of DMA in p53(+/-) knockout and Mmh/8-OXOG-DNA glycolase (OGG1) mutant mice; (7) promoting effects of DMA and related organic arsenicals in rat liver; (8) promoting effects of DMA and related organic arsenicals in a rat multi-organ carcinogenesis test; and (9) 2-year carcinogenicity tests of monomethylarsonic acid (MMA) and trimethylarsine oxide (TMAO) in rats. The results revealed that the adverse effects of arsenic occurred either by promoting and initiating carcinogenesis. These data, as covered in the present review, suggest that several mechanisms may be involved in arsenic carcinogenesis

Arsenic Removal from Groundwater by Solar Driven Inline-Electrolytic Induced Co-Precipitation and Filtration—A Long Term Field Test Conducted in West Bengal

Science.gov (United States)

Malakar, Pradyut; Jana, Bana Bihari; Benz, Florian; Goldmaier, Alexander; Feistel, Ulrike; Jana, Joydev; Lahiri, Susmita; Alvarez, Juan Antonio

2017-01-01

Arsenic contamination in drinking water resources is of major concern in the Ganga delta plains of West Bengal in India and Bangladesh. Here, several laboratory and field studies on arsenic removal from drinking water resources were conducted in the past and the application of strong-oxidant-induced co-precipitation of arsenic on iron hydroxides is still considered as the most promising mechanism. This paper suggests an autonomous, solar driven arsenic removal setting and presents the findings of a long term field test conducted in West Bengal. The system applies an inline-electrolytic cell for in situ chlorine production using the natural chloride content of the water and by that substituting the external dosing of strong oxidants. Co-precipitation of As(V) occurs on freshly formed iron hydroxide, which is removed by Manganese Greensand Plus® filtration. The test was conducted for ten months under changing source water conditions considering arsenic (187 ± 45 µg/L), iron (5.5 ± 0.8 mg/L), manganese (1.5 ± 0.4 mg/L), phosphate (2.4 ± 1.3 mg/L) and ammonium (1.4 ± 0.5 mg/L) concentrations. Depending on the system setting removal rates of 94% for arsenic (10 ± 4 µg/L), >99% for iron (0.03 ± 0.03 mg/L), 96% for manganese (0.06 ± 0.05 mg/L), 72% for phosphate (0.7 ± 0.3 mg/L) and 84% for ammonium (0.18 ± 0.12 mg/L) were achieved—without the addition of any chemicals/adsorbents. Loading densities of arsenic on iron hydroxides averaged to 31 µgAs/mgFe. As the test was performed under field conditions and the here proposed removal mechanisms work fully autonomously, it poses a technically feasible treatment alternative, especially for rural areas. PMID:28974053

Arsenic Removal from Groundwater by Solar Driven Inline-Electrolytic Induced Co-Precipitation and Filtration-A Long Term Field Test Conducted in West Bengal.

Science.gov (United States)

Otter, Philipp; Malakar, Pradyut; Jana, Bana Bihari; Grischek, Thomas; Benz, Florian; Goldmaier, Alexander; Feistel, Ulrike; Jana, Joydev; Lahiri, Susmita; Alvarez, Juan Antonio

2017-10-02

Arsenic contamination in drinking water resources is of major concern in the Ganga delta plains of West Bengal in India and Bangladesh. Here, several laboratory and field studies on arsenic removal from drinking water resources were conducted in the past and the application of strong-oxidant-induced co-precipitation of arsenic on iron hydroxides is still considered as the most promising mechanism. This paper suggests an autonomous, solar driven arsenic removal setting and presents the findings of a long term field test conducted in West Bengal. The system applies an inline-electrolytic cell for in situ chlorine production using the natural chloride content of the water and by that substituting the external dosing of strong oxidants. Co-precipitation of As(V) occurs on freshly formed iron hydroxide, which is removed by Manganese Greensand Plus ® filtration. The test was conducted for ten months under changing source water conditions considering arsenic (187 ± 45 µg/L), iron (5.5 ± 0.8 mg/L), manganese (1.5 ± 0.4 mg/L), phosphate (2.4 ± 1.3 mg/L) and ammonium (1.4 ± 0.5 mg/L) concentrations. Depending on the system setting removal rates of 94% for arsenic (10 ± 4 µg/L), >99% for iron (0.03 ± 0.03 mg/L), 96% for manganese (0.06 ± 0.05 mg/L), 72% for phosphate (0.7 ± 0.3 mg/L) and 84% for ammonium (0.18 ± 0.12 mg/L) were achieved-without the addition of any chemicals/adsorbents. Loading densities of arsenic on iron hydroxides averaged to 31 µgAs/mgFe. As the test was performed under field conditions and the here proposed removal mechanisms work fully autonomously, it poses a technically feasible treatment alternative, especially for rural areas.

Arsenic Removal from Groundwater by Solar Driven Inline-Electrolytic Induced Co-Precipitation and Filtration—A Long Term Field Test Conducted in West Bengal

Directory of Open Access Journals (Sweden)

Philipp Otter

2017-10-01

Full Text Available Arsenic contamination in drinking water resources is of major concern in the Ganga delta plains of West Bengal in India and Bangladesh. Here, several laboratory and field studies on arsenic removal from drinking water resources were conducted in the past and the application of strong-oxidant-induced co-precipitation of arsenic on iron hydroxides is still considered as the most promising mechanism. This paper suggests an autonomous, solar driven arsenic removal setting and presents the findings of a long term field test conducted in West Bengal. The system applies an inline-electrolytic cell for in situ chlorine production using the natural chloride content of the water and by that substituting the external dosing of strong oxidants. Co-precipitation of As(V occurs on freshly formed iron hydroxide, which is removed by Manganese Greensand Plus® filtration. The test was conducted for ten months under changing source water conditions considering arsenic (187 ± 45 µg/L, iron (5.5 ± 0.8 mg/L, manganese (1.5 ± 0.4 mg/L, phosphate (2.4 ± 1.3 mg/L and ammonium (1.4 ± 0.5 mg/L concentrations. Depending on the system setting removal rates of 94% for arsenic (10 ± 4 µg/L, >99% for iron (0.03 ± 0.03 mg/L, 96% for manganese (0.06 ± 0.05 mg/L, 72% for phosphate (0.7 ± 0.3 mg/L and 84% for ammonium (0.18 ± 0.12 mg/L were achieved—without the addition of any chemicals/adsorbents. Loading densities of arsenic on iron hydroxides averaged to 31 µgAs/mgFe. As the test was performed under field conditions and the here proposed removal mechanisms work fully autonomously, it poses a technically feasible treatment alternative, especially for rural areas.

Sumoylation of the Tumor Suppressor Promyelocytic Leukemia Protein Regulates Arsenic Trioxide-Induced Collagen Synthesis in Osteoblasts.

Science.gov (United States)

Xu, Wen-Xiao; Liu, Sheng-Zhi; Wu, Di; Qiao, Guo-Fen; Yan, Jinglong

2015-01-01

Promyelocytic leukemia (PML) protein is a tumor suppressor that fuses with retinoic acid receptor-α (PML-RARα) to contribute to the initiation of acute promyelocytic leukemia (APL). Arsenic trioxide (ATO) upregulates expression of TGF-β1, promoting collagen synthesis in osteoblasts, and ATO binds directly to PML to induce oligomerization, sumoylation, and ubiquitination. However, how ATO upregulates TGF-β1 expression is uncertain. Thus, we suggested that PML sumoylation is responsible for regulation of TGF-β1 protein expression. Kunming mice were treated with ATO, and osteoblasts were counted under scanning electron microscopy. Masson's staining was used to quantify collagen content. hFOB1.19 cells were transfected with siRNA against UBC9 or RNF4, and then treated with ATO or FBS. TGF-β1, PML expression, and sumoylation were quantified with Western blot, and collagen quantified via immunocytochemistry. ATO enhanced osteoblast accumulation, collagen synthesis, and PML-NB formation in vivo. Knocking down UBC9 in hFOB1.19 cells inhibited ATO- and FBS-induced PML sumoylation, TGF-β1 expression, and collagen synthesis. Conversely, knocking down RNF4 enhanced ATO- and FBS-induced PML sumoylation, TGF-β1 expression, and collagen synthesis. These data suggest that PML sumoylation is required for ATO-induced collagen synthesis in osteoblasts. © 2015 S. Karger AG, Basel.

MRP-1 expression levels determine strain-specific susceptibility to sodium arsenic-induced renal injury between C57BL/6 and BALB/c mice

International Nuclear Information System (INIS)

Kimura, Akihiko; Ishida, Yuko; Wada, Takashi; Yokoyama, Hitoshi; Mukaida, Naofumi; Kondo, Toshikazu

2005-01-01

To clarify the pathophysiological mechanism underlying acute renal injury caused by acute exposure to arsenic, we subcutaneously injected both BALB/c and C57BL/6 mice with sodium arsenite (NaAs; 13.5 mg/kg). BALB/c mice exhibited exaggerated elevation of serum blood urea nitrogen (BUN) and creatinine (CRE) levels, compared with C57BL/6 mice. Moreover, half of BALB/c mice died by 24 h, whereas all C57BL/6 mice survived. Histopathological examination on kidney revealed severe hemorrhages, acute tubular necrosis, neutrophil infiltration, cast formation, and disappearance of PAS-positive brush borders in BALB/c mice, later than 10 h. These pathological changes were remarkably attenuated in C57BL/6 mice, accompanied with lower intrarenal arsenic concentrations, compared with BALB/c mice. Among heavy metal inducible proteins including multidrug resistance-associated protein (MRP)-1, multidrug resistance gene (MDR)-1, metallothionein (MT)-1, and arsenite inducible, cysteine- and histidine-rich RNA-associated protein (AIRAP), intrarenal MDR-1, MT-1, and AIRAP gene expression was enhanced to a similar extent in both strains, whereas NaAs challenge augmented intrarenal MRP-1 mRNA and protein expression levels in C57BL/6 but not BALB/c mice. Moreover, the administration of a specific inhibitor of MRP-1, MK-571, significantly exaggerated acute renal injury in C57BL/6 mice. Thus, MRP-1 is crucially involved in arsenic efflux and eventually prevention of acute renal injury upon acute exposure to NaAs

Bioleaching of Arsenic-Rich Gold Concentrates by Bacterial Flora before and after Mutation

Directory of Open Access Journals (Sweden)

Xuehui Xie

2013-01-01

Full Text Available In order to improve the bioleaching efficiency of arsenic-rich gold concentrates, a mixed bacterial flora had been developed, and the mutation breeding method was adopted to conduct the research. The original mixed bacterial flora had been enrichedin acid mine drainage of Dexing copper mine, Jiangxi Province, China. It was induced by UV (ultraviolet, ultrasonic, and microwave, and their combination mutation. The most efficient bacterial flora after mutation was collected for further bioleaching of arsenic-rich gold concentrates. Results indicated that the bacterial flora after mutation by UV 60 s combined with ultrasonic 10 min had the best oxidation rate of ferrous, the biggest density of cells, and the most activity of total protein. During bioleaching of arsenic-rich gold concentrates, the density of the mutant bacterial cells reached to 1.13×108 cells/mL at 15 days, more than 10 times compared with that of the original culture. The extraction of iron reached to 95.7% after 15 days, increased by 9.9% compared with that of the original culture. The extraction of arsenic reached to 92.6% after 12 days, which was increased by 46.1%. These results suggested that optimum combined mutation could improve leaching ability of the bacterial flora more significantly.

Bioleaching of Arsenic-Rich Gold Concentrates by Bacterial Flora before and after Mutation

Science.gov (United States)

Xie, Xuehui; Yuan, Xuewu; Liu, Na; Chen, Xiaoguang; Abdelgadir, Awad; Liu, Jianshe

2013-01-01

In order to improve the bioleaching efficiency of arsenic-rich gold concentrates, a mixed bacterial flora had been developed, and the mutation breeding method was adopted to conduct the research. The original mixed bacterial flora had been enrichedin acid mine drainage of Dexing copper mine, Jiangxi Province, China. It was induced by UV (ultraviolet), ultrasonic, and microwave, and their combination mutation. The most efficient bacterial flora after mutation was collected for further bioleaching of arsenic-rich gold concentrates. Results indicated that the bacterial flora after mutation by UV 60 s combined with ultrasonic 10 min had the best oxidation rate of ferrous, the biggest density of cells, and the most activity of total protein. During bioleaching of arsenic-rich gold concentrates, the density of the mutant bacterial cells reached to 1.13 × 108 cells/mL at 15 days, more than 10 times compared with that of the original culture. The extraction of iron reached to 95.7% after 15 days, increased by 9.9% compared with that of the original culture. The extraction of arsenic reached to 92.6% after 12 days, which was increased by 46.1%. These results suggested that optimum combined mutation could improve leaching ability of the bacterial flora more significantly. PMID:24381948

Relationship between arsenic and selenium in workers occupationally exposed to inorganic arsenic.

Science.gov (United States)

Janasik, Beata; Zawisza, Anna; Malachowska, Beata; Fendler, Wojciech; Stanislawska, Magdalena; Kuras, Renata; Wasowicz, Wojciech

2017-07-01

The interaction between arsenic (As) and selenium (Se) has been one of the most extensively studied. The antagonism between As and Se suggests that low Se status plays an important role in aggravating arsenic toxicity in diseases development. The objective of this study was to assess the Se contents in biological samples of inorganic As exposed workers (n=61) and in non-exposed subjects (n=52). Median (Me) total arsenic concentration in urine of exposed workers was 21.83μg/g creat. (interquartile range (IQR) 15.49-39.77) and was significantly higher than in the control group - (Me 3.75μg/g creat. (IQR 2.52-9.26), piAs+MMA+DMA) was significantly associated with the high total selenium urine excretion (B=0.14 (95%CI (confidence interval) 0.05-0.23)). Combination of both arsenic and selenium status to assess the risk of arsenic-induced diseases requires more studies with regard to both the analysis of speciation, genetics and the influence of factors such as nutritional status. Copyright © 2017 Elsevier GmbH. All rights reserved.

Chronic exposure to arsenic, estrogen, and their combination causes increased growth and transformation in human prostate epithelial cells potentially by hypermethylation-mediated silencing of MLH1.

Science.gov (United States)

Treas, Justin; Tyagi, Tulika; Singh, Kamaleshwar P

2013-11-01

Chronic exposure to arsenic and estrogen is associated with risk of prostate cancer, but their mechanism is not fully understood. Additionally, the carcinogenic effects of their co-exposure are not known. Therefore, the objective of this study was to evaluate the effects of chronic exposure to arsenic, estrogen, and their combination, on cell growth and transformation, and identify the mechanism behind these effects. RWPE-1 human prostate epithelial cells were chronically exposed to arsenic and estrogen alone and in combination. Cell growth was measured by cell count and cell cycle, whereas cell transformation was evaluated by colony formation assay. Gene expression was measured by quantitative real-time PCR and confirmed at protein level by Western blot analysis. MLH1 promoter methylation was determined by pyrosequencing method. Exposure to arsenic, estrogen, and their combinations increases cell growth and transformation in RWPE-1 cells. Increased expression of Cyclin D1 and Bcl2, whereas decreased expression of mismatch repair genes MSH4, MSH6, and MLH1 was also observed. Hypermethylation of MLH1 promoter further suggested the epigenetic inactivation of MLH1 expression in arsenic and estrogen treated cells. Arsenic and estrogen combination caused greater changes than their individual treatments. Findings of this study for the first time suggest that arsenic and estrogen exposures cause increased cell growth and survival potentially through epigenetic inactivation of MLH1 resulting in decreased MLH1-mediated apoptotic response, and consequently increased cellular transformation. © 2013 Wiley Periodicals, Inc.

Arsenic trioxide promotes mitochondrial DNA mutation and cell apoptosis in primary APL cells and NB4 cell line.

Science.gov (United States)

Meng, Ran; Zhou, Jin; Sui, Meng; Li, ZhiYong; Feng, GuoSheng; Yang, BaoFeng

2010-01-01

This study aimed to investigate the effects of arsenic trioxide (As(2)O(3)) on the mitochondrial DNA (mtDNA) of acute promyelocytic leukemia (APL) cells. The NB4 cell line was treated with 2.0 micromol/L As(2)O(3) in vitro, and the primary APL cells were treated with 2.0 micromol/L As(2)O(3) in vitro and 0.16 mg kg(-1) d(-1) As(2)O(3) in vivo. The mitochondrial DNA of all the cells above was amplified by PCR, directly sequenced and analyzed by Sequence Navigatore and Factura software. The apoptosis rates were assayed by flow cytometry. Mitochondrial DNA mutation in the D-loop region was found in NB4 and APL cells before As(2)O(3) use, but the mutation spots were remarkably increased after As(2)O(3) treatment, which was positively correlated to the rates of cellular apoptosis, the correlation coefficient: r (NB4-As2O3)=0.973818, and r (APL-As2O3)=0.934703. The mutation types include transition, transversion, codon insertion or deletion, and the mutation spots in all samples were not constant and regular. It is revealed that As(2)O(3) aggravates mtDNA mutation in the D-loop region of acute promyelocytic leukemia cells both in vitro and in vivo. Mitochondrial DNA might be one of the targets of As(2)O(3) in APL treatment.

Hijacking membrane transporters for arsenic phytoextraction

Science.gov (United States)

LeBlanc, Melissa S.; McKinney, Elizabeth C.; Meagher, Richard B.; Smith, Aaron P.

2012-01-01

Arsenic is a toxic metalloid and recognized carcinogen. Arsenate and arsenite are the most common arsenic species available for uptake by plants. As an inorganic phosphate (Pi) analog, arsenate is acquired by plant roots through endogenous Pi transport systems. Inside the cell, arsenate is reduced to the thiol-reactive form arsenite. Glutathione (GSH)-conjugates of arsenite may be extruded from the cell or sequestered in vacuoles by members of the ATP-binding cassette (ABC) family of transporters. In the present study we sought to enhance both plant arsenic uptake through Pi transporter overexpression, and plant arsenic tolerance through ABC transporter overexpression. We demonstrate that Arabidopsis thaliana plants overexpressing the high-affinity Pi transporter family members, AtPht1;1 or AtPht1;7, are hypersensitive to arsenate due to increased arsenate uptake. These plants do not exhibit increased sensitivity to arsenite. Co-overexpression of the yeast ABC transporter YCF1 in combination with AtPht1;1 or AtPht1;7 suppresses the arsenate-sensitive phenotype while further enhancing arsenic uptake. Taken together, our results support an arsenic transport mechanism in which arsenate uptake is increased through Pi transporter overexpression, and arsenic tolerance is enhanced through YCF1-mediated vacuolar sequestration. This work substantiates the viability of coupling enhanced uptake and vacuolar sequestration as a means for developing a prototypical engineered arsenic hyperaccumulator. PMID:23108027

Modulation of cell adhesion and viability of cultured murine bone marrow cells by arsenobetaine, a major organic arsenic compound in marine animals.

Science.gov (United States)

Sakurai, T; Fujiwara, K

2001-01-01

1. In this study, we investigated the biological effects of trimethyl (carboxymethyl) arsonium zwitterion, namely arsenobetaine (AsBe), which is a major organic arsenic compound in marine animals using murine bone marrow (BM) cells and compared them with those of an inorganic arsenical, sodium arsenite, in vitro. 2. Sodium arsenite showed strong cytotoxicity in BM cells, and its IC(50) was 6 microM. In contrast, AsBe significantly enhanced the viability of BM cells in a dose-dependent manner during a 72-h incubation; about a twofold increase in the viability of cells compared with that of control cells cultured with the medium alone was observed with a microM level of AsBe. 3. In morphological investigations, AsBe enhanced the numbers of large mature adherent cells, especially granulocytes, during a 72-h BM culture. When BM cells were cultured together with AsBe and a low dose (1 u ml(-1)) of recombinant murine granulocyte/macrophage colony-stimulating factor (rMu GM-CSF), significant additive-like increasing effects were observed on the numbers of both granulocytes and macrophages originated from BM cells. However, AsBe did not cause proliferation of BM cells at all as determined by colony-forming assay using a gelatinous medium. 4. These findings demonstrate the unique and potent biological effects in mammalian cells of AsBe, a major organic arsenic compound in various marine animals which are ingested daily as seafood in many countries.

Health Effects of Chronic Arsenic Exposure

Directory of Open Access Journals (Sweden)

Young-Seoub Hong

2014-09-01

Full Text Available Arsenic is a unique element with distinct physical characteristics and toxicity whose importance in public health is well recognized. The toxicity of arsenic varies across its different forms. While the carcinogenicity of arsenic has been confirmed, the mechanisms behind the diseases occurring after acute or chronic exposure to arsenic are not well understood. Inorganic arsenic has been confirmed as a human carcinogen that can induce skin, lung, and bladder cancer. There are also reports of its significant association to liver, prostate, and bladder cancer. Recent studies have also suggested a relationship with diabetes, neurological effects, cardiac disorders, and reproductive organs, but further studies are required to confirm these associations. The majority of research to date has examined cancer incidence after a high exposure to high concentrations of arsenic. However, numerous studies have reported various health effects caused by chronic exposure to low concentrations of arsenic. An assessment of the health effects to arsenic exposure has never been performed in the South Korean population; thus, objective estimates of exposure levels are needed. Data should be collected on the biological exposure level for the total arsenic concentration, and individual arsenic concentration by species. In South Korea, we believe that biological exposure assessment should be the first step, followed by regular health effect assessments.

Sequestration of arsenic in ombrotrophic peatlands

Science.gov (United States)

Rothwell, James; Hudson-Edwards, Karen; Taylor, Kevin; Polya, David; Evans, Martin; Allott, Tim

2014-05-01

Peatlands can be important stores of arsenic but we are lacking spectroscopic evidence of the sequestration pathways of this toxic metalloid in peatland environments. This study reports on the solid-phase speciation of anthropogenically-derived arsenic in atmospherically contaminated peat from the Peak District National Park (UK). Surface and sub-surface peat samples were analysed by synchrotron X-ray absorption spectroscopy on B18 beamline at Diamond Light Source (UK). The results suggest that there are contrasting arsenic sequestration mechanisms in the peat. The bulk arsenic speciation results, in combination with strong arsenic-iron correlations at the surface, suggest that iron (hydr)oxides are key phases for the immobilisation of arsenic at the peat surface. In contrast, the deeper peat samples are dominated by arsenic sulphides (arsenopyrite, realgar and orpiment). Given that these peats receive inputs solely from the atmosphere, the presence of these sulphide phases suggests an in-situ authigenic formation. Redox oscillations in the peat due to a fluctuating water table and an abundant store of legacy sulphur from historic acid rain inputs may favour the precipitation of arsenic sequestering sulphides in sub-surface horizons. Oxidation-induced loss of these arsenic sequestering sulphur species by water table drawdown has important implications for the mobility of arsenic and the quality of waters draining peatlands.

Arsenic adsorption of lateritic soil, limestone powder, lime and fly ash on arsenic-contaminated soil

Directory of Open Access Journals (Sweden)

Wuthiphun, L.

2007-05-01

Full Text Available Arsenic adsorption efficiency of soil covering materials (lateritic soil, limestone powder, lime and fly ash on arsenic-contaminated soil obtained from Ronpiboon District, Nakhon Sri Thammarat Province tosolve arsenic air pollution problem was investigated using batch experiments. The four types of the aforementioned soil covering materials were examined to determine their arsenic adsorption efficiency, equilibriumtime as well as adsorption isotherms.The results revealed that among soil covering materials mixed with arsenic-contaminated soil at 10% w/w, the efficiency of arsenic adsorption of fly ash, lateritic soil, lime and limestone powder were 84, 60,38 and 1% respectively. The equilibrium time for lateritic soil at pH 4 was achieved within 4 hrs, whereas pH 7 and 12, the equilibrium time was 6 hrs. For fly ash, 2 hrs were required to reach the equilibrium at pH 12, while the equilibrium time was attained within 6 hrs at pH 4 and 7. Furthermore, lateritic soil possessedhigh arsenic adsorption efficiency at pH 7 and 4 and best fit with the Langmuir isotherm. The fly ash showing high arsenic adsorption efficiency at pH 12 and 7 fit the Freundlich isotherm at pH 12 and Langmuirisotherm at pH 7.This indicated that lateritic soil was suitable for arsenic adsorption at low pH, whilst at high pH,arsenic was well adsorbed by fly ash. The Freundlich and Langmuir isotherm could be used to determine quantities of soil covering materials for arsenic adsorption to prevent arsenic air pollution from arseniccontaminated soils.

Different effects of inorganic and dimethylated arsenic compounds on cell morphology, cytoskeletal organization, and DNA synthesis in cultured Chinese hamster V79 cells

Energy Technology Data Exchange (ETDEWEB)

Ochi, Takafumi; Nakajima, Fumie [Department of Environmental Toxicology, Faculty of Pharmaceutical Sciences, Teikyo University, Sagamiko, Kanagawa (Japan); Fukumori, Nobutaka [Department of Toxicology, Tokyo Metropolitan Research Laboratory of Public Health, Hyakuninchou, Shinjyuku (Japan)

1998-09-01

Changes in cytoskeletal organization of cultured V79 cells exposed to arsenite and dimethylarsinic acid (DMAA), a methylated derivative of inorganic arsenics, and related changes, such as mitotic arrest and induction of multinucleated cells, were investigated in comparison with their effects on DNA synthesis. DMAA caused mitotic arrest and induction of multinucleated cells with a delay of 12 h relative to the mitotic arrest. By contrast, arsenite at equitoxic concentrations to DMAA was less effective than DMAA in causing mitotic arrest and in inducing multinucleated cells. Post-mitotic incubation of cells arrested in metaphase by 6 h incubation with 10 mM DMAA showed that the incidence of multinucleated cells increased conversely with a rapid decrease in metaphase cells. This suggests that metaphase-arrested cells can escape from metaphase, resulting in the appearance of multinucleated cells. The mitotic arrest caused by DMAA was accompanied by disruption of the microtubule network. By contrast, both arsenite and DMAA did not cause disorganization of actin stress fibers even when incubated at concentrations that caused a marked retardation of cell growth. Cells exposed to arsenite for 6 h showed marked inhibition of DNA synthesis, whereas inhibition by DMAA was not observed. When incubation was prolonged by 18 h, the arsenite-induced inhibition of DNA synthesis was mitigated. By contrast, inhibition of DNA synthesis by DMAA occurred in parallel with an increase in the population of mitotic cells. These results suggest that DMAA caused growth retardation and morphological changes via disruption of the microtubule network, and that arsenite-induced retardation of cell growth and inhibition of DNA synthesis were not attributable to the cytoskeletal changes. (orig.) (orig.) With 7 figs., 31 refs.

The effect of arsenic contamination on amino acids metabolism in Spinacia oleracea L.

Science.gov (United States)

Pavlík, Milan; Pavlíková, Daniela; Staszková, Ludmila; Neuberg, Marek; Kaliszová, Regina; Száková, Jirina; Tlustos, Pavel

2010-09-01

Changes of amino acid concentrations (proline, glutamate, asparagine, aspartate, alanine) and glutamate kinase activity (GKA) in plants under arsenic chronic stress reported here reveal their role in plant arsenic stress adaptation. Results of the pot experiment confirmed the toxic effect of arsenic at tested levels (As1=25 mg As kg(-1) soil, As2=50 mg As kg(-1) soil, As3=75 mg As kg(-1) soil) for spinach. Growing available arsenic contents in soil were associated with the strong inhibition of above-ground biomass and with the enhancement of As plant content. The changes of glutamate, asparagine, aspartate and proline levels in the plants showed strong linear dependences on arsenic concentration in plants (R2=0.60-0.90). Compared to the untreated control, concentrations of free proline and aspartate of As3 treatment were enhanced up to 381% and 162%, respectively. The significant changes of glutamate were observed on As2 and As3 treatments (increased level up to 188, i.e. 617%). Arsenic in plants was shown to be an inhibitor of glutamase kinase activity (R2=0.91). Inhibition of GKA resulted in an increase in the content of glutamate that is used in synthesis of phytochelatins in plant cells. Concentration of alanine did not have a confirmed linear dependence on arsenic concentration in plant (R2=0.05). The changes of its concentrations could be affected by changes of pH in plant cell or induction of alanine aminotransferase by hypoxia. Copyright (c) 2010 Elsevier Inc. All rights reserved.

Multiple Bowen's disease and epithelioid malignant peripheral nerve sheath tumor in a patient who experienced chronic arsenic poisoning

Directory of Open Access Journals (Sweden)

Ching-En Chen

2017-01-01

Full Text Available The Southwest coastal plain of Taiwan is an endemic area of arsenic contamination. Residents who lived there before the 1970s and who used raw groundwater for drinking have a higher risk of arsenic poisoning. In 1968, Tseng et al. described Blackfoot disease as a peripheral vascular disease caused by chronic exposure to arsenic, thereby introducing the concept of arsenic-induced systemic illness in Taiwan. Multiple Bowen's disease (BD is one of the characteristic consequences of chronic arsenic poisoning and it usually presents as cutaneous carcinoma in situ. Multiple BD can also be associated with squamous cell carcinoma and basal cell carcinoma of the skin, as well as lung, liver, gastrointestinal, and bladder cancers. We encountered a 79-year-old male from Yun-Lin, a county in Southwest Taiwan, who presented with a progressing tumor in his right anterior chest wall. In addition, numerous keratoses and scaly skin lesions were noted on his trunk and extremities, some of which were combined with erosions. The patient was diagnosed with chronic arsenic poisoning with multiple BD and the huge tumor was confirmed as an epithelioid malignant peripheral nerve sheath tumor.

Resveratrol, a Natural Antioxidant, Has a Protective Effect on Liver Injury Induced by Inorganic Arsenic Exposure

Directory of Open Access Journals (Sweden)

Zhigang Zhang

2014-01-01

Full Text Available Resveratrol (Rev can ameliorate cytotoxic chemotherapy-induced toxicity and oxidative stress. Arsenic trioxide (As2O3 is a known cytotoxic environmental toxicant and a potent chemotherapeutic agent. However, the mechanisms by which resveratrol protects the liver against the cytotoxic effects of As2O3 are not known. Therefore, in the present study we investigated the mechanisms involved in the action of resveratrol using a cat model in which hepatotoxicity was induced by means of As2O3 treatment. We found that pretreatment with resveratrol, administered using a clinically comparable dose regimen, reversed changes in As2O3-induced morphological and liver parameters and resulted in a significant improvement in hepatic function. Resveratrol treatment also improved the activities of antioxidant enzymes and attenuated As2O3-induced increases in reactive oxygen species and malondialdehyde production. In addition, resveratrol attenuated the As2O3-induced reduction in the ratio of reduced glutathione to oxidized glutathione and the retention of arsenic in liver tissue. These findings provide a better understanding of the mechanisms whereby resveratrol modulates As2O3-induced changes in liver function and tissue morphology. They also provide a stronger rationale for the clinical utilization of resveratrol for the reduction of As2O3-induced hepatotoxicity.

Metabolic profiling reveals potential metabolic markers associated with Hypoxia Inducible Factor-mediated signalling in hypoxic cancer cells.

Science.gov (United States)

Armitage, Emily G; Kotze, Helen L; Allwood, J William; Dunn, Warwick B; Goodacre, Royston; Williams, Kaye J

2015-10-28

Hypoxia inducible factors (HIFs) plays an important role in oxygen compromised environments and therefore in tumour survival. In this research, metabolomics has been applied to study HIFs metabolic function in two cell models: mouse hepatocellular carcinoma and human colon carcinoma, whereby the metabolism has been profiled for a range of oxygen potentials. Wild type cells have been compared to cells deficient in HIF signalling to reveal its effect on cellular metabolism under normal oxygen conditions as well as low oxygen, hypoxic and anoxic environments. Characteristic responses to hypoxia that were conserved across both cell models involved the anti-correlation between 2-hydroxyglutarate, 2-oxoglutarate, fructose, hexadecanoic acid, hypotaurine, pyruvate and octadecenoic acid with 4-hydroxyproline, aspartate, cysteine, glutamine, lysine, malate and pyroglutamate. Further to this, network-based correlation analysis revealed HIF specific pathway responses to each oxygen condition that were also conserved between cell models. From this, 4-hydroxyproline was revealed as a regulating hub in low oxygen survival of WT cells while fructose appeared to be in HIF deficient cells. Pathways surrounding these hubs were built from the direct connections of correlated metabolites that look beyond traditional pathways in order to understand the mechanism of HIF response to low oxygen environments.

Arsenic bioavailability in soils before and after soil washing: the use of Escherichia coli whole-cell bioreporters.

Science.gov (United States)

Yoon, Youngdae; Kang, Yerin; Chae, Yooeun; Kim, Sunghoon; Lee, Youngshim; Jeong, Seung-Woo; An, Youn-Joo

2016-02-01

We investigated the quantification of bioavailable arsenic in contaminated soils and evaluation of soil-washing processes in the aspect of bioavailability using a novel bacterial bioreporter developed in present study. The whole-cell bioreporter (WCB) was genetically engineered by fusing the promoter of nik operon from Escherichia coli and green fluorescent protein as a sensing domain and reporter domain. Among eight well-known hazardous heavy metals and metalloid, this system responded specifically to arsenic, thereby inferring association of As(III) with NikR inhibits the repression. Moreover, the response was proportional to the concentration of As(III), thereby it was capable to determine the amount of bioavailable arsenic quantitatively in contaminated soils. The bioavailable portion of arsenic was 5.9 (3.46-10.96) and 0.9 (0.27-1.74) % of total from amended and site soils, respectively, suggesting the bioavailability of arsenic in soils was related to the soil properties and duration of aging. On the other hand, only 1.37 (0.21-2.97) % of total arsenic was extracted into soil solutions and 19.88 (11.86-28.27) % of arsenic in soil solution was bioavailable. This result showed that the soluble arsenic is not all bioavailable and most of bioavailable arsenic in soils is water non-extractable. In addition, the bioavailable arsenic was increased after soil-washing while total amount was decreased, thereby suggesting the soil-washing processes release arsenic associated with soil materials to be bioavailable. Therefore, it would be valuable to have a tool to assess bioavailability and the bioavailability should be taken into consideration for soil remediation plans.

Phosphorus improves arsenic phytoremediation by Anadenanthera peregrina by alleviating induced oxidative stress.

Science.gov (United States)

Gomes, M P; Carvalho, M; Carvalho, G S; Marques, T C L L S M; Garcia, Q S; Guilherme, L R G; Soares, A M

2013-01-01

Due to similarities in their chemical behaviors, studies examining interactions between arsenic (As)--in special arsenate--and phosphorus (P) are important for better understanding arsenate uptake, toxicity, and accumulation in plants. We evaluated the effects of phosphate addition on plant biomass and on arsenate and phosphate uptake by Anadenanthera peregrina, an important Brazilian savanna legume. Plants were grown for 35 days in substrates that received combinations of 0, 10, 50, and 100 mg kg(-1) arsenate and 0, 200, and 400 mg kg(-1) phosphate. The addition of P increased the arsenic-phytoremediation capacity of A. peregrina by increasing As accumulation, while also alleviating As-induced oxidative stress. Arsenate phytotoxicity in A. peregrina is due to lipid peroxidation, but not hydrogen peroxide accumulation. Added P also increased the activity of important reactive oxygen species-scavenging enzymes (catalase and ascorbate peroxidase) that help prevent lipid peroxidation in leaves. Our findings suggest that applying P represents a feasible strategy for more efficient As phytoremediation using A. peregrina.

Combined effects of DNA methyltransferase 1 and 3A polymorphisms and urinary total arsenic levels on the risk for clear cell renal cell carcinoma

Energy Technology Data Exchange (ETDEWEB)

Yang, Shu-Mei [School of Public Health, College of Public Health and Nutrition, Taipei Medical University, Taipei, Taiwan (China); Huang, Chao-Yuan [Department of Urology, National Taiwan University Hospital, College of Medicine National Taiwan University, Taipei, Taiwan (China); Shiue, Horng-Sheng [Department of Chinese Medicine, Chang Gung Memorial Hospital and College of Medicine, Chang Gung University, Taoyuan, Taiwan (China); Pu, Yeong-Shiau [Department of Urology, National Taiwan University Hospital, College of Medicine National Taiwan University, Taipei, Taiwan (China); Hsieh, Yi-Hsun; Chen, Wei-Jen [School of Public Health, College of Public Health and Nutrition, Taipei Medical University, Taipei, Taiwan (China); Lin, Ying-Chin [Department of Family Medicine, Shung Ho Hospital, Taipei Medical University, Taipei, Taiwan (China); Department of Health Examination, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan (China); Division of Family Medicine, School of Medicine, Taipei Medical University, Taipei, Taiwan (China); Hsueh, Yu-Mei, E-mail: ymhsueh@tmu.edu.tw [School of Public Health, College of Public Health and Nutrition, Taipei Medical University, Taipei, Taiwan (China); Department of Public Health, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan (China)

2016-08-15

Our previous study showed that high urinary total arsenic levels were associated with higher odds ratio (OR) for renal cell carcinoma (RCC). Single nucleotide polymorphisms (SNPs) of DNA methyltransferases (DNMTs) might influence DNMT enzyme activity associated with tumorigenesis. In this study, we investigated the association of five SNPs from DNMT1 (rs8101626 and rs2228611), DNMT3A (rs34048824 and rs1550117), and DNMT3B (rs1569686) with the risk of clear cell renal cell carcinoma (ccRCC). We also examined the combined effects of DNMT genotypes and urinary arsenic levels on ccRCC risk. We conducted a hospital-based case-control study, which included 293 subjects with ccRCC and 293 age- and gender-matched controls. The urinary arsenic species were determined by a high performance liquid chromatography-linked hydride generator and atomic absorption spectrometry. Genotypes were investigated using polymerase chain reaction and restriction fragment length polymorphism analyses. We observed that the DNMT1 rs8101626 G/G genotype was significantly associated with reduced odds ratio (OR) of ccRCC [OR = 0.38, 95% confidence interval (CI) 0.14–0.99]. Subjects with concurrent DNMT1 rs8101626 A/A + A/G and DNMT3A rs34048824 T/T + T/C genotypes had significantly higher OR for ccRCC [OR = 2.88, 95% CI 1.44–5.77]. Participants with the high-risk genotype of DNMT1 rs8101626 and DNMT3A rs34048824 with concurrently high urinary total arsenic levels had even higher OR of ccRCC in a dose-response manner. This is the first study to evaluate variant DNMT1 rs8101626 and DNMT3A rs34048824 genotypes that modify the arsenic-related ccRCC risk in a geographic area without significant arsenic exposure in Taiwan. - Highlights: • High urinary total arsenic level or polymorphism of DNMT1 increased the OR of ccRCC. • High risk genotypes of combination of DNMT1 and DNMT3A increased the OR of ccRCC. • A joint effect of urinary total arsenic level and DNMTs genotypes may affect ccRCC.

Nrf2 protects human bladder urothelial cells from arsenite and monomethylarsonous acid toxicity

International Nuclear Information System (INIS)

Wang Xiaojun; Sun Zheng; Chen Weimin; Eblin, Kylee E.; Gandolfi, Jay A.; Zhang, Donna D.

2007-01-01

Arsenic is widely spread in our living environment and imposes a big challenge on human health worldwide. Arsenic damages biological systems through multiple mechanisms including the generation of reactive oxygen species. The transcription factor Nrf2 regulates the cellular antioxidant response that protects cells from various insults. In this study, the protective role of Nrf2 in arsenic toxicity was investigated in a human bladder urothelial cell line, UROtsa. Using a UROtsa cell line stably infected with Nrf2-siRNA, we clearly demonstrate that compromised Nrf2 expression sensitized the cells to As(III)- and MMA(III)-induced toxicity. On the other hand, the activation of the Nrf2 pathway by tert-butylhydroquinone (tBHQ) and sulforaphane (SF), the known Nrf2-inducers, rendered UROtsa cells more resistant to As(III) and MMA(III). Furthermore, the wild-type mouse embryo fibroblast (WT-MEF) cells were protected from As(III)- and MMA(III)-induced toxicity following Nrf2 activation by tBHQ or SF, whereas neither tBHQ nor SF conferred protection in the Nrf2 -/- MEF cells, demonstrating that tBHQ- or SF-mediated protection against As(III)- and MMA(III)-induced toxicity depends on Nrf2 activation. These results, obtained by both loss of function and gain of function analyses, clearly demonstrate the protective role of Nrf2 in arsenic-induced toxicity. The current work lays the groundwork for using Nrf2 activators for therapeutic and dietary interventions against adverse effects of arsenic

Transcriptomic Response of Purple Willow (Salix purpurea to Arsenic Stress

Directory of Open Access Journals (Sweden)

Aymeric Yanitch

2017-06-01

Full Text Available Arsenic (As is a toxic element for plants and one of the most common anthropogenic pollutants found at contaminated sites. Despite its severe effects on plant metabolism, several species can accumulate substantial amounts of arsenic and endure the associated stress. However, the genetic mechanisms involved in arsenic tolerance remains obscure in many model plant species used for land decontamination (phytoremediation, including willows. The present study assesses the potential of Salix purpurea cv. ‘Fish Creek’ for arsenic phytoextraction and reveals the genetic responses behind arsenic tolerance, phytoextraction and metabolism. Four weeks of hydroponic exposure to 0, 5, 30 and 100 mg/L revealed that plants were able to tolerate up to 5 mg/L arsenic. Concentrations of 0 and 5 mg/L of arsenic treatment were then used to compare alterations in gene expression of roots, stems and leaves using RNA sequencing. Differential gene expression revealed transcripts encoding proteins putatively involved in entry of arsenic into the roots, storage in vacuoles and potential transport through the plant as well as primary and secondary (indirect toxicity tolerance mechanisms. A major role for tannin as a compound used to relieve cellular toxicity is implicated as well as unexpected expression of the cadmium transporter CAX2, providing a potential means for internal arsenic mobility. These insights into the underpinning genetics of a successful phytoremediating species present novel opportunities for selection of dedicated arsenic tolerant crops as well as the potential to integrate such tolerances into a wider Salix ideotype alongside traits including biomass yield, biomass quality, low agricultural inputs and phytochemical production.

Transcriptomic Response of Purple Willow (Salix purpurea) to Arsenic Stress

Science.gov (United States)

Yanitch, Aymeric; Brereton, Nicholas J. B.; Gonzalez, Emmanuel; Labrecque, Michel; Joly, Simon; Pitre, Frederic E.

2017-01-01

Arsenic (As) is a toxic element for plants and one of the most common anthropogenic pollutants found at contaminated sites. Despite its severe effects on plant metabolism, several species can accumulate substantial amounts of arsenic and endure the associated stress. However, the genetic mechanisms involved in arsenic tolerance remains obscure in many model plant species used for land decontamination (phytoremediation), including willows. The present study assesses the potential of Salix purpurea cv. ‘Fish Creek’ for arsenic phytoextraction and reveals the genetic responses behind arsenic tolerance, phytoextraction and metabolism. Four weeks of hydroponic exposure to 0, 5, 30 and 100 mg/L revealed that plants were able to tolerate up to 5 mg/L arsenic. Concentrations of 0 and 5 mg/L of arsenic treatment were then used to compare alterations in gene expression of roots, stems and leaves using RNA sequencing. Differential gene expression revealed transcripts encoding proteins putatively involved in entry of arsenic into the roots, storage in vacuoles and potential transport through the plant as well as primary and secondary (indirect) toxicity tolerance mechanisms. A major role for tannin as a compound used to relieve cellular toxicity is implicated as well as unexpected expression of the cadmium transporter CAX2, providing a potential means for internal arsenic mobility. These insights into the underpinning genetics of a successful phytoremediating species present novel opportunities for selection of dedicated arsenic tolerant crops as well as the potential to integrate such tolerances into a wider Salix ideotype alongside traits including biomass yield, biomass quality, low agricultural inputs and phytochemical production. PMID:28702037

Role of microRNAs in senescence and its contribution to peripheral neuropathy in the arsenic exposed population of West Bengal, India.

Science.gov (United States)

Chatterjee, Debmita; Bandyopadhyay, Apurba; Sarma, Nilendu; Basu, Santanu; Roychowdhury, Tarit; Roy, Sib Sankar; Giri, Ashok K

2018-02-01

Arsenic induced senescence (AIS) has been identified in the population of West Bengal, India very recently. Also there is a high incidence of arsenic induced peripheral neuropathy (PN) throughout India. However, the epigenetic regulation of AIS and its contribution in arsenic induced PN remains unexplored. We recruited seventy two arsenic exposed and forty unexposed individuals from West Bengal to evaluate the role of senescence associated miRNAs (SA-miRs) in AIS and their involvement if any, in PN. The downstream molecules of the miRNA associated with the disease outcome, was also checked by immuoblotting. In vitro studies were conducted with HEK 293 cells and sodium arsenite exposure. Our results show that all the SA-miRs were upregulated in comparison to unexposed controls. miR-29a was the most significantly altered, highest expression being in the arsenic exposed group with PN, suggesting its association with the occurrence of PN. We looked for the expression of peripheral myelin protein 22 (PMP22), a specific target of miR-29a associated with myelination and found that both in vitro and in vivo results showed over-expression of the protein. Since this was quite contrary to miRNA regulation, we checked for intermediate players β-catenin and GSK-3β upon arsenic exposure which affects PMP22 expression. We found that β-catenin was upregulated in vitro and was also highest in the arsenic exposed group with PN while GSK-3β followed the reverse pattern. Our findings suggest that arsenic exposure alters the expression of SA-miRs and the mir-29a/beta catenin/PMP22 axis might be responsible for arsenic induced PN. Copyright © 2017. Published by Elsevier Ltd.

Hydrogen-enriched water restoration of impaired calcium propagation by arsenic in primary keratinocytes

Science.gov (United States)

Yu, Wei-Tai; Chiu, Yi-Ching; Lee, Chih-Hung; Yoshioka, Tohru; Yu, Hsin-Su

2013-11-01

Endemic contamination of artesian water for drinking by arsenic is known to cause several human cancers, including cancers of the skin, bladder, and lungs. In skin, multiple arsenic-induced Bowen's disease (As-BD) can develop into invasive cancers after decades of arsenic exposure. The characteristic histological features of As-BD include full-layer epidermal dysplasia, apoptosis, and abnormal proliferation. Calcium propagation is an essential cellular event contributing to keratinocyte differentiation, proliferation, and apoptosis, all of which occur in As-BD. This study investigated how arsenic interferes calcium propagation of skin keratinocytes through ROS production and whether hydrogen-enriched water would restore arsenic-impaired calcium propagation. Arsenic was found to induce oxidative stress and inhibit ATP- and thapsigaragin-induced calcium propagation. Pretreatment of arsenic-treated keratinocytes by hydrogen-enriched water or beta-mercaptoethanol with potent anti-oxidative effects partially restored the propagation of calcium by ATP and by thapsigaragin. It was concluded that arsenic may impair calcium propagation, likely through oxidative stress and interactions with thiol groups in membrane proteins.

Enhanced urinary bladder and liver carcinogenesis in male CD1 mice exposed to transplacental inorganic arsenic and postnatal diethylstilbestrol or tamoxifen

International Nuclear Information System (INIS)

Waalkes, Michael P.; Liu Jie; Ward, Jerrold M.; Diwan, Bhalchandra A.

2006-01-01

Pregnant CD1 mice received 85 ppm arsenite in the drinking water from gestation day 8 to 18, groups (n = 35) of male offspring were subsequently injected on postpartum days 1 through 5 with diethylstilbestrol (DES; 2 μg/pup/day) or tamoxifen (TAM; 10 μg/pup/day), and tumor formation was assessed over 90 weeks. Arsenic alone increased hepatocellular carcinoma (14%), adenoma (23%) and total tumors (31%) compared to control (0, 2 and 2%, respectively). Arsenic alone also increased lung adenocarcinoma, adrenal cortical adenoma and renal cystic tubular hyperplasia compared to control. Compared to arsenic alone, arsenic plus DES increased liver tumor incidence in mice at risk 2.2-fold and increased liver tumor multiplicity (tumors/liver) 1.8-fold. The treatments alone did not impact urinary bladder carcinogenesis, but arsenic plus TAM significantly increased formation of urinary bladder transitional cell tumors (papilloma and carcinoma; 13%) compared to control (0%). Urinary bladder proliferative lesions (combined tumors and hyperplasia) were also increased by arsenic plus TAM (40%) or arsenic plus DES (43%) compared to control (0%) or the treatments alone. Urinary bladder proliferative lesions occurred in the absence of any evidence of uroepithelial cytotoxic lesions. Urinary bladder lesions and hepatocellular carcinoma induced by arsenic plus TAM and/or DES overexpressed estrogen receptor-α, indicating that aberrant estrogen signaling may have been a factor in the enhanced carcinogenic response. Thus, in male CD1 mice, gestational arsenic exposure alone induced liver adenoma and carcinoma, lung adenocarcinoma, adrenal adenoma and renal cystic hyperplasia. Furthermore, DES enhanced transplacental arsenic-induced hepatocarcinogenesis. In utero arsenic also initiated urinary bladder tumor formation when followed by postnatal TAM and uroepithelial proliferative lesions when followed by TAM or DES

Environmental biochemistry of arsenic

Energy Technology Data Exchange (ETDEWEB)

Tamaki, S.; Frankenberger, W.T. Jr. (Department of Soil and Environmental Sciences, University of California, Riverside (United States))

1992-01-01

Microorganisms are involved in the redistribution and global cycling of arsenic. Arsenic can accumulate and can be subject to various biotransformations including reduction, oxidation, and methylation. Bacterial methylation of inorganic arsenic is coupled to the methane biosynthetic pathway in methanogenic bacteria under anaerobic conditions and may be a mechanism for arsenic detoxification. The pathway proceeds by reduction of arsenate to arsenite followed by methylation to dimethylarsine. Fungi are also able to transform inorganic and organic arsenic compounds into volatile methylarsines. The pathway proceeds aerobically by arsenate reduction to arsenite followed by several methylation steps producing trimethylarsine. Volatile arsine gases are very toxic to mammals because they destroy red blood cells (LD50 in rats; 3.0 mg kg-1). Further studies are needed on dimethylarsine and trimethylarsine toxicity tests through inhalation of target animals. Marine algae transform arsenate into non-volatile methylated arsenic compounds (methanearsonic and dimethylarsinic acids) in seawater. This is considered to be a beneficial step not only to the primary producers, but also to the higher trophic levels, since non-volatile methylated arsenic is much less toxic to marine invertebrates. Freshwater algae like marine algae synthesize lipid-soluble arsenic compounds and do not produce volatile methylarsines. Aquatic plants also synthesize similar lipid-soluble arsenic compounds. In terrestrial plants, arsenate is preferentially taken up 3 to 4 times the rate of arsenite. In the presence of phosphate, arsenate uptake is inhibited while in the presence of arsenate, phosphate uptake is only slightly inhibited. There is a competitive interaction between arsenate and phosphate for the same uptake system in terrestrial plants.

Microvascular dysfunction with increased vascular leakage response in mice systemically exposed to arsenic.

Science.gov (United States)

Chen, Shih-Chieh; Huang, Shin-Yin; Lu, Chi-Yu; Hsu, Ya-Hung; Wang, Dean-Chuan

2014-09-01

The mechanisms underlying cardiovascular disease induced by arsenic exposure are not completely understood. The objectives of this study were to investigate whether arsenic-fed mice have an increased vascular leakage response to vasoactive agents and whether enhanced type-2 protein phosphatase (PP2A) activity is involved in mustard oil-induced leakage. ICR mice were fed water or sodium arsenite (20 mg/kg) for 4 or 8 weeks. The leakage response to vasoactive agents was quantified using the Evans blue (EB) technique or vascular labeling with carbon particles. Increased EB leakage and high density of carbon-labeled microvessels were detected in arsenic-fed mice treated with mustard oil. Histamine induced significantly higher vascular leakage in arsenic-fed mice than in water-fed mice. Pretreatment with the PP2A inhibitor okadaic acid or the neurokinin 1 receptor (NK1R) blocker RP67580 significantly reduced mustard oil-induced vascular leakage in arsenic-fed mice. The protein levels of PP2Ac and NK1R were similar in both groups. PP2A activity was significantly higher in the arsenic-fed mice compared with the control group. These findings indicate that microvessels generally respond to vasoactive agents, and that the increased PP2A activity is involved in mustard oil-induced vascular leakage in arsenic-fed mice. Arsenic may initiate endothelial dysfunction, resulting in vascular leakage in response to vasoactive agents.

Urinary arsenic speciation and its correlation with 8-OHdG in Chinese residents exposed to arsenic through coal burning

Energy Technology Data Exchange (ETDEWEB)

Li, X.; Pi, J.B.; Li, B.; Xu, Y.Y.; Jin, Y.P.; Sun, G.F. [China Medical University, Shenyang (China). Dept. for Occupational & Environmental Health

2008-10-15

In contrast to arsenicosis caused by consumption of water contaminated by naturally occurring inorganic arsenic, human exposure to this metalloid through coal burning has been rarely reported. In this study, arsenic speciation and 8-hydroxy-2'-deoxyguanosine (8-OHdG) levels in urine were determined in the Chinese residents exposed to arsenic through coal burning in Guizhou, China, an epidemic area of chronic arsenic poisoning caused by coal burning. The urinary concentrations of inorganic arsenic (iAs), monomethylarsonic acid (MMA), dimethylarsinic acid (DMA) and total arsenic (tAs) of high-arsenic exposed subjects were significantly higher than those of low-arsenic exposed residents. A biomarker of oxidative DNA damage, urinary 8-OHdG level was significantly higher in high-arsenic exposed subjects than that of low exposed. Significant positive correlations were found between 8-OHdG levels and concentrations of iAs, MMA, DMA and tAs, respectively. In addition, a significant negative correlation was observed between 8-OHdG levels and the secondary methylation ratio (DMA/(MMA + DMA)). The results suggest that chronic arsenic exposure through burning coal rich in arsenic is associated with oxidative DNA damages, and that secondary methylation capacity is potentially related to the susceptibility of individuals to oxidative DNA damage induced by arsenic exposure through coal burning in domestic living.

Modulatory role of dietary Chlorella vulgaris powder against arsenic-induced immunotoxicity and oxidative stress in Nile tilapia (Oreochromis niloticus).

Science.gov (United States)

Zahran, Eman; Risha, Engy

2014-12-01

Arsenic intoxicant have long been regarded as an impending carcinogenic, genotoxic, and immunotoxic heavy metal to human and animals as well. In this respect, we evaluated biomarkers of the innate immune response and oxidative stress metabolism in gills and liver of Nile tilapia (Oreochromis niloticus) after arsenic exposure, and the protective role of Chlorella vulgaris (Ch) dietary supplementation were elucidated. Protective role of C. vulgaris (Ch), as supplementary feeds (5% and 10% of the diet) was studied in Nile tilapia (O. niloticus) against arsenic induced toxicity (NaAsO2 at 7 ppm) for 21 days exposure period. A significant down-regulation in innate immune response; including, respiratory burst, lysozyme, and bactericidal activity followed due to deliberately As(+3) exposure. Similarly, oxidative stress response; like nitric oxide (NO), catalase (CAT), glutathione (GSH), glutathione peroxidase (GPx), malondialdehyde (MDA) and hydrogen peroxide (H2O2) levels were significantly decreased. Combined treatment of Ch and As(+3) significantly enhanced the innate immune response and antioxidant activity. Strikingly, Ch supplementation at 10% has been considered the optimum for Nile tilapia since it exhibited enhancement of innate immune response and antioxidant activity over the level 5%, and even better than that of control level. Thus, our results concluded that dietary Ch supplementation could protect Nile tilapia against arsenic induced immunosuppression and oxidative stresses. Copyright © 2014 Elsevier Ltd. All rights reserved.

Ameliorating effect of microdoses of a potentized homeopathic drug, Arsenicum Album, on arsenic-induced toxicity in mice

Directory of Open Access Journals (Sweden)

Guha B

2003-10-01

Full Text Available Abstract Background Arsenic in groundwater and its accumulation in plants and animals have assumed a menacing proportion in a large part of West Bengal, India and adjoining areas of Bangladesh. Because of the tremendous magnitude of the problem, there seems to be no way to tackle the problem overnight. Efforts to provide arsenic free water to the millions of people living in these dreaded zones are being made, but are awfully inadequate. In our quest for finding out an easy, safe and affordable means to combat this problem, a homeopathic drug, Arsenicum Album-30, appears to yield promising results in mice. The relative efficacies of two micro doses of this drug, namely, Arsenicum Album-30 and Arsenicum Album-200, in combating arsenic toxicity have been determined in the present study on the basis of some accepted biochemical protocols. Methods Mice were divided into different sets of control (both positive and negative and treated series (As-intoxicated, As-intoxicated plus drug-fed. Alanine amino transferase (ALT and aspartate amino transferase (AST activities and reduced glutathione (GSH level in liver and blood were analyzed in the different series of mice at six different fixation intervals. Results Both Arsenicum Album-30 and Arsenicum Album-200 ameliorated arsenic-induced toxicity to a considerable extent as compared to various controls. Conclusions The results lend further support to our earlier views that microdoses of potentized Arsenicum Album are capable of combating arsenic intoxication in mice, and thus are strong candidates for possible use in human subjects in arsenic contaminated areas under medical supervision.

Arsenic and Antimony Transporters in Eukaryotes

Directory of Open Access Journals (Sweden)

Ewa Maciaszczyk-Dziubinska

2012-03-01

Full Text Available Arsenic and antimony are toxic metalloids, naturally present in the environment and all organisms have developed pathways for their detoxification. The most effective metalloid tolerance systems in eukaryotes include downregulation of metalloid uptake, efflux out of the cell, and complexation with phytochelatin or glutathione followed by sequestration into the vacuole. Understanding of arsenic and antimony transport system is of high importance due to the increasing usage of arsenic-based drugs in the treatment of certain types of cancer and diseases caused by protozoan parasites as well as for the development of bio- and phytoremediation strategies for metalloid polluted areas. However, in contrast to prokaryotes, the knowledge about specific transporters of arsenic and antimony and the mechanisms of metalloid transport in eukaryotes has been very limited for a long time. Here, we review the recent advances in understanding of arsenic and antimony transport pathways in eukaryotes, including a dual role of aquaglyceroporins in uptake and efflux of metalloids, elucidation of arsenic transport mechanism by the yeast Acr3 transporter and its role in arsenic hyperaccumulation in ferns, identification of vacuolar transporters of arsenic-phytochelatin complexes in plants and forms of arsenic substrates recognized by mammalian ABC transporters.

Arsenic and Antimony Transporters in Eukaryotes

Science.gov (United States)

Maciaszczyk-Dziubinska, Ewa; Wawrzycka, Donata; Wysocki, Robert

2012-01-01

Arsenic and antimony are toxic metalloids, naturally present in the environment and all organisms have developed pathways for their detoxification. The most effective metalloid tolerance systems in eukaryotes include downregulation of metalloid uptake, efflux out of the cell, and complexation with phytochelatin or glutathione followed by sequestration into the vacuole. Understanding of arsenic and antimony transport system is of high importance due to the increasing usage of arsenic-based drugs in the treatment of certain types of cancer and diseases caused by protozoan parasites as well as for the development of bio- and phytoremediation strategies for metalloid polluted areas. However, in contrast to prokaryotes, the knowledge about specific transporters of arsenic and antimony and the mechanisms of metalloid transport in eukaryotes has been very limited for a long time. Here, we review the recent advances in understanding of arsenic and antimony transport pathways in eukaryotes, including a dual role of aquaglyceroporins in uptake and efflux of metalloids, elucidation of arsenic transport mechanism by the yeast Acr3 transporter and its role in arsenic hyperaccumulation in ferns, identification of vacuolar transporters of arsenic-phytochelatin complexes in plants and forms of arsenic substrates recognized by mammalian ABC transporters. PMID:22489166

Arsenic efflux from Microcystis aeruginosa under different phosphate regimes.

Directory of Open Access Journals (Sweden)

Changzhou Yan

Full Text Available Phytoplankton plays an important role in arsenic speciation, distribution, and cycling in freshwater environments. Little information, however, is available on arsenic efflux from the cyanobacteria Microcystis aeruginosa under different phosphate regimes. This study investigated M. aeruginosa arsenic efflux and speciation by pre-exposing it to 10 µM arsenate or arsenite for 24 h during limited (12 h and extended (13 d depuration periods under phosphate enriched (+P and phosphate depleted (-P treatments. Arsenate was the predominant species detected in algal cells throughout the depuration period while arsenite only accounted for no greater than 45% of intracellular arsenic. During the limited depuration period, arsenic efflux occurred rapidly and only arsenate was detected in solutions. During the extended depuration period, however, arsenate and dimethylarsinic acid (DMA were found to be the two predominant arsenic species detected in solutions under -P treatments, but arsenate was the only species detected under +P treatments. Experimental results also suggest that phosphorus has a significant effect in accelerating arsenic efflux and promoting arsenite bio-oxidation in M. aeruginosa. Furthermore, phosphorus depletion can reduce arsenic efflux from algal cells as well as accelerate arsenic reduction and methylation. These findings can contribute to our understanding of arsenic biogeochemistry in aquatic environments and its potential environmental risks under different phosphorus levels.

Vorinostat enhances chemosensitivity to arsenic trioxide in K562 cell line

Directory of Open Access Journals (Sweden)

Nainong Li

2015-05-01

Full Text Available Objective. This study aimed to investigate the chemosensitive augmentation effect and mechanism of HDAC inhibitor Vorinostat (SAHA in combination with arsenic trioxide (ATO on proliferation and apoptosis of K562 cells.Methods. The CCK-8 assay was used to compare proliferation of the cells. Annexin-V and PI staining by flow cytometry and acridine orange/ethidium bromide stains were used to detect and quantify apoptosis. Western blot was used to detect expression of p21, Akt, pAkt, p210, Acetyl-Histone H3, and Acetyl-Histone H4 proteins.Results. SAHA and ATO inhibited proliferation of K562 cells in an additive and time- and dose-dependent manner. SAHA in combination with ATO showed significant apoptosis of K562 cells in comparison to the single drugs alone (p < 0.01. Both SAHA and ATO alone and in combination showed lower levels of p210 expression. SAHA and SAHA and ATO combined treatment showed increased levels of Acetyl-Histone H3 and Acetyl-Histone H4 protein expression. SAHA alone showed increased expression of p21, while ATO alone and in combination with SAHA showed no significant change. SAHA and ATO combined therapy showed lower levels of Akt and pAkt protein expression than SAHA or ATO alone.Conclusion. SAHA and ATO combined treatment inhibited proliferation, induced apoptosis, and showed a chemosensitive augmentation effect on K562 cells. The mechanism might be associated with increasing histone acetylation levels as well as regulating the Akt signaling pathway.

Evaluation of genetic damage in tobacco and arsenic exposed population of Southern Assam, India using buccal cytome assay and comet assay.

Science.gov (United States)

Roy, Prasenjit; Mukherjee, Anita; Giri, Sarbani

2016-02-01

Ground water is the principal source of drinking water in Assam. Ground water contamination of arsenic in drinking water is a great concern for human health and considered as a human carcinogen. The present cytogenetic biomonitoring study was undertaken to investigate the genotoxic effects associated with people of southern Assam consuming arsenic contaminated water and chewing tobacco. Employing the buccal cytome assay, exfoliated cells were analyzed in 138 individuals of age range 22-42 years and divided into four groups. Group I (n=54) are participants residing in localities where ground water contains arsenic concentration below the permissible limit (comet assay, percent of tail DNA gradually increases among the groups and has statistical significance. Spearman correlation revealed strong positive correlation between the arsenic exposed peoples and the binucleated cells (r=0.4763; Pcomet assay. Copyright © 2015 Elsevier Inc. All rights reserved.

Significantly increased risk of carotid atherosclerosis with arsenic exposure and polymorphisms in arsenic metabolism genes

International Nuclear Information System (INIS)

Hsieh, Yi-Chen; Lien, Li-Ming; Chung, Wen-Ting; Hsieh, Fang-I; Hsieh, Pei-Fan; Wu, Meei-Maan; Tseng, Hung-Pin; Chiou, Hung-Yi; Chen, Chien-Jen

2011-01-01

Individual susceptibility to arsenic-induced carotid atherosclerosis might be associated with genetic variations in arsenic metabolism. The purpose of this study is to explore the interaction effect on risk of carotid atherosclerosis between arsenic exposure and risk genotypes of purine nucleoside phosphorylase (PNP), arsenic (+3) methyltransferase (As3MT), and glutathione S-transferase omega 1 (GSTO1) and omega 2 (GSTO2). A community-based case-control study was conducted in northeastern Taiwan to investigate the arsenic metabolic-related genetic susceptibility to carotid atherosclerosis. In total, 863 subjects, who had been genotyped and for whom the severity of carotid atherosclerosis had been determined, were included in the present study. Individual well water was collected and arsenic concentration determined using hydride generation combined with flame atomic absorption spectrometry. The result showed that a significant dose-response trend (P=0.04) of carotid atherosclerosis risk associated with increasing arsenic concentration. Non-significant association between genetic polymorphisms of PNP Gly51Ser, Pro57Pro, As3MT Met287Thr, GSTO1 Ala140Asp, and GSTO2 A-183G and the risk for development of carotid atherosclerosis were observed. However, the significant interaction effect on carotid atherosclerosis risk was found for arsenic exposure (>50 μg/l) and the haplotypes of PNP (p=0.0115). A marked elevated risk of carotid atherosclerosis was observed in subjects with arsenic exposure of >50 μg/l in drinking water and those who carried the PNP A-T haplotype and at least either of the As3MT risk polymorphism or GSTO risk haplotypes (OR, 6.43; 95% CI, 1.79-23.19). In conclusion, arsenic metabolic genes, PNP, As3MT, and GSTO, may exacerbate the formation of atherosclerosis in individuals with high levels of arsenic concentration in well water (>50 μg/l). - Highlights: →Arsenic metabolic genes might be associated with carotid atherosclerosis. → A case

Significantly increased risk of carotid atherosclerosis with arsenic exposure and polymorphisms in arsenic metabolism genes

Energy Technology Data Exchange (ETDEWEB)

Hsieh, Yi-Chen [School of Public Health, College of Public Health and Nutrition, Taipei Medical University, 250 Wusing St., Taipei 11031, Taiwan (China); Lien, Li-Ming [Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan (China); School of Medicine, Taipei Medical University, Taipei, Taiwan (China); Department of Neurology, Shin Kong WHS Memorial Hospital, Taipei, Taiwan (China); Chung, Wen-Ting [Department of Neurology, Wanfang Hospital, Taipei Medical University, Taipei, Taiwan (China); Graduate Institute of Clinical Medicine, Taipei Medical University, Taipei, Taiwan (China); Hsieh, Fang-I; Hsieh, Pei-Fan [School of Public Health, College of Public Health and Nutrition, Taipei Medical University, 250 Wusing St., Taipei 11031, Taiwan (China); Wu, Meei-Maan [School of Public Health, College of Public Health and Nutrition, Taipei Medical University, 250 Wusing St., Taipei 11031, Taiwan (China); Graduate Institute of Basic Medicine, College of Medicine, Fu-Jen Catholic University, Taipei, Taiwan (China); Tseng, Hung-Pin [Department of Neurology, Lotung Poh-Ai Hospital, I-Lan, Taiwan (China); Chiou, Hung-Yi, E-mail: hychiou@tmu.edu.tw [School of Public Health, College of Public Health and Nutrition, Taipei Medical University, 250 Wusing St., Taipei 11031, Taiwan (China); Chen, Chien-Jen [Genomics Research Center, Academia Sinica, Taipei, Taiwan (China)

2011-08-15

Individual susceptibility to arsenic-induced carotid atherosclerosis might be associated with genetic variations in arsenic metabolism. The purpose of this study is to explore the interaction effect on risk of carotid atherosclerosis between arsenic exposure and risk genotypes of purine nucleoside phosphorylase (PNP), arsenic (+3) methyltransferase (As3MT), and glutathione S-transferase omega 1 (GSTO1) and omega 2 (GSTO2). A community-based case-control study was conducted in northeastern Taiwan to investigate the arsenic metabolic-related genetic susceptibility to carotid atherosclerosis. In total, 863 subjects, who had been genotyped and for whom the severity of carotid atherosclerosis had been determined, were included in the present study. Individual well water was collected and arsenic concentration determined using hydride generation combined with flame atomic absorption spectrometry. The result showed that a significant dose-response trend (P=0.04) of carotid atherosclerosis risk associated with increasing arsenic concentration. Non-significant association between genetic polymorphisms of PNP Gly51Ser, Pro57Pro, As3MT Met287Thr, GSTO1 Ala140Asp, and GSTO2 A-183G and the risk for development of carotid atherosclerosis were observed. However, the significant interaction effect on carotid atherosclerosis risk was found for arsenic exposure (>50 {mu}g/l) and the haplotypes of PNP (p=0.0115). A marked elevated risk of carotid atherosclerosis was observed in subjects with arsenic exposure of >50 {mu}g/l in drinking water and those who carried the PNP A-T haplotype and at least either of the As3MT risk polymorphism or GSTO risk haplotypes (OR, 6.43; 95% CI, 1.79-23.19). In conclusion, arsenic metabolic genes, PNP, As3MT, and GSTO, may exacerbate the formation of atherosclerosis in individuals with high levels of arsenic concentration in well water (>50 {mu}g/l). - Highlights: {yields}Arsenic metabolic genes might be associated with carotid atherosclerosis. {yields

Protective Effects of Combined Selenium and Punica granatum Treatment on Some Inflammatory and Oxidative Stress Markers in Arsenic-Induced Hepatotoxicity in Rats.

Science.gov (United States)

Shafik, Noha M; El Batsh, Maha M

2016-01-01

Oxidative stress is one of the major mechanisms implicated in inorganic arsenic poisoning. Punica granatum is known by its free radical scavenging properties. The aim of this study was to evaluate the protective role of combined selenium and P. granatum against arsenic-induced liver injury. Seventy-five female albino rats were divided into five groups (of 15 rats each). Toxicity was induced by oral sodium arsenite (5.5 mg/kg body weight (bw) daily) (group ІІ). Treatment of arsenic-intoxicated rats was induced by daily oral administration of sodium selenite (3 mg/kg bw) (group ІІІ), 100 mg of P. granatum ethanol extract per kilogram body weight dissolved in 300 mL distilled water in three divided doses (100 mL of this suspension every 8 h) (group IV), and combined daily oral treatment with both selenite and P. granatum ethanol extract (group V). After 3 weeks, serum and liver tissues were obtained from the decapitated rats for different estimations. Hepatotoxicity was demonstrated by significant elevation in liver weights and activities of liver enzymes, alanine aminotransferase (ALT) and aspartate aminotransferase (AST), and decrease in serum total proteins and albumin (p granatum and selenium. It was concluded that combined P. granatum and selenium treatment had a synergistic hepatoprotective effect against arsenic toxicity through activation of Nrf2 anti-oxidant pathway.

Evidence against the nuclear in situ binding of arsenicals-oxidative stress theory of arsenic carcinogenesis

International Nuclear Information System (INIS)

Kitchin, Kirk T.; Wallace, Kathleen

2008-01-01

A large amount of evidence suggests that arsenicals act via oxidative stress in causing cancer in humans and experimental animals. It is possible that arsenicals could bind in situ close to nuclear DNA followed by Haber-Weiss type oxidative DNA damage. Therefore, we tested this hypothesis by using radioactive 73 As labeled arsenite and vacuum filtration methodology to determine the binding affinity and capacity of 73 As arsenite to calf thymus DNA and Type 2A unfractionated histones, histone H3, H4 and horse spleen ferritin. Arsenicals are known to release redox active Fe from ferritin. At concentrations up to about 1 mM, neither DNA nor any of the three proteins studied, Type II-A histones, histone H3, H4 or ferritin, bound radioactive arsenite in a specific manner. Therefore, it appears highly unlikely that initial in situ binding of trivalent arsenicals, followed by in situ oxidative DNA damage, can account for arsenic's carcinogenicity. This experimental evidence (lack of arsenite binding to DNA, histone Type II-A and histone H3, H4) does not rule out other possible oxidative stress modes of action for arsenic such as (a) diffusion of longer lived oxidative stress molecules, such as H 2 O 2 into the nucleus and ensuing oxidative damage, (b) redox chemistry by unbound arsenicals in the nucleus, or (c) arsenical-induced perturbations in Fe, Cu or other metals which are already known to oxidize DNA in vitro and in vivo

Arsenic pollution of groundwater in Vietnam exacerbated by deep aquifer exploitation for more than a century

Science.gov (United States)

Winkel, Lenny H. E.; Trang, Pham Thi Kim; Lan, Vi Mai; Stengel, Caroline; Amini, Manouchehr; Ha, Nguyen Thi; Viet, Pham Hung; Berg, Michael

2011-01-01

Arsenic contamination of shallow groundwater is among the biggest health threats in the developing world. Targeting uncontaminated deep aquifers is a popular mitigation option although its long-term impact remains unknown. Here we present the alarming results of a large-scale groundwater survey covering the entire Red River Delta and a unique probability model based on three-dimensional Quaternary geology. Our unprecedented dataset reveals that ∼7 million delta inhabitants use groundwater contaminated with toxic elements, including manganese, selenium, and barium. Depth-resolved probabilities and arsenic concentrations indicate drawdown of arsenic-enriched waters from Holocene aquifers to naturally uncontaminated Pleistocene aquifers as a result of > 100 years of groundwater abstraction. Vertical arsenic migration induced by large-scale pumping from deep aquifers has been discussed to occur elsewhere, but has never been shown to occur at the scale seen here. The present situation in the Red River Delta is a warning for other As-affected regions where groundwater is extensively pumped from uncontaminated aquifers underlying high arsenic aquifers or zones. PMID:21245347

Experimental study on effect of arsenic trioxide on vascular smooth muscle cells

International Nuclear Information System (INIS)

Lu Qin; An Yanli; Niu Huanzhang; Teng Gaojun; Wang Zihao; Zhang Dongsheng; Fang Juanjuan

2007-01-01

Objective: To investigate the effect of arsenic trioxide (As 2 O 3 ) nanoparticles on rabbit vascular smooth muscle cells in vitro in comparison with normal form As 2 O 3 . Methods: The rabbit vascular smooth muscle cells were cultured in vitro. Nano and normal forms of As 2 O 3 with drug concentrations of 3 μmol/L were added into the cells. Cell proliferation curve was drawn according to the light absorption values of MTT test. Flow cytometry was applied to observe the apoptosis. DNA was extracted and underwent electrophoresis. Results: Cell proliferation treated with the 3 μmol/L concentration of As 2 O 3 was inhibited. Cell growth was inhibited markedly with increased treatment time, and the inhibition effect of nano drug form seemed stronger than that of normal form. MTT light absorption values of cells treated at 24, 48 and 72 h showed statistically significant difference (H=10.934, 15.039, 15.539, P 2 O 3 , normal drug form of As 2 O 3 and control group of cells without As 2 O 3 were 44.97%, 58.54%, 74.02% respectively. The early apoptosis rates were 16.89%, 11.27%, 11.20%, late apoptosis rates were 26.56%, 23.60%, 12.46%, and necrosis rates were 11.58%, 6.59%, 2.32% respectively. Agarose gel electrophoresis showed 'ladder' strand of DNA, with more strands and obscurity for nano drug form treated cells. Conclusion: Arsenic trioxide may inhibit the growth of rabbit vascular smooth muscle cells. The nano drug form showed stronger inhibition effect than that of the normal drug form. (authors)

Transient light-induced intracellular oxidation revealed by redox biosensor

Energy Technology Data Exchange (ETDEWEB)

Kolossov, Vladimir L., E-mail: viadimer@illinois.edu [Institute for Genomic Biology, University of Illinois at Urbana-Champaign, 1206 W. Gregory Drive, Urbana, IL 61801 (United States); Beaudoin, Jessica N. [Institute for Genomic Biology, University of Illinois at Urbana-Champaign, 1206 W. Gregory Drive, Urbana, IL 61801 (United States); Department of Animal Sciences, University of Illinois at Urbana-Champaign, 1207 W. Gregory Drive, Urbana, IL 61801 (United States); Hanafin, William P. [Institute for Genomic Biology, University of Illinois at Urbana-Champaign, 1206 W. Gregory Drive, Urbana, IL 61801 (United States); DiLiberto, Stephen J. [Institute for Genomic Biology, University of Illinois at Urbana-Champaign, 1206 W. Gregory Drive, Urbana, IL 61801 (United States); Department of Animal Sciences, University of Illinois at Urbana-Champaign, 1207 W. Gregory Drive, Urbana, IL 61801 (United States); Kenis, Paul J.A. [Institute for Genomic Biology, University of Illinois at Urbana-Champaign, 1206 W. Gregory Drive, Urbana, IL 61801 (United States); Department of Chemical and Biomolecular Engineering, University of Illinois at Urbana-Champaign, 600 S. Mathews Avenue, Urbana, IL 61801 (United States); Rex Gaskins, H. [Institute for Genomic Biology, University of Illinois at Urbana-Champaign, 1206 W. Gregory Drive, Urbana, IL 61801 (United States); Department of Animal Sciences, University of Illinois at Urbana-Champaign, 1207 W. Gregory Drive, Urbana, IL 61801 (United States); Department of Pathobiology, University of Illinois at Urbana-Champaign, 2001 S. Lincoln Avenue, Urbana, IL 61801 (United States); Division of Nutritional Sciences, University of Illinois at Urbana-Champaign, 905 S. Goodwin Avenue, Urbana, IL 61801 (United States)

2013-10-04

Highlights: •Time-resolved live cell imaging revealed light-induced oxidation. •Only the roGFP probe fused with glutaredoxin reveals photooxidation. •The transient oxidation is rapidly reduced by the cytosolic antioxidant system. •Intracellular photooxidation is media-dependent. •Oxidation is triggered exclusively by exposure to short wavelength excitation. -- Abstract: We have implemented a ratiometric, genetically encoded redox-sensitive green fluorescent protein fused to human glutaredoxin (Grx1-roGFP2) to monitor real time intracellular glutathione redox potentials of mammalian cells. This probe enabled detection of media-dependent oxidation of the cytosol triggered by short wavelength excitation. The transient nature of light-induced oxidation was revealed by time-lapse live cell imaging when time intervals of less than 30 s were implemented. In contrast, transient ROS generation was not observed with the parental roGFP2 probe without Grx1, which exhibits slower thiol-disulfide exchange. These data demonstrate that the enhanced sensitivity of the Grx1-roGFP2 fusion protein enables the detection of short-lived ROS in living cells. The superior sensitivity of Grx1-roGFP2, however, also enhances responsiveness to environmental cues introducing a greater likelihood of false positive results during image acquisition.

Transient light-induced intracellular oxidation revealed by redox biosensor

International Nuclear Information System (INIS)

Kolossov, Vladimir L.; Beaudoin, Jessica N.; Hanafin, William P.; DiLiberto, Stephen J.; Kenis, Paul J.A.; Rex Gaskins, H.

2013-01-01

Highlights: •Time-resolved live cell imaging revealed light-induced oxidation. •Only the roGFP probe fused with glutaredoxin reveals photooxidation. •The transient oxidation is rapidly reduced by the cytosolic antioxidant system. •Intracellular photooxidation is media-dependent. •Oxidation is triggered exclusively by exposure to short wavelength excitation. -- Abstract: We have implemented a ratiometric, genetically encoded redox-sensitive green fluorescent protein fused to human glutaredoxin (Grx1-roGFP2) to monitor real time intracellular glutathione redox potentials of mammalian cells. This probe enabled detection of media-dependent oxidation of the cytosol triggered by short wavelength excitation. The transient nature of light-induced oxidation was revealed by time-lapse live cell imaging when time intervals of less than 30 s were implemented. In contrast, transient ROS generation was not observed with the parental roGFP2 probe without Grx1, which exhibits slower thiol-disulfide exchange. These data demonstrate that the enhanced sensitivity of the Grx1-roGFP2 fusion protein enables the detection of short-lived ROS in living cells. The superior sensitivity of Grx1-roGFP2, however, also enhances responsiveness to environmental cues introducing a greater likelihood of false positive results during image acquisition

Mouse arsenic (+3 oxidation state) methyltransferase genotype affects metabolism and tissue dosimetry of arsenicals after arsenite administration in drinking water.

Science.gov (United States)

Chen, Baowei; Arnold, Lora L; Cohen, Samuel M; Thomas, David J; Le, X Chris

2011-12-01

Arsenic (+3 oxidation state) methyltransferase (As3mt) catalyzes methylation of inorganic arsenic (iAs) producing a number of methylated arsenic metabolites. Although methylation has been commonly considered a pathway for detoxification of arsenic, some highly reactive methylated arsenicals may contribute to toxicity associated with exposure to inorganic arsenic. Here, adult female wild-type (WT) C57BL/6 mice and female As3mt knockout (KO) mice received drinking water that contained 1, 10, or 25 ppm (mg/l) of arsenite for 33 days and blood, liver, kidney, and lung were taken for arsenic speciation. Genotype markedly affected concentrations of arsenicals in tissues. Summed concentrations of arsenicals in plasma were higher in WT than in KO mice; in red blood cells, summed concentrations of arsenicals were higher in KO than in WT mice. In liver, kidney, and lung, summed concentrations of arsenicals were greater in KO than in WT mice. Although capacity for arsenic methylation is much reduced in KO mice, some mono-, di-, and tri-methylated arsenicals were found in tissues of KO mice, likely reflecting the activity of other tissue methyltransferases or preabsorptive metabolism by the microbiota of the gastrointestinal tract. These results show that the genotype for arsenic methylation determines the phenotypes of arsenic retention and distribution and affects the dose- and organ-dependent toxicity associated with exposure to inorganic arsenic.

Arsenic trioxide (AT) is a novel human neutrophil pro-apoptotic agent: effects of catalase on AT-induced apoptosis, degradation of cytoskeletal proteins and de novo protein synthesis.

Science.gov (United States)

Binet, François; Cavalli, Hélène; Moisan, Eliane; Girard, Denis

2006-02-01

The anti-cancer drug arsenic trioxide (AT) induces apoptosis in a variety of transformed or proliferating cells. However, little is known regarding its ability to induce apoptosis in terminally differentiated cells, such as neutrophils. Because neutropenia has been reported in some cancer patients after AT treatment, we hypothesised that AT could induce neutrophil apoptosis, an issue that has never been investigated. Herein, we found that AT-induced neutrophil apoptosis and gelsolin degradation via caspases. AT did not increase neutrophil superoxide production and did not induce mitochondrial generation of reactive oxygen species. AT-induced apoptosis in PLB-985 and X-linked chronic granulomatous disease (CGD) cells (PLB-985 cells deficient in gp91(phox) mimicking CGD) at the same potency. Addition of catalase, an inhibitor of H2O2, reversed AT-induced apoptosis and degradation of the cytoskeletal proteins gelsolin, alpha-tubulin and lamin B1. Unexpectedly, AT-induced de novo protein synthesis, which was reversed by catalase. Cycloheximide partially reversed AT-induced apoptosis. We conclude that AT induces neutrophil apoptosis by a caspase-dependent mechanism and via de novo protein synthesis. H2O2 is of major importance in AT-induced neutrophil apoptosis but its production does not originate from nicotinamide adenine dinucleotide phosphate dehydrogenase activation and mitochondria. Cytoskeletal structures other than microtubules can now be considered as novel targets of AT.

Inorganic arsenic levels in baby rice are of concern

International Nuclear Information System (INIS)

Meharg, Andrew A.; Sun, Guoxin; Williams, Paul N.; Adomako, Eureka; Deacon, Claire; Zhu, Yong-Guan; Feldmann, Joerg; Raab, Andrea

2008-01-01

Inorganic arsenic is a chronic exposure carcinogen. Analysis of UK baby rice revealed a median inorganic arsenic content (n = 17) of 0.11 mg/kg. By plotting inorganic arsenic against total arsenic, it was found that inorganic concentrations increased linearly up to 0.25 mg/kg total arsenic, then plateaued at 0.16 mg/kg at higher total arsenic concentrations. Inorganic arsenic intake by babies (4-12 months) was considered with respect to current dietary ingestion regulations. It was found that 35% of the baby rice samples analysed would be illegal for sale in China which has regulatory limit of 0.15 mg/kg inorganic arsenic. EU and US food regulations on arsenic are non-existent. When baby inorganic arsenic intake from rice was considered, median consumption (expressed as μg/kg/d) was higher than drinking water maximum exposures predicted for adults in these regions when water intake was expressed on a bodyweight basis. - Median consumption of organic arsenic levels for UK babies from baby rice is above threshold considered safe

Correlation of Breastmilk Arsenic With Maternal, Infant Urinary Arsenic and Drinking Water Arsenic in an Arsenic Affected Area of Bangladesh

Science.gov (United States)

Alauddin, M.; Islam, M. R.; Milton, A. H.; Alauddin, S. T.; Mouly, T.; Behri, E.; Ayesha, A.; Akter, S.; Islam, M. M.

2016-12-01

About 97% of population in Bangladesh depend on groundwater as the principle source of drinking water and this water is highly contaminated with inorganic arsenic. Consumption of arsenic contaminated drinking water by pregnant women raises the prospect of early life exposure to inorganic arsenic for newborn which may be lead to adverse health effect in later life. This work was carried out in parts of Gopalganj district in Bangladesh, a region affected by arsenic contamination in groundwater. The objective of the work was to assess potential early life exposure to arsenic for infants through breastfeeding by mothers who were drinking water with arsenic levels ranging from 100 to 300 µg/l. A cohort of 30 mother-baby pairs were selected for the current study. Breastmilk samples from mothers, urine samples from each pair of subjects at 1, 6 and 9 month age of infant were collected and total arsenic were determined in these samples. In addition speciation of urinary arsenic and metabolites were carried out in 12 mother-baby pairs. Median level for breastmilk arsenic were 0.50 µg/l. Urinary arsenic of infants did not correlate with breastmilk arsenic with progressing age of infants. Maternal and infant urinary total arsenic at 1 month age of infant showed some positive correlation (r = 0.39). In infant urine major metabolite were dimethyl arsenic acid (DMA) (approximately 70%) indicating good methylating capacity for infants at 1 and 6 months of age. In conclusion, infants were not exposed to arsenic through breastfeeding even though mothers were exposed to significant levels of arsenic through drinking water.

Protective Effect of Psidium guajava in Arsenic-induced Oxidative Stress and Cytological Damage in Rats

Science.gov (United States)

Tandon, Neeraj; Roy, Manju; Roy, Sushovan; Gupta, Neelu

2012-01-01

This study was undertaken to evaluate the protective effect of aqueous extract of Psidium guajava leaves against sodium arsenite-induced toxicity in experimental rats. Animals were divided into four groups. Control group received arsenic free distilled water and three treatment groups (II, III, and IV) exposed to the arsenic (NaAsO2) (20 mg/kg b.wt) through drinking water. Group III and IV were administered a daily oral dose of P. guajava leaf extract 50 and 100 mg/kg b.wt. (AEPG50 and AEPG100) for the period of 6 weeks. Blood samples and organs were collected at the end of the experiment. Arsenic exposure resulted in significant rise in lipid peroxidation (LPO) levels in erythrocyte, liver, kidney, and brain. In addition toxin decreased (Pguajava) @100 mg/kg body weight) significantly restored activities of oxidative stress markers like LPO levels, GSH levels, SOD, and CAT activities but having the limited protective activity of the herbal extract was observed on tissues architecture. It is therefore concluded that prophylactic co-administration of AEPG could provide specific protection from oxidative injury and to some extent on tissue damage. PMID:23293461

[Study of relationship between arsenic methylation and skin lesion in a population with long-term high arsenic exposure].

Science.gov (United States)

Su, Liqin; Cheng, Yibin; Lin, Shaobin; Wu, Chuanye

2007-05-01

To investigate the difference of arsenic metabolism in populations with long-term high arsenic exposure and explore the relationship between arsenic metabolism diversity and skin lesion. 327 residents in an arsenic polluted village were voluntarily enrolled in this study. Questionnaire survey and medical examination were carried out to learn basic information and detect skin lesions. Urinary inorganic and methylated arsenic were speciated by high performance liquid chromatography combined with hydride-generation atomic fluorescence spectrometry. Total arsenic concentration in hair was determined with DDC-Ag method. Hair arsenic content of studied polutions was generally high, but no significant difference were found among the studied four groups. MMA and DMA concentration in urine increased with studied polution age, and were positively related with skin lesion grade. The relative proportion of MMA in serious skin lesion group was significantly higher than in other 3 groups, while DMA/MMA ratio was significantly lower than control and mild group. The relative proportion of MMA was positively related with skin lesion grade, DMA/ MMA ratio was negatively related with skin lesion grade. Males could have higher arsenic cumulation and lower methylation capacity than those of females. The population of above 40 years old may have higher methylation capacity than those of adults below 40yeas old. Smokers and drinkers seemed lower methylation capacity than those of non-smokers and non-drinkers respectively. The methylation of arsenic could affect by several factors, including age gender, smoking and drinking. Arsenic methylation copacity mey be associated with skin lesion induced by arsenic exposure.

Enhanced suppression of tumor growth by concomitant treatment of human lung cancer cells with suberoylanilide hydroxamic acid and arsenic trioxide

International Nuclear Information System (INIS)

Chien, Chia-Wen; Yao, Ju-Hsien; Chang, Shih-Yu; Lee, Pei-Chih; Lee, Te-Chang

2011-01-01

The efficacy of arsenic trioxide (ATO) against acute promyelocytic leukemia (APL) and relapsed APL has been well documented. ATO may cause DNA damage by generating reactive oxygen intermediates. Suberoylanilide hydroxamic acid (SAHA), a histone deacetylase inhibitor, modulates gene and protein expression via histone-dependent or -independent pathways that may result in chromatin decondensation, cell cycle arrest, differentiation, and apoptosis. We investigated whether ATO and SAHA act synergistically to enhance the death of cancer cells. Our current findings showed that combined treatment with ATO and SAHA resulted in enhanced suppression of non-small-cell lung carcinoma in vitro in H1299 cells and in vivo in a xenograft mouse model. Flow cytometric analysis of annexin V+ cells showed that apoptotic cell death was significantly enhanced after combined treatment with ATO and SAHA. At the doses used, ATO did not interfere with cell cycle progression, but SAHA induced p21 expression and led to G1 arrest. A Comet assay demonstrated that ATO, but not SAHA, induced DNA strand breaks in H1299 cells; however, co-treatment with SAHA significantly increased ATO-induced DNA damage. Moreover, SAHA enhanced acetylation of histone H3 and sensitized genomic DNA to DNase I digestion. Our results suggest that SAHA may cause chromatin relaxation and increase cellular susceptibility to ATO-induced DNA damage. Combined administration of SAHA and ATO may be an effective approach to the treatment of lung cancer. -- Highlights: ► ATO and SAHA are therapeutic agents with different action modes. ► Combination of ATO and SAHA synergistically inhibits tumor cell growth. ► SAHA loosens chromatin structure resulting in increased sensitivity to DNase I. ► ATO-induced DNA damage and apoptosis are enhanced by co-treatment with SAHA.

Changes in serum thioredoxin among individuals chronically exposed to arsenic in drinking water

Energy Technology Data Exchange (ETDEWEB)

Li, Yuanyuan; Gao, Yanhui; Zhao, Lijun [Center for Endemic Disease Control, Chinese Center for Disease Control and Prevention, Harbin Medical University, Key Lab of Etiology and Epidemiology, Education Bureau of Hei Long Jiang Province and Ministry of Health (23618104), Harbin 150081 (China); Wei, Yudan [Department of Community Medicine, Mercer University School of Medicine, Macon 31207, GA (United States); Feng, Hongqi; Wang, Cheng; Wei, Wei; Ding, Yunpeng [Center for Endemic Disease Control, Chinese Center for Disease Control and Prevention, Harbin Medical University, Key Lab of Etiology and Epidemiology, Education Bureau of Hei Long Jiang Province and Ministry of Health (23618104), Harbin 150081 (China); Sun, Dianjun, E-mail: hrbmusdj@163.com [Center for Endemic Disease Control, Chinese Center for Disease Control and Prevention, Harbin Medical University, Key Lab of Etiology and Epidemiology, Education Bureau of Hei Long Jiang Province and Ministry of Health (23618104), Harbin 150081 (China)

2012-02-15

It is well known that oxidative damage plays a key role in the development of chronic arsenicosis. There is a complex set of mechanisms of redox cycling in vivo to protect cells from the damage. In this study, we examined the differences in the levels of serum thioredoxin1 (TRX1) among individuals exposed to different levels of arsenic in drinking water and detected early biomarkers of arsenic poisoning before the appearance of skin lesions. A total of 157 subjects from endemic regions of China were selected and divided into arsenicosis group with skin lesions (total intake of arsenic: 8.68–45.71 mg-year) and non-arsenicosis group without skin lesions, which further divided into low (0.00–1.06 mg-year), medium (1.37–3.55 mg-year), and high (4.26–48.13 mg-year) arsenic exposure groups. Concentrations of serum TRX1 were analyzed by an ELISA method. Levels of water arsenic and urinary speciated arsenics, including inorganic arsenic (iAs), monomethylated arsenic (MMA), and dimethylated arsenic (DMA), were determined by hydride generation atomic absorption spectrometry. Our results showed that the levels of serum TRX1 in arsenicosis patients were significantly higher than that of the subjects who were chronically exposed to arsenic, but without skin lesions. A positive correlation was seen between the levels of serum TRX1 and the total water arsenic intake or the levels of urinary arsenic species. The results of this study indicate that arsenic exposure could significantly change the levels of human serum TRX1, which can be detected before arsenic-specific dermatological symptoms occur. This study provides further evidence on revealing the mechanism of arsenic toxicity. -- Highlights: ► Three regions are selected as the areas affected by endemic arsenicosis of China. ► We first examine changes in serum TRX1 among individuals exposed to arsenic. ► A positive correlation was seen between serum TRX1 and total water arsenic intake. ► The same relationship

Changes in serum thioredoxin among individuals chronically exposed to arsenic in drinking water

International Nuclear Information System (INIS)

Li, Yuanyuan; Gao, Yanhui; Zhao, Lijun; Wei, Yudan; Feng, Hongqi; Wang, Cheng; Wei, Wei; Ding, Yunpeng; Sun, Dianjun

2012-01-01

It is well known that oxidative damage plays a key role in the development of chronic arsenicosis. There is a complex set of mechanisms of redox cycling in vivo to protect cells from the damage. In this study, we examined the differences in the levels of serum thioredoxin1 (TRX1) among individuals exposed to different levels of arsenic in drinking water and detected early biomarkers of arsenic poisoning before the appearance of skin lesions. A total of 157 subjects from endemic regions of China were selected and divided into arsenicosis group with skin lesions (total intake of arsenic: 8.68–45.71 mg-year) and non-arsenicosis group without skin lesions, which further divided into low (0.00–1.06 mg-year), medium (1.37–3.55 mg-year), and high (4.26–48.13 mg-year) arsenic exposure groups. Concentrations of serum TRX1 were analyzed by an ELISA method. Levels of water arsenic and urinary speciated arsenics, including inorganic arsenic (iAs), monomethylated arsenic (MMA), and dimethylated arsenic (DMA), were determined by hydride generation atomic absorption spectrometry. Our results showed that the levels of serum TRX1 in arsenicosis patients were significantly higher than that of the subjects who were chronically exposed to arsenic, but without skin lesions. A positive correlation was seen between the levels of serum TRX1 and the total water arsenic intake or the levels of urinary arsenic species. The results of this study indicate that arsenic exposure could significantly change the levels of human serum TRX1, which can be detected before arsenic-specific dermatological symptoms occur. This study provides further evidence on revealing the mechanism of arsenic toxicity. -- Highlights: ► Three regions are selected as the areas affected by endemic arsenicosis of China. ► We first examine changes in serum TRX1 among individuals exposed to arsenic. ► A positive correlation was seen between serum TRX1 and total water arsenic intake. ► The same relationship

Concentrations and chemical species of arsenic in human urine and hair

Energy Technology Data Exchange (ETDEWEB)

Yamato, Naohisa (St. Marianna Univ. School of Medicine, Kawasaki (Japan))

1988-05-01

Because marine products are rich in arsenic, the concentration of arsenic in the human urine varies greatly with the state of ingestion of marine products. It has been revealed that inorganic arsenic is methylated in the human body to form MAA (methylarsonic acid) and DMAA (dimethylarsinic acid). It appears therefore that the arsenic present in the human urine is a mixture of the arsenic originating from marine products and the arsenic metabolized in vivo. Recent studies have shown that inorganic arsenic and methylarsenic compounds are quite different in toxicity and effect on the living body due to their difference in chemical species. Finding the chemical species of arsenic in the urine and hair of normal subjects will therefore provide valuable basal data for the biological monitoring of arsenic exposure and for toxicological studies of arsenic.

Arsenite-induced autophagy is associated with proteotoxicity in human lymphoblastoid cells

Energy Technology Data Exchange (ETDEWEB)

Bolt, Alicia M.; Zhao, Fei; Pacheco, Samantha; Klimecki, Walter T., E-mail: klimecki@pharmacy.arizona.edu

2012-10-15

Epidemiological studies of arsenic-exposed populations have provided evidence that arsenic exposure in humans is associated with immunosuppression. Previously, we have reported that arsenite-induced toxicity is associated with the induction of autophagy in human lymphoblastoid cell lines (LCL). Autophagy is a cellular process that functions in the degradation of damaged cellular components, including protein aggregates formed by misfolded or damaged proteins. Accumulation of misfolded or damaged proteins in the endoplasmic reticulum (ER) lumen causes ER stress and activates the unfolded protein response (UPR). In an effort to investigate the mechanism of autophagy induction by arsenite in the LCL model, we examined the potential contribution of ER stress and activation of the UPR. LCL exposed to sodium arsenite for 8-days induced expression of UPR-activated genes, including CHOP and GRP78, at the RNA and the protein level. Evidence for activation of the three arms of the UPR was observed. The arsenite-induced activation of the UPR was associated with an accumulation of protein aggregates containing p62 and LC3, proteins with established roles in the sequestration and autophagic clearance of protein aggregates. Taken together, these data provide evidence that arsenite-induced autophagy is associated with the generation of ER stress, activation of the UPR, and formation of protein aggregates that may be targeted to the lysosome for degradation. -- Highlights: ► Arsenite induces endoplasmic reticulum stress and the unfolded protein response. ► Arsenite induces the formation of protein aggregates that contain p62 and LC3-II. ► Time-course data suggests that arsenite-induced autophagy precedes ER stress.

Oligofructose protects against arsenic-induced liver injury in a model of environment/obesity interaction

Energy Technology Data Exchange (ETDEWEB)

Massey, Veronica L. [Department of Pharmacology and Toxicology, University of Louisville Health Sciences Center, Louisville, KY 40292 (United States); Stocke, Kendall S. [Department of Environmental and Occupational Health Sciences, School of Public Health, University of Louisville Health Sciences Center, Louisville, KY 40292 (United States); Schmidt, Robin H.; Tan, Min [Department of Pharmacology and Toxicology, University of Louisville Health Sciences Center, Louisville, KY 40292 (United States); Ajami, Nadim [Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, TX (United States); Alkek Center for Metagenomics and Microbiome Research, Baylor College of Medicine, Houston, TX (United States); Neal, Rachel E. [Department of Environmental and Occupational Health Sciences, School of Public Health, University of Louisville Health Sciences Center, Louisville, KY 40292 (United States); Petrosino, Joseph F. [Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, TX (United States); Alkek Center for Metagenomics and Microbiome Research, Baylor College of Medicine, Houston, TX (United States); Barve, Shirish [Department of Medicine, University of Louisville Health Sciences Center, Louisville, KY 40292 (United States); Arteel, Gavin E., E-mail: gavin.arteel@louisville.edu [Department of Pharmacology and Toxicology, University of Louisville Health Sciences Center, Louisville, KY 40292 (United States)

2015-05-01

Arsenic (As) tops the ATSDR list of hazardous environmental chemicals and is known to cause liver injury. Although the concentrations of As found in the US water supply are generally too low to directly damage the liver, subhepatotoxic doses of As sensitize the liver to experimental NAFLD. It is now suspected that GI microbiome dysbiosis plays an important role in development of NALFD. Importantly, arsenic has also been shown to alter the microbiome. The purpose of the current study was to test the hypothesis that the prebiotic oligofructose (OFC) protects against enhanced liver injury caused by As in experimental NAFLD. Male C57Bl6/J mice were fed low fat diet (LFD), high fat diet (HFD), or HFD containing oligofructose (OFC) during concomitant exposure to either tap water or As-containing water (4.9 ppm as sodium arsenite) for 10 weeks. HFD significantly increased body mass and caused fatty liver injury, as characterized by an increased liver weight-to-body weight ratio, histologic changes and transaminases. As observed previously, As enhanced HFD-induced liver damage, which was characterized by enhanced inflammation. OFC supplementation protected against the enhanced liver damage caused by As in the presence of HFD. Interestingly, arsenic, HFD and OFC all caused unique changes to the gut flora. These data support previous findings that low concentrations of As enhance liver damage caused by high fat diet. Furthermore, these results indicate that these effects of arsenic may be mediated, at least in part, by GI tract dysbiosis and that prebiotic supplementation may confer significant protective effects. - Highlights: • Arsenic (As) enhances liver damage caused by a high-fat (HFD) diet in mice. • Oligofructose protects against As-enhanced liver damage caused by HFD. • As causes dysbiosis in the GI tract and exacerbates the dysbiosis caused by HFD. • OFC prevents the dysbiosis caused by HFD and As, increasing commensal bacteria.

Oligofructose protects against arsenic-induced liver injury in a model of environment/obesity interaction

International Nuclear Information System (INIS)

Massey, Veronica L.; Stocke, Kendall S.; Schmidt, Robin H.; Tan, Min; Ajami, Nadim; Neal, Rachel E.; Petrosino, Joseph F.; Barve, Shirish; Arteel, Gavin E.

2015-01-01

Arsenic (As) tops the ATSDR list of hazardous environmental chemicals and is known to cause liver injury. Although the concentrations of As found in the US water supply are generally too low to directly damage the liver, subhepatotoxic doses of As sensitize the liver to experimental NAFLD. It is now suspected that GI microbiome dysbiosis plays an important role in development of NALFD. Importantly, arsenic has also been shown to alter the microbiome. The purpose of the current study was to test the hypothesis that the prebiotic oligofructose (OFC) protects against enhanced liver injury caused by As in experimental NAFLD. Male C57Bl6/J mice were fed low fat diet (LFD), high fat diet (HFD), or HFD containing oligofructose (OFC) during concomitant exposure to either tap water or As-containing water (4.9 ppm as sodium arsenite) for 10 weeks. HFD significantly increased body mass and caused fatty liver injury, as characterized by an increased liver weight-to-body weight ratio, histologic changes and transaminases. As observed previously, As enhanced HFD-induced liver damage, which was characterized by enhanced inflammation. OFC supplementation protected against the enhanced liver damage caused by As in the presence of HFD. Interestingly, arsenic, HFD and OFC all caused unique changes to the gut flora. These data support previous findings that low concentrations of As enhance liver damage caused by high fat diet. Furthermore, these results indicate that these effects of arsenic may be mediated, at least in part, by GI tract dysbiosis and that prebiotic supplementation may confer significant protective effects. - Highlights: • Arsenic (As) enhances liver damage caused by a high-fat (HFD) diet in mice. • Oligofructose protects against As-enhanced liver damage caused by HFD. • As causes dysbiosis in the GI tract and exacerbates the dysbiosis caused by HFD. • OFC prevents the dysbiosis caused by HFD and As, increasing commensal bacteria

Catalase plays an important role in a genotoxic pathway of methylated arsenicals

Science.gov (United States)

Arsenic is a common contaminant of drinking water in many parts of the world. Consumption of arsenic-contaminated drinking water has been implicated in both cancerous and non-cancerous health conditions. However, the pathways that lead to arsenic-induced health conditions have no...

Folate deficiency enhances arsenic effects on expression of genes involved in epidermal differentiation in transgenic K6/ODC mouse skin

International Nuclear Information System (INIS)

Nelson, Gail M.; Ahlborn, Gene J.; Delker, Don A.; Kitchin, Kirk T.; O'Brien, Thomas G.; Chen Yan; Kohan, Michael J.; Roop, Barbara C.; Ward, William O.; Allen, James W.

2007-01-01

Chronic arsenic exposure in humans is associated with cancers of the skin, lung, bladder and other tissues. There is evidence that folate deficiency may increase susceptibility to arsenic effects, including skin lesions. K6/ODC mice develop skin tumors when exposed to 10 ppm sodium arsenite for 5 months. In the current study, K6/ODC mice maintained on either a folate deficient or folate sufficient diet were exposed to 0, 1, or 10 ppm sodium arsenite in the drinking water for 30 days. Total RNA was isolated from skin samples and gene expression analyzed using Affymetrix Mouse 430 2.0 GeneChips. Data from 24 samples, with 4 mice in each of the 6 treatment groups, were RMA normalized and analyzed by two-way ANOVA using GeneSpring TM . Top gene ontology (GO) categories for genes responding significantly to both arsenic treatment and folate deficiency include nucleotide metabolism and cell organization and biogenesis. For many of these genes, folate deficiency magnifies the response to arsenic treatment. In particular, expression of markers of epidermal differentiation, e.g., loricrin, small proline rich proteins and involucrin, was significantly reduced by arsenic in the folate sufficient animals, and reduced further or at a lower arsenic dose in the folate deficient animals. In addition, expression of a number of epidermal cell growth/proliferation genes and cellular movement genes was altered. These results indicate that arsenic disrupts the normal balance of cell proliferation and differentiation, and that folate deficiency exacerbates these effects, consistent with the view that folate deficiency is a nutritional susceptibility factor for arsenic-induced skin tumorigenesis

Binational Arsenic Exposure Survey: Methodology and Estimated Arsenic Intake from Drinking Water and Urinary Arsenic Concentrations

Directory of Open Access Journals (Sweden)

Robin B. Harris

2012-03-01

Full Text Available The Binational Arsenic Exposure Survey (BAsES was designed to evaluate probable arsenic exposures in selected areas of southern Arizona and northern Mexico, two regions with known elevated levels of arsenic in groundwater reserves. This paper describes the methodology of BAsES and the relationship between estimated arsenic intake from beverages and arsenic output in urine. Households from eight communities were selected for their varying groundwater arsenic concentrations in Arizona, USA and Sonora, Mexico. Adults responded to questionnaires and provided dietary information. A first morning urine void and water from all household drinking sources were collected. Associations between urinary arsenic concentration (total, organic, inorganic and estimated level of arsenic consumed from water and other beverages were evaluated through crude associations and by random effects models. Median estimated total arsenic intake from beverages among participants from Arizona communities ranged from 1.7 to 14.1 µg/day compared to 0.6 to 3.4 µg/day among those from Mexico communities. In contrast, median urinary inorganic arsenic concentrations were greatest among participants from Hermosillo, Mexico (6.2 µg/L whereas a high of 2.0 µg/L was found among participants from Ajo, Arizona. Estimated arsenic intake from drinking water was associated with urinary total arsenic concentration (p < 0.001, urinary inorganic arsenic concentration (p < 0.001, and urinary sum of species (p < 0.001. Urinary arsenic concentrations increased between 7% and 12% for each one percent increase in arsenic consumed from drinking water. Variability in arsenic intake from beverages and urinary arsenic output yielded counter intuitive results. Estimated intake of arsenic from all beverages was greatest among Arizonans yet participants in Mexico had higher urinary total and inorganic arsenic concentrations. Other contributors to urinary arsenic concentrations should be evaluated.

Nucleophosmin in the pathogenesis of arsenic-related bladder carcinogenesis revealed by quantitative proteomics

International Nuclear Information System (INIS)

Chen Shuhui; Wang Yiwen; Hsu Jueliang; Chang Hongyi; Wang Chiyun; Shen Potsun; Chiang Chiwu; Chuang Jingjing; Tsai Hungwen; Gu Powen; Chang Fangchih; Liu Hsiaosheng; Chow Nanhaw

2010-01-01

To investigate the molecular mechanisms of arsenic (As)-associated carcinogenesis, we performed proteomic analysis on E7 immortalized human uroepithelial cells after treatment with As in vitro. Quantitative proteomics was performed using stable isotope dimethyl labeling coupled with two-dimensional liquid chromatography peptide separation and mass spectrometry (MS)/MS analysis. Among 285 proteins, a total of 26 proteins were upregulated (ratio > 2.0) and 18 proteins were downregulated (ratio < 0.65) by As treatment, which are related to nucleotide binding, lipid metabolism, protein folding, protein biosynthesis, transcription, DNA repair, cell cycle control, and signal transduction. This study reports the potential significance of nucleophosmin (NPM) in the As-related bladder carcinogenesis. NPM was universally expressed in all of uroepithelial cell lines examined, implying that NPM may play a role in human bladder carcinogenesis. Upregulation of NPM tends to be dose- and time-dependent after As treatment. Expression of NPM was associated with cell proliferation, migration and anti-apoptosis. On the contrary, soy isoflavones inhibited the expression of NPM in vitro. The results suggest that NPM may play a role in the As-related bladder carcinogenesis, and soybean-based foods may have potential in the suppression of As/NPM-related tumorigenesis.

Arsenite and monomethylarsonous acid generate oxidative stress response in human bladder cell culture

International Nuclear Information System (INIS)

Eblin, K.E.; Bowen, M.E.; Cromey, D.W.; Bredfeldt, T.G.; Mash, E.A.; Lau, S.S.; Gandolfi, A.J.

2006-01-01

Arsenicals have commonly been seen to induce reactive oxygen species (ROS) which can lead to DNA damage and oxidative stress. At low levels, arsenicals still induce the formation of ROS, leading to DNA damage and protein alterations. UROtsa cells, an immortalized human urothelial cell line, were used to study the effects of arsenicals on the human bladder, a site of arsenical bioconcentration and carcinogenesis. Biotransformation of As(III) by UROtsa cells has been shown to produce methylated species, namely monomethylarsonous acid [MMA(III)], which has been shown to be 20 times more cytotoxic. Confocal fluorescence images of UROtsa cells treated with arsenicals and the ROS sensing probe, DCFDA, showed an increase of intracellular ROS within five min after 1 μM and 10 μM As(III) treatments. In contrast, 50 and 500 nM MMA(III) required pretreatment for 30 min before inducing ROS. The increase in ROS was ameliorated by preincubation with either SOD or catalase. An interesting aspect of these ROS detection studies is the noticeable difference between concentrations of As(III) and MMA(III) used, further supporting the increased cytotoxicity of MMA(III), as well as the increased amount of time required for MMA(III) to cause oxidative stress. These arsenical-induced ROS produced oxidative DNA damage as evidenced by an increase in 8-hydroxyl-2'-deoxyguanosine (8-oxo-dG) with either 50 nM or 5 μM MMA(III) exposure. These findings provide support that MMA(III) cause a genotoxic response upon generation of ROS. Both As(III) and MMA(III) were also able to induce Hsp70 and MT protein levels above control, showing that the cells recognize the ROS and respond. As(III) rapidly induces the formation of ROS, possibly through it oxidation to As(V) and further metabolism to MMA(III)/(V). These studies provide evidence for a different mechanism of MMA(III) toxicity, one that MMA(III) first interacts with cellular components before an ROS response is generated, taking longer to

Molecular processes in cellular arsenic metabolism

International Nuclear Information System (INIS)

Thomas, David J.

2007-01-01

Elucidating molecular processes that underlie accumulation, metabolism and binding of iAs and its methylated metabolites provides a basis for understanding the modes of action by which iAs acts as a toxin and a carcinogen. One approach to this problem is to construct a conceptual model that incorporates available information on molecular processes involved in the influx, metabolism, binding and efflux of arsenicals in cells. This conceptual model is initially conceived as a non-quantitative representation of critical molecular processes that can be used as a framework for experimental design and prediction. However, with refinement and incorporation of additional data, the conceptual model can be expressed in mathematical terms and should be useful for quantitative estimates of the kinetic and dynamic behavior of iAs and its methylated metabolites in cells. Development of a quantitative model will be facilitated by the availability of tools and techniques to manipulate molecular processes underlying transport of arsenicals across cell membranes or expression and activity of enzymes involved in methylation of arsenicals. This model of cellular metabolism might be integrated into more complex pharmacokinetic models for systemic metabolism of iAs and its methylated metabolites. It may also be useful in development of biologically based dose-response models describing the toxic and carcinogenic actions of arsenicals

Microtubules as a Critical Target for Arsenic Toxicity in Lung Cells in Vitro and in Vivo

Directory of Open Access Journals (Sweden)

Yinzhi Zhao

2012-02-01

Full Text Available To understand mechanisms for arsenic toxicity in the lung, we examined effects of sodium m-arsenite (As3+ on microtubule (MT assembly in vitro (0–40 µM, in cultured rat lung fibroblasts (RFL6, 0–20 µM for 24 h and in the rat animal model (intratracheal instillation of 2.02 mg As/kg body weight, once a week for 5 weeks. As3+ induced a dose-dependent disassembly of cellular MTs and enhancement of the free tubulin pool, initiating an autoregulation of tubulin synthesis manifest as inhibition of steady-state mRNA levels of βI-tubulin in dosed lung cells and tissues. Spindle MT injuries by As3+ were concomitant with chromosomal disorientations. As3+ reduced the binding to tubulin of [3H]N-ethylmaleimide (NEM, an -SH group reagent, resulting in inhibition of MT polymerization in vitro with bovine brain tubulins which was abolished by addition of dithiothreitol (DTT suggesting As3+ action upon tubulin through -SH groups. In response to As3+, cells elevated cellular thiols such as metallothionein. Taxol, a tubulin polymerization agent, antagonized both As3+ and NEM induced MT depolymerization. MT–associated proteins (MAPs essential for the MT stability were markedly suppressed in As3+-treated cells. Thus, tubulin sulfhydryls and MAPs are major molecular targets for As3+ damage to the lung triggering MT disassembly cascades.

Urinary 8-hydroxydeoxyguanosine and urothelial carcinoma risk in low arsenic exposure area

International Nuclear Information System (INIS)

Chung, C.-J.; Huang, C.-J.; Pu, Y.-S.; Su, C.-T.; Huang, Y.-K.; Chen, Y.-T.; Hsueh, Y.-M.

2008-01-01

Arsenic is a well-documented human carcinogen and is known to cause oxidative stress in cultured cells and animals. A hospital-based case-control study was conducted to evaluate the relationship among the levels of urinary 8-hydroxydeoxyguanosine (8-OHdG), the arsenic profile, and urothelial carcinoma (UC). Urinary 8-OHdG was measured by using high-sensitivity enzyme-linked immunosorbent assay (ELISA) kits. The urinary species of inorganic arsenic and their metabolites were analyzed by high-performance liquid chromatography (HPLC) and hydride generator-atomic absorption spectrometry (HG-AAS). This study showed that the mean urinary concentration of total arsenics was significantly higher, at 37.67 ± 2.98 μg/g creatinine, for UC patients than for healthy controls of 21.10 ± 0.79 μg/g creatinine (p < 0.01). Urinary 8-OHdG levels correlated with urinary total arsenic concentrations (r = 0.19, p < 0.01). There were significantly higher 8-OHdG levels, of 7.48 ± 0.97 ng/mg creatinine in UC patients, compared to healthy controls of 5.95 ± 0.21 ng/mg creatinine. Furthermore, female UC patients had higher 8-OHdG levels of 9.22 ± 0.75 than those of males at 5.76 ± 0.25 ng/mg creatinine (p < 0.01). Multiple linear regression analyses revealed that high urinary 8-OHdG levels were associated with increased total arsenic concentrations, inorganic arsenite, monomethylarsonic acid (MMA), and dimethylarsenate (DMA) as well as the primary methylation index (PMI) even after adjusting for age, gender, and UC status. The results suggest that oxidative DNA damage was associated with arsenic exposure, even at low urinary level of arsenic

Contribution of arsenic species in unicellular algae to the cycling of arsenic in marine ecosystems.

Science.gov (United States)

Duncan, Elliott G; Maher, William A; Foster, Simon D

2015-01-06

This review investigates the arsenic species produced by and found in marine unicellular algae to determine if unicellular algae contribute to the formation of arsenobetaine (AB) in higher marine organisms. A wide variety of arsenic species have been found in marine unicellular algae including inorganic species (mainly arsenate--As(V)), methylated species (mainly dimethylarsenate (DMA)), arsenoribosides (glycerol, phosphate, and sulfate) and metabolites (dimethylarsenoethanol (DMAE)). Subtle differences in arsenic species distributions exist between chlorophyte and heterokontophyte species with As(V) commonly found in water-soluble cell fractions of chlorophyte species, while DMA is more common in heterokontophyte species. Additionally, different arsenoriboside species are found in each phyla with glycerol and phosphate arsenoribosides produced by chlorophytes, whereas glycerol, phosphate, and sulfate arsenoribosides are produced by heterokontophytes, which is similar to existing data for marine macro-algae. Although arsenoribosides are the major arsenic species in many marine unicellular algal species, AB has not been detected in unicellular algae which supports the hypothesis that AB is formed in marine animals via the ingestion and further metabolism of arsenoribosides. The observation of significant DMAE concentrations in some unicellular algal cultures suggests that unicellular algae-based detritus contains arsenic species that can be further metabolized to form AB in higher marine organisms. Future research establishing how environmental variability influences the production of arsenic species by marine unicellular algae and what effect this has on arsenic cycling within marine food webs is essential to clarify the role of these organisms in marine arsenic cycling.

Chromosome analysis of arsenic affected cattle

Directory of Open Access Journals (Sweden)

S. Shekhar

2014-10-01

Full Text Available Aim: The aim was to study the chromosome analysis of arsenic affected cattle. Materials and Methods: 27 female cattle (21 arsenic affected and 6 normal were selected for cytogenetical study. The blood samples were collected, incubated, and cultured using appropriate media and specific methods. The samples were analyzed for chromosome number and morphology, relative length of the chromosome, arm ratio, and centromere index of X chromosome and chromosomal abnormalities in arsenic affected cattle to that of normal ones. Results: The diploid number of metaphase chromosomes in arsenic affected cattle as well as in normal cattle were all 2n=60, 58 being autosomes and 2 being sex chromosomes. From the centromeric position, karyotyping studies revealed that all the 29 pair of autosomes was found to be acrocentric or telocentric, and the sex chromosomes (XX were submetacentric in both normal and arsenic affected cattle. The relative length of all the autosome pairs and sex chrosomosome pair was found to be higher in normal than that of arsenic affected cattle. The mean arm ratio of X-chromosome was higher in normal than that of arsenic affected cattle, but it is reverse in case of centromere index value of X-chromosome. There was no significant difference of arm ratio and centromere index of X-chromosomes between arsenic affected and normal cattle. No chromosomal abnormalities were found in arsenic affected cattle. Conclusion: The chromosome analysis of arsenic affected cattle in West Bengal reported for the first time in this present study which may serve as a guideline for future studies in other species. These reference values will also help in comparison of cytological studies of arsenic affected cattle to that of various toxicants.

Arsenic biotransformation by a cyanobacterium Nostoc sp. PCC 7120.

Science.gov (United States)

Xue, Xi-Mei; Yan, Yu; Xiong, Chan; Raber, Georg; Francesconi, Kevin; Pan, Ting; Ye, Jun; Zhu, Yong-Guan

2017-09-01

Nostoc sp. PCC 7120 (Nostoc), a typical filamentous cyanobacterium ubiquitous in aquatic system, is recognized as a model organism to study prokaryotic cell differentiation and nitrogen fixation. In this study, Nostoc cells incubated with arsenite (As(III)) for two weeks were extracted with dichloromethane/methanol (DCM/MeOH) and the extract was partitioned between water and DCM. Arsenic species in aqueous and DCM layers were determined using high performance liquid chromatography - inductively coupled plasma mass spectrometer/electrospray tandem mass spectrometry (HPLC-ICPMS/ESIMSMS). In addition to inorganic arsenic (iAs), the aqueous layer also contained monomethylarsonate (MAs(V)), dimethylarsinate (DMAs(V)), and the two arsenosugars, namely a glycerol arsenosugar (Oxo-Gly) and a phosphate arsenosugar (Oxo-PO4). Two major arsenosugar phospholipids (AsSugPL982 and AsSugPL984) were detected in DCM fraction. Arsenic in the growth medium was also investigated by HPLC/ICPMS and shown to be present mainly as the inorganic forms As(III) and As(V) accounting for 29%-38% and 29%-57% of the total arsenic respectively. The total arsenic of methylated arsenic, arsenosugars, and arsenosugar phospholipids in Nostoc cells with increasing As(III) exposure were not markedly different, indicating that the transformation to organoarsenic in Nostoc was not dependent on As(III) concentration in the medium. Our results provide new insights into the role of cyanobacteria in the biogeochemical cycling of arsenic. Copyright © 2017 Elsevier Ltd. All rights reserved.

Heavy metal, total arsenic, and inorganic arsenic contents of algae food products.

Science.gov (United States)

Almela, C; Algora, S; Benito, V; Clemente, M J; Devesa, V; Súñer, M A; Vélez, D; Montoro, R

2002-02-13

The total arsenic, inorganic arsenic, lead, cadmium, and mercury contents of 18 algae food products currently on sale in Spain were determined. The suitability of the analytical methodologies for this type of matrix was confirmed by evaluating their analytical characteristics. The concentration ranges found for each contaminant, expressed in milligrams per kilogram of dry weight, were as follows: total arsenic, 2.3-141; inorganic arsenic, 0.15-88; lead, mercury, 0.004-0.04. There is currently no legislation in Spain regarding contaminants in algae food products, but some of the samples analyzed revealed Cd and inorganic As levels higher than those permitted by legislation in other countries. Given the high concentrations of inorganic As found in Hizikia fusiforme, a daily consumption of 1.7 g of the product would reach the Provisional Tolerable Weekly Intake recommended by the WHO for an average body weight of 68 kg. A more comprehensive study of the contents and toxicological implications of the inorganic As present in the algae food products currently sold in Spain may be necessary, which might then be the basis for the introduction of specific sales restrictions.

Immunotoxicity and biodistribution analysis of arsenic trioxide in C57Bl/6 mice following a 2-week inhalation exposure

International Nuclear Information System (INIS)

Burchiel, Scott W.; Mitchell, Leah A.; Lauer, Fredine T.; Sun Xi; McDonald, Jacob D.; Hudson, Laurie G.; Liu Kejian

2009-01-01

In these studies the immunotoxicity of arsenic trioxide (ATO, As 2 O 3 ) was evaluated in mice following 14 days of inhalation exposures (nose only, 3 h per day) at concentrations of 50 μg/m 3 and 1 mg/m 3 . A biodistribution analysis performed immediately after inhalation exposures revealed highest levels of arsenic in the kidneys, bladder, liver, and lung. Spleen cell levels were comparable to those found in the blood, with the highest concentration of arsenic detected in the spleen being 150 μg/g tissue following the 1 mg/m 3 exposures. No spleen cell cytotoxicity was observed at either of the two exposure levels. There were no changes in spleen cell surface marker expression for B cells, T cells, macrophages, and natural killer (NK) cells. There were also no changes detected in the B cell (LPS-stimulated) and T cell (Con A-stimulated) proliferative responses of spleen cells, and no changes were found in the NK-mediated lysis of Yac-1 target cells. The primary T-dependent antibody response was, however, found to be highly susceptible to ATO suppression. Both the 50 μg/m 3 and 1 mg/m 3 exposures produced greater than 70% suppression of the humoral immune response to sheep red blood cells. Thus, the primary finding of this study is that the T-dependent humoral immune response is extremely sensitive to suppression by ATO and assessment of humoral immune responses should be considered in evaluating the health effects of arsenic containing agents.

Arsenic exposure in pregnant mice disrupts placental vasculogenesis and causes spontaneous abortion.

Science.gov (United States)

He, Wenjie; Greenwell, Robert J; Brooks, Diane M; Calderón-Garcidueñas, Lilian; Beall, Howard D; Coffin, J Douglas

2007-09-01

Arsenic is an abundant toxicant in ground water and soil around areas with extractive industries. Human epidemiological studies have shown that arsenic exposure is linked to developmental defects and miscarriage. The placenta is known to utilize vasculogenesis to develop its circulation. The hypothesis tested here states the following: arsenic exposure causes placental dysmorphogenesis and defective placental vasculogenesis resulting in placental insufficiency and subsequent spontaneous abortion. To test this hypothesis, pregnant mice were exposed to sodium arsenite (AsIII) through drinking water from conception through weanling stages. Neonatal assessment of birth rates, pup weights, and litter sizes in arsenic exposed and control mothers revealed that AsIII-exposed mothers had only 40% the fecundity of controls. Preterm analysis at E12.5 revealed a loss of fecundity at E12.5 from either 20 ppm or greater exposures to AsIII. There was no loss of fecundity at E7.5 suggesting that spontaneous abortion occurs during placentation. Histomorphometry on E12.5 placentae from arsenic-exposed mice revealed placental dysplasia especially in the vasculature. These results suggest that arsenic toxicity is causative for mammalian spontaneous abortion by virtue of aberrant placental vasculogenesis and placental insufficiency.

Arsenic trioxide decreases the amount and inhibits the function of regulatory T cells, which may contribute to its efficacy in the treatment of acute promyelocytic leukemia.

Science.gov (United States)

Xu, Wen; Li, Xiaoxia; Quan, Lina; Yao, Jiying; Mu, Guannan; Guo, Jingjie; Wang, Yitong

2018-03-01

Arsenic trioxide (ATO) exhibits substantial clinical efficacy in the treatment of acute promyelocytic leukemia (APL). Here, we investigated whether ATO exerts its efficacy by affecting regulatory T (Treg) cells. We determined whether ATO treatment influenced the amount and function of purified Treg cells. We also examined the effect of ATO treatment on Treg cells from APL patients. ATO treatment induced apoptosis in purified Treg cells and dampened the inhibition of effector T (Teff) cells proliferation and the secretion of cytokine by Treg cells. Treg cell levels in the peripheral blood and serum IL-10 levels were dramatically decreased in APL patients after single ATO treatment. In summary, our results show that ATO decreases the amount and inhibits the function of Treg cells, thereby enhancing Teff cell function and overall anti-tumor immunity.

A review on environmental factors regulating arsenic methylation in humans

International Nuclear Information System (INIS)

Tseng, C.-H.

2009-01-01

Subjects exposed to arsenic show significant inter-individual variation in urinary patterns of arsenic metabolites but insignificant day-to-day intra-individual variation. The inter-individual variation in arsenic methylation can be partly responsible for the variation in susceptibility to arsenic toxicity. Wide inter-ethnic variation and family correlation in urinary arsenic profile suggest a genetic effect on arsenic metabolism. In this paper the environmental factors affecting arsenic metabolism are reviewed. Methylation capacity might reduce with increasing dosage of arsenic exposure. Furthermore, women, especially at pregnancy, have better methylation capacity than their men counterparts, probably due to the effect of estrogen. Children might have better methylation capacity than adults and age shows inconsistent relevance in adults. Smoking and alcohol consumption might be associated with a poorer methylation capacity. Nutritional status is important in the methylation capacity and folate may facilitate the methylation and excretion of arsenic. Besides, general health conditions and medications might influence the arsenic methylation capacity; and technical problems can cause biased estimates. The consumption of seafood, seaweed, rice and other food with high arsenic contents and the extent of cooking and arsenic-containing water used in food preparation may also interfere with the presentation of the urinary arsenic profile. Future studies are necessary to clarify the effects of the various arsenic metabolites including the trivalent methylated forms on the development of arsenic-induced human diseases with the consideration of the effects of confounding factors and the interactions with other effect modifiers

Combined Efficacy of Gallic Acid and MiADMSA with Limited Beneficial Effects Over MiADMSA Against Arsenic-induced Oxidative Stress in Mouse

OpenAIRE

Pachauri, Vidhu; Flora, SJS

2015-01-01

Gallic acid is an organic acid known for its antioxidant and anticancer properties. The present study is focused on evaluating the role of gallic acid in providing better therapeutic outcomes against arsenic-induced toxicity. Animals pre-exposed to arsenic were treated with monoisoamyl meso -2,3-dimercaptosuccinic acid (MiADMSA), a new chelating drug, alone and in combination with gallic acid, consecutively for 10 days. The study suggests that (1) gallic acid in presence of MiADMSA is only mo...

Phytoextraction by arsenic hyperaccumulator Pteris vittata L. from six arsenic-contaminated soils: Repeated harvests and arsenic redistribution

Energy Technology Data Exchange (ETDEWEB)

Gonzaga, Maria I.S.; Santos, Jorge A.G. [Department of Soil Chemistry, Universidade Federal da Bahia, Cruz das Almas, 44380000 (Brazil); Ma, Lena Q. [Soil and Water Science Department, University of Florida, 2169 McCarty Hall, Gainesville, FL 32611-0290 (United States)], E-mail: lqma@ifas.ufl.edu

2008-07-15

This greenhouse experiment evaluated arsenic removal by Pteris vittata and its effects on arsenic redistribution in soils. P. vittata grew in six arsenic-contaminated soils and its fronds were harvested and analyzed for arsenic in October, 2003, April, 2004, and October, 2004. The soil arsenic was separated into five fractions via sequential extraction. The ferns grew well and took up arsenic from all soils. Fern biomass ranged from 24.8 to 33.5 g plant{sup -1} after 4 months of growth but was reduced in the subsequent harvests. The frond arsenic concentrations ranged from 66 to 6,151 mg kg{sup -1}, 110 to 3,056 mg kg{sup -1}, and 162 to 2,139 mg kg{sup -1} from the first, second and third harvest, respectively. P. vittata reduced soil arsenic by 6.4-13% after three harvests. Arsenic in the soils was primarily associated with amorphous hydrous oxides (40-59%), which contributed the most to arsenic taken up by P. vittata (45-72%). It is possible to use P. vittata to remediate arsenic-contaminated soils by repeatedly harvesting its fronds. - Pteris vittata was effective in continuously removing arsenic from contaminated soils after three repeated harvests.

Environmental arsenic exposure, selenium and sputum alpha-1 antitrypsin

DEFF Research Database (Denmark)

Burgess, Jefferey L; Kurzius-Spencer, Margaret; Poplin, Gerald S

2014-01-01

Exposure to arsenic in drinking water is associated with increased respiratory disease. Alpha-1 antitrypsin (AAT) protects the lung against tissue destruction. The objective of this study was to determine whether arsenic exposure is associated with changes in airway AAT concentration and whether...... this relationship is modified by selenium. A total of 55 subjects were evaluated in Ajo and Tucson, Arizona. Tap water and first morning void urine were analyzed for arsenic species, induced sputum for AAT and toenails for selenium and arsenic. Household tap-water arsenic, toenail arsenic and urinary inorganic...... arsenic and metabolites were significantly higher in Ajo (20.6±3.5 μg/l, 0.54±0.77 μg/g and 27.7±21.2 μg/l, respectively) than in Tucson (3.9±2.5 μg/l, 0.16±0.20 μg/g and 13.0±13.8 μg/l, respectively). In multivariable models, urinary monomethylarsonic acid (MMA) was negatively, and toenail selenium...

Arsenic biotransformation and volatilization in transgenic rice

Science.gov (United States)

Meng, Xiang-Yan; Qin, Jie; Wang, Li-Hong; Duan, Gui-Lan; Sun, Guo-Xin; Wu, Hui-Lan; Chu, Cheng-Cai; Ling, Hong-Qing; Rosen, Barry P.; Zhu, Yong-Guan

2011-01-01

Summary Biotransformation of arsenic includes oxidation, reduction, methylation and conversion to more complex organic arsenicals. Members of the class of arsenite [As(III)] S-adenosylmethyltransferase enzymes catalyze As(III) methylation to a variety of mono-, di- and trimethylated species, some of which are less toxic than As(III) itself. However, no methyltransferase gene has been identified in plants. Here, an arsM gene from the soil bacterium Rhodopseudomonas palustris was expressed in Japonica rice (Oryza sativa L.) cultivar Nipponbare, and the transgenic rice produced methylated arsenic species, which were measured by inductively coupled plasma mass spectrometry (ICP-MS) and high performance liquid chromatography-inductively coupled plasma-mass spectrometry (HPLC-ICP-MS). Both monomethylarsenate [MAs(V)] and dimethylarsenate [DMAs(V)] were detected in the root and shoot of transgenic rice. After 12-d exposure to As(III), the transgenic rice gave off 10-fold more volatile arsenicals. The present study demonstrates that expression of an arsM gene in rice induces arsenic methylation and volatilization, providing a potential stratagem for phytoremediation theoretically. PMID:21517874

Arsenic pollution sources.

Science.gov (United States)

Garelick, Hemda; Jones, Huw; Dybowska, Agnieszka; Valsami-Jones, Eugenia

2008-01-01

Arsenic is a widely dispersed element in the Earth's crust and exists at an average concentration of approximately 5 mg/kg. There are many possible routes of human exposure to arsenic from both natural and anthropogenic sources. Arsenic occurs as a constituent in more than 200 minerals, although it primarily exists as arsenopyrite and as a constituent in several other sulfide minerals. The introduction of arsenic into drinking water can occur as a result of its natural geological presence in local bedrock. Arsenic-containing bedrock formations of this sort are known in Bangladesh, West Bengal (India), and regions of China, and many cases of endemic contamination by arsenic with serious consequences to human health are known from these areas. Significant natural contamination of surface waters and soil can arise when arsenic-rich geothermal fluids come into contact with surface waters. When humans are implicated in causing or exacerbating arsenic pollution, the cause can almost always be traced to mining or mining-related activities. Arsenic exists in many oxidation states, with arsenic (III) and (V) being the most common forms. Similar to many metalloids, the prevalence of particular species of arsenic depends greatly on the pH and redox conditions of the matrix in which it exists. Speciation is also important in determining the toxicity of arsenic. Arsenic minerals exist in the environment principally as sulfides, oxides, and phosphates. In igneous rocks, only those of volcanic origin are implicated in high aqueous arsenic concentrations. Sedimentary rocks tend not to bear high arsenic loads, and common matrices such as sands and sandstones contain lower concentrations owing to the dominance of quartz and feldspars. Groundwater contamination by arsenic arises from sources of arsenopyrite, base metal sulfides, realgar and orpiment, arsenic-rich pyrite, and iron oxyhydroxide. Mechanisms by which arsenic is released from minerals are varied and are accounted for by

Combined application of arsenic trioxide and lithium chloride augments viability reduction and apoptosis induction in human rhabdomyosarcoma cell lines.

Directory of Open Access Journals (Sweden)

Sabine B Schleicher

Full Text Available Rhabdomyosarcomas (RMS are the most prevalent soft tissue sarcomas affecting children and adolescents. Despite intensive treatment consisting of multimodal chemotherapy and surgery RMS patients diagnosed with metastatic disease expect long term survival rates of only 20%. Often multidrug resistance arises upon initial response emphasizing the need for new therapeutic drugs to improve treatment efficiency. Previously, we demonstrated the efficacy of the FDA approved drug arsenic trioxide (ATO specifically inhibiting viability and clonal growth as well as inducing cell death in human RMS cell lines of different subtypes. In this study, we combined low dose ATO with lithium chloride (LiCl, which is approved as mood stabilizer for the treatment of bipolar disorder, but also inhibits growth and survival of different cancer cell types in pre-clinical research. Indeed, we could show additive effects of LiCl and ATO on viability reduction, decrease of colony formation as well as cell death induction. In the course of this, LiCl induced inhibitory glycogen synthase kinase-3β (GSK-3β serine 9 phosphorylation, whereas glioma associated oncogene family 1 (GLI1 protein expression was particularly reduced by combined ATO and LiCl treatment in RD and RH-30 cell lines, showing high rates of apoptotic cell death. These results imply that combination of ATO with LiCl or another drug targeting GSK-3 is a promising strategy to enforce the treatment efficiency in resistant and recurrent RMS.

Alpha-lipoic acid protects oxidative stress, changes in cholinergic system and tissue histopathology during co-exposure to arsenic-dichlorvos in rats.

Science.gov (United States)

Dwivedi, Nidhi; Flora, Govinder; Kushwaha, Pramod; Flora, Swaran J S

2014-01-01

We investigated protective efficacy of α-lipoic acid (LA), an antioxidant against arsenic and DDVP co-exposed rats. Biochemical variables suggestive of oxidative stress, neurological dysfunction, and tissue histopathological alterations were determined. Male rats were exposed either to 50 ppm sodium arsenite in drinking water or in combination with DDVP (4 mg/kg, subcutaneously) for 10 weeks. α-Lipoic acid (50mg/kg, pos) was also co-administered in above groups. Arsenic exposure led to significant oxidative stress along, hepatotoxicity, hematotoxicity and altered brain biogenic amines levels accompanied by increased arsenic accumulation in blood and tissues. These altered biochemical variables were supported by histopathological examinations leading to oxidative stress and cell death. These biochemical alterations were significantly restored by co-administration of α-lipoic acid with arsenic and DDVP alone and concomitantly. The results indicate that arsenic and DDVP induced oxidative stress and cholinergic dysfunction can be significantly protected by the supplementation of α-lipoic acid. Copyright © 2013 Elsevier B.V. All rights reserved.

Urinary arsenic species, toenail arsenic, and arsenic intake estimates in a Michigan population with low levels of arsenic in drinking water.

Science.gov (United States)

Rivera-Núñez, Zorimar; Meliker, Jaymie R; Meeker, John D; Slotnick, Melissa J; Nriagu, Jerome O

2012-01-01

The large disparity between arsenic concentrations in drinking water and urine remains unexplained. This study aims to evaluate predictors of urinary arsenic in a population exposed to low concentrations (≤50 μg/l) of arsenic in drinking water. Urine and drinking water samples were collected from a subsample (n=343) of a population enrolled in a bladder cancer case-control study in southeastern Michigan. Total arsenic in water and arsenic species in urine were determined using ICP-MS: arsenobetaine (AsB), arsenite (As[III]), arsenate (As[V]), methylarsenic acid (MMA[V]), and dimethylarsenic acid (DMA[V]). The sum of As[III], As[V], MMA[V], and DMA[V] was denoted as SumAs. Dietary information was obtained through a self-reported food intake questionnaire. Log(10)-transformed drinking water arsenic concentration at home was a significant (Pwater were removed and further improved when analyses were applied to individuals who consumed amounts of home drinking water above the median volume (R(2)=0.40, Pwater was 0.42. Results show that arsenic exposure from drinking water consumption is an important determinant of urinary arsenic concentrations, even in a population exposed to relatively low levels of arsenic in drinking water, and suggest that seafood intake may influence urinary DMA[V] concentrations.

Study of arsenic injury to rice plant

Energy Technology Data Exchange (ETDEWEB)

Tsujimoto, T; Matsumoto, H; Okahashi, C; Wada, M

1968-01-01

Growth injury happened to rice plants when waste liquid flowed from a mercury refinery into paddy fields in July 1967. Arsenic turned out to be the main cause of the growth injury. Investigation of the contaminated fields revealed that the injury was the most severe at the water inlet to the field, and was comparatively slight in the middle of it. The quantity of arsenic absorbed in the soil was very large at the inlet and was decreasingly small towards the centre of them. Moreover, excessive quantities of arsenic were often found on the surface of the fields. The constituent was seen permeating the lower layers of the soil. The permeation was deep in proportion to the good drainage of soil. Drastic measures should be taken with a special reference to quantity of arsenic and type of soil.

ARSENIC-INDUCED SKIN CONDITIONS IDENTIFIED IN SOUTHWEST DERMATOLOGY PRACTICE: AN EPIDEMIOLOGIC TOOL?

Science.gov (United States)

Populations living in the Southwest United States are more likely to be exposed to elevated drinking water arsenic levels compared to other areas of the country. Skin changes, including hyperpigmentation and generalized hyperkeratosis, are the most common signs of chronic arsenic...

Low selenium status affects arsenic metabolites in an arsenic exposed population with skin lesions.

Science.gov (United States)

Huang, Zhi; Pei, Qiuling; Sun, Guifan; Zhang, Sichum; Liang, Jiang; Gao, Yi; Zhang, Xinrong

2008-01-01

The antagonistic effects between selenium (Se) and arsenic (As) suggest that low selenium status plays important roles in arsenism development. However, no study has been reported for humans suffering from chronic arsenic exposure with low selenium status. Sixty-three subjects were divided into 2 experimental groups by skin lesions (including hyperkeratosis, depigmentation, and hyperpigmentation). Total urine and serum concentrations of arsenic and selenium were determined by ICP-MS with collision/reaction cell. Arsenic species were analysed by ICP-MS coupled with HPLC. The mean concentration of As in the drinking waters was 41.5 microg/l. The selenium dietary intake for the studied population was 31.7 microg Se/d, and which for the cases and controls were 25.9 and 36.3 microg Se/d, respectively. Compared with the controls, the skin lesions cases had lower selenium concentrations in serum and urine (41.4 vs 49.6 microg/l and 71.0 vs 78.8 microg/l, respectively), higher inorganic arsenic (iAs) in serum (5.2 vs 3.4 microg/l, PiAs in serum and urine (20.2) vs 16.9% and 18.3 vs 14.5%, respectively, PiAs and its inhibition to be biotransformed to DMA occurred in human due to chronic exposure of low selenium status.

Rapid onset of multiple concurrent squamous cell carcinomas associated with the use of an arsenic-containing traditional medicine for chronic plaque psoriasis.

Science.gov (United States)

Siefring, Mark Louis; Lu, Doanh; States, J Christopher; Van Hoang, Minh

2018-03-30

We report a case of a 46-year-old Vietnamese man who developed widespread, numerous and concurrent cutaneous squamous cell carcinomas (SCCs) in non-sun exposed skin areas after taking a traditional medicine (TM) formulation for chronic plaque psoriasis. The SCC lesions began to develop within 12-15 months after beginning the arsenic-containing TM. The patient experienced both acute and chronic symptoms consistent with arsenic exposure. Laboratory investigation of a collected hair sample showed a significant arsenic level. The TM formulation used by the patient was tested and demonstrated an extremely high concentration of arsenic. © BMJ Publishing Group Ltd (unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

Aspects réglementaires sur l'arsenic

OpenAIRE

Morin , Anne; Jullien , Dominique

2000-01-01

L'arsenic, élément connu depuis l'antiquité autant pour ses vertus médicinales que pour sa renommée de poison, suscite aujourd'hui de grandes inquiétudes du fait du caractère hautement toxique de certains de ses composés et des quantités importantes d'arsenic présentes dans l'environnement. On peut considérer qu'il existe un niveau " normal " d'arsenic dans les sols, dans les eaux fluviales (par lessivage des minerais), mais les sources anthropogéniques sont évidemment celles qui sont visées ...

Rapid biotransformation of arsenic by a model protozoan Tetrahymena thermophila

Energy Technology Data Exchange (ETDEWEB)

Yin Xixiang [Key Lab of Urban Environment and Health, Institute of Urban Environment, Chinese Academy of Sciences, Xiamen 361021 (China); State Key Lab of Urban and Regional Ecology, Research Center for Eco-environmental Sciences, Chinese Academy of Sciences, 18 Shuangqing Road, Beijing 100085 (China); Zhang Yongyu; Yang Jun [Key Lab of Urban Environment and Health, Institute of Urban Environment, Chinese Academy of Sciences, Xiamen 361021 (China); Zhu Yongguan, E-mail: ygzhu@rcees.ac.cn [Key Lab of Urban Environment and Health, Institute of Urban Environment, Chinese Academy of Sciences, Xiamen 361021 (China); State Key Lab of Urban and Regional Ecology, Research Center for Eco-environmental Sciences, Chinese Academy of Sciences, 18 Shuangqing Road, Beijing 100085 (China)

2011-04-15

Arsenic biomethylation and biovolatilization are thought to be two important metabolic pathways in aquatic and soil environments. Tetrahymena thermophila is a genus of free-living ciliated protozoan that is widely distributed in freshwater environments around the world. In this study, we studied arsenic accumulation, speciation, efflux, methylation and volatilization in this unicellular eukaryote exposed to various concentrations of arsenate. Our results show that T. thermophila accumulated 187 mg.kg{sup -1} dry weight of arsenic when exposed to 40 {mu}M for 48 h, with MMAs(V) (monomethylarsenate) and DMAs(V) (dimethylarsenate) as the dominant species, accounting for 66% of the total arsenic. Meanwhile, arsenate, arsenite, MMAs(V) and DMAs(V) were detected in the culture medium; the last three were released by the cells. The production of volatile arsenic increased with increasing external As(V) concentrations and exposure time. To our knowledge, this is the first study on arsenic metabolism, particularly biomethylation and biovolatilization, in protozoa. - Tetrahymena thermophila can rapidly methylate arsenic, and produce volatile arsenicals.

Risk of Erectile Dysfunction Induced by Arsenic Exposure through Well Water Consumption in Taiwan

Science.gov (United States)

Hsieh, Fang-I; Hwang, Ti-Sheng; Hsieh, Yi-Chen; Lo, Hsiu-Chiung; Su, Chien-Tien; Hsu, Hui-Shing; Chiou, Hung-Yi; Chen, Chien-Jen

2008-01-01

Background Erectile dysfunction (ED) has a profound impact on the quality of life of many men. Many risk factors are associated with ED, such as aging, sex hormone levels, hypertension, cardiovascular diseases, and diabetes mellitus. Arsenic exposure could damage peripheral vessels and increase the risk of cardiovascular disease. However, the relationship between arsenic exposure and ED has seldom been evaluated. Objectives In this study we aimed to investigate whether exposure to arsenic enhances the risk of ED. Methods We recruited 177 males ≥ 50 years of age through health examinations conducted in three hospitals in Taiwan. We used a questionnaire (International Index of Erectile Function-5) to measure the level of erectile function. Sex hormones, including total testosterone and sex hormone–binding globulin, were determined by radioimmunoassay. We used another standardized questionnaire to collect background and behavioral information (e.g., cigarette smoking; alcohol, tea, or coffee drinking; and physical activity). Results The prevalence of ED was greater in the arsenic-endemic area (83.3%) than in the non–arsenic-endemic area (66.7%). Subjects with arsenic exposure > 50 ppb had a significantly higher risk of developing ED than those with exposure ≤ 50 ppb, after adjusting for age, cigarette smoking, diabetes mellitus, hypertension, and cardiovascular disease [odds ratio (OR) = 3.4]. Results also showed that the risk of developing severe ED was drastically enhanced by arsenic exposure (OR = 7.5), after adjusting for free testosterone and traditional risk factors of ED. Conclusions Results suggested that chronic arsenic exposure has a negative impact on erectile function. PMID:18414639

Arsenic exposure from drinking water is associated with decreased gene expression and increased DNA methylation in peripheral blood

Energy Technology Data Exchange (ETDEWEB)

Ameer, Syeda Shegufta [Department of Laboratory Medicine, Division of Occupational and Environmental Medicine, Lund University, Lund (Sweden); Engström, Karin [Department of Laboratory Medicine, Division of Occupational and Environmental Medicine, Lund University, Lund (Sweden); Institute of Environmental Medicine, Unit of Metals & Health, Karolinska Institutet, Stockholm (Sweden); Hossain, Mohammad Bakhtiar [Department of Laboratory Medicine, Division of Occupational and Environmental Medicine, Lund University, Lund (Sweden); Concha, Gabriela [Science Department, Risk Benefit Assessment Unit, National Food Agency, Uppsala (Sweden); Vahter, Marie [Institute of Environmental Medicine, Unit of Metals & Health, Karolinska Institutet, Stockholm (Sweden); Broberg, Karin, E-mail: Karin.broberg@ki.se [Institute of Environmental Medicine, Unit of Metals & Health, Karolinska Institutet, Stockholm (Sweden)

2017-04-15

Background: Exposure to inorganic arsenic increases the risk of cancer and non-malignant diseases. Inefficient arsenic metabolism is a marker for susceptibility to arsenic toxicity. Arsenic may alter gene expression, possibly by altering DNA methylation. Objectives: To elucidate the associations between arsenic exposure, gene expression, and DNA methylation in peripheral blood, and the modifying effects of arsenic metabolism. Methods: The study participants, women from the Andes, Argentina, were exposed to arsenic via drinking water. Arsenic exposure was assessed as the sum of arsenic metabolites in urine (U-As), using high performance liquid-chromatography hydride-generation inductively-coupled-plasma-mass-spectrometry, and arsenic metabolism efficiency was assessed by the urinary fractions (%) of the individual metabolites. Genome-wide gene expression (N = 80 women) and DNA methylation (N = 93; 80 overlapping with gene expression) in peripheral blood were measured using Illumina DirectHyb HumanHT-12 v4.0 and Infinium Human-Methylation 450K BeadChip, respectively. Results: U-As concentrations, ranging 10–1251 μg/L, was associated with decreased gene expression: 64% of the top 1000 differentially expressed genes were down-regulated with increasing U-As. U-As was also associated with hypermethylation: 87% of the top 1000 CpGs were hypermethylated with increasing U-As. The expression of six genes and six individual CpG sites were significantly associated with increased U-As concentration. Pathway analyses revealed enrichment of genes related to cell death and cancer. The pathways differed somewhat depending on arsenic metabolism efficiency. We found no overlap between arsenic-related gene expression and DNA methylation for individual genes. Conclusions: Increased arsenic exposure was associated with lower gene expression and hypermethylation in peripheral blood, but with no evident overlap. - Highlights: • Women exposed to inorganic arsenic were studied for

Identification of Novel Gene Targets and Putative Regulators of Arsenic-Associated DNA Methylation in Human Urothelial Cells and Bladder Cancer

Science.gov (United States)

Rager, Julia E.; Miller, Sloane; Tulenko, Samantha E.; Smeester, Lisa; Ray, Paul D.; Yosim, Andrew; Currier, Jenna M.; Ishida, María C.; González-Horta, Maria del Carmen; Sánchez-Ramírez, Blanca; Ballinas-Casarrubias, Lourdes; Gutiérrez-Torres, Daniela S.; Drobná, Zuzana; Del Razo, Luz M.; García-Vargas, Gonzalo G.; Kim, William Y.; Zhou, Yi-Hui; Wright, Fred A.; Stýblo, Miroslav; Fry, Rebecca C.

2016-01-01

There is strong epidemiologic evidence linking chronic exposure to inorganic arsenic (iAs) to a myriad of adverse health effects, including cancer of the bladder. The present study set out to identify DNA methylation patterns associated with iAs and its metabolites in exfoliated urothelial cells (EUCs) that originate primarily from the urinary bladder, one of the targets of arsenic (As)-induced carcinogenesis. Genome-wide, gene-specific promoter DNA methylation levels were assessed in EUCs from 46 residents of Chihuahua, Mexico, and the relationship was examined between promoter methylation profiles and the intracellular concentrations of total As (tAs) and As species. A set of 49 differentially methylated genes was identified with increased promoter methylation associated with EUC tAs, iAs, and/or monomethylated As (MMAs) enriched for their roles in metabolic disease and cancer. Notably, no genes had differential methylation associated with EUC dimethylated As (DMAs), suggesting that DMAs may influence DNA methylation-mediated urothelial cell responses to a lesser extent than iAs or MMAs. Further analysis showed that 22 of the 49 As-associated genes (45%) are also differentially methylated in bladder cancer tissue identified using The Cancer Genome Atlas repository. Both the As- and cancer-associated genes are enriched for the binding sites of common transcription factors known to play roles in carcinogenesis, demonstrating a novel potential mechanistic link between iAs exposure and bladder cancer. PMID:26039340

An insight of environmental contamination of arsenic on animal health

Directory of Open Access Journals (Sweden)

Paramita Mandal

2017-03-01

Full Text Available The main threats to human health from heavy metals are associated with exposure to lead, cadmium, mercury and arsenic. Exposure to arsenic is mainly via intake of food and drinking water, food being the most important source in most populations. Although adverse health effects of heavy metals have been known for a long time, exposure to heavy metals continues and is even increasing in some areas. Long-term exposure to arsenic in drinking-water is mainly related to increased risks of skin cancer, but also some other cancers, as well as other skin lesions such as hyperkeratosis and pigmentation changes. Therefore, measures should be taken to reduce arsenic exposure in the general population in order to minimize the risk of adverse health effects. Animal are being exposed to arsenic through contaminated drinking water, feedstuff, grasses, vegetables and different leaves. Arsenic has been the most common causes of inorganic chemical poisoning in farm animals. Although, sub-chronic and chronic exposure of arsenic do not generally reveal external signs or symptoms in farm animals but arsenic (or metabolites concentrations in blood, hair, hoofs and urine are remained high in animals of arsenic contaminated zones. So it is assumed that concentration of arsenic in blood, urine, hair or milk have been used as biomarkers of arsenic exposure in field animals.

Methylated trivalent arsenicals are potent inhibitors of glucose stimulated insulin secretion by murine pancreatic islets

International Nuclear Information System (INIS)

Douillet, Christelle; Currier, Jenna; Saunders, Jesse; Bodnar, Wanda M.; Matoušek, Tomáš; Stýblo, Miroslav

2013-01-01

Epidemiologic evidence has linked chronic exposure to inorganic arsenic (iAs) with an increased prevalence of diabetes mellitus. Laboratory studies have identified several mechanisms by which iAs can impair glucose homeostasis. We have previously shown that micromolar concentrations of arsenite (iAs III ) or its methylated trivalent metabolites, methylarsonite (MAs III ) and dimethylarsinite (DMAs III ), inhibit the insulin-activated signal transduction pathway, resulting in insulin resistance in adipocytes. Our present study examined effects of the trivalent arsenicals on insulin secretion by intact pancreatic islets isolated from C57BL/6 mice. We found that 48-hour exposures to low subtoxic concentrations of iAs III , MAs III or DMAs III inhibited glucose-stimulated insulin secretion (GSIS), but not basal insulin secretion. MAs III and DMAs III were more potent than iAs III as GSIS inhibitors with estimated IC 50 ≤ 0.1 μM. The exposures had little or no effects on insulin content of the islets or on insulin expression, suggesting that trivalent arsenicals interfere with mechanisms regulating packaging of the insulin transport vesicles or with translocation of these vesicles to the plasma membrane. Notably, the inhibition of GSIS by iAs III , MAs III or DMAs III could be reversed by a 24-hour incubation of the islets in arsenic-free medium. These results suggest that the insulin producing pancreatic β-cells are among the targets for iAs exposure and that the inhibition of GSIS by low concentrations of the methylated metabolites of iAs may be the key mechanism of iAs-induced diabetes. - Highlights: ► Trivalent arsenicals inhibit glucose stimulated insulin secretion by pancreatic islets. ► MAs III and DMAs III are more potent inhibitors than arsenite with IC 50 ∼ 0.1 μM. ► The arsenicals have little or no effects on insulin expression in pancreatic islets. ► The inhibition of insulin secretion by arsenite, MAs III or DMAs III is reversible. ► Thus

Reactive oxygen species-dependent HSP90 protein cleavage participates in arsenical As+3- and MMA+3-induced apoptosis through inhibition of telomerase activity via JNK activation

International Nuclear Information System (INIS)

Shen, S.-C.; Yang, L.-Y.; Lin, H.-Y.; Wu, C.-Y.; Su, T.-H.; Chen, Y.-C.

2008-01-01

The effects of six arsenic compounds including As +3 , MMA +3 , DMA +3 , As +5 , MMA +5 , and DMA +5 on the viability of NIH3T3 cells were examined. As +3 and MMA +3 , but not the others, exhibited significant cytotoxic effects in NIH3T3 cells through apoptosis induction. The apoptotic events such as DNA fragmentation and chromosome condensation induced by As +3 and MMA +3 were prevented by the addition of NAC and CAT, and induction of HO-1 gene expression in accordance with cleavage of the HSP90 protein, and suppression of telomerase activity were observed in NIH3T3 cells under As +3 and MMA +3 treatments. An increase in the intracellular peroxide level was examined in As +3 - and MMA +3 -treated NIH3T3 cells, and As +3 - and MMA +3 -induced apoptotic events were blocked by NAC, CAT, and DPI addition. HSP90 inhibitors, GA and RD, significantly attenuated the telomerase activity in NIH3T3 cells with an enhancement of As +3 - and MMA +3 -induced cytotoxicity. Suppression of JNKs significantly inhibited As +3 - and MMA +3 -induced apoptosis by blocking HSP90 protein cleavage and telomerase reduction in NIH3T3 cells. Furthermore, Hb, SnPP, and dexferosamine showed no effect against As +3 - and MMA +3 -induced apoptosis, and overexpression of HO-1 protein or inhibition of HO-1 protein expression did not affect the apoptosis induced by As +3 or MMA +3 . These data provide the first evidence to indicate that apoptosis induced by As +3 and MMA +3 is mediated by an ROS-dependent degradation of HSP90 protein and reduction of telomerase via JNK activation, and HO-1 induction might not be involved

Evaluation of the sustainability of deep groundwater as an arsenic-safe resource in the Bengal Basin

OpenAIRE

Michael, Holly A.; Voss, Clifford I.

2008-01-01

Tens of millions of people in the Bengal Basin region of Bangladesh and India drink groundwater containing unsafe concentrations of arsenic. This high-arsenic groundwater is produced from shallow (150 m where groundwater arsenic concentrations are nearly uniformly low, and many more wells are needed, however, the sustainability of deep, arsenic-safe groundwater has not been previously assessed. Deeper pumping could induce downward migration of dissolved arsenic, permanently destroying the dee...

Blockade of maitotoxin-induced oncotic cell death reveals zeiosis

Directory of Open Access Journals (Sweden)

Schilling William P

2002-01-01

Full Text Available Abstract Background Maitotoxin (MTX initiates cell death by sequentially activating 1 Ca2+ influx via non-selective cation channels, 2 uptake of vital dyes via formation of large pores, and 3 release of lactate dehydrogenase, an indication of cell lysis. MTX also causes formation of membrane blebs, which dramatically dilate during the cytolysis phase. To determine the role of phospholipase C (PLC in the cell death cascade, U73122, a specific inhibitor of PLC, and U73343, an inactive analog, were examined on MTX-induced responses in bovine aortic endothelial cells. Results Addition of either U73122 or U73343, prior to MTX, produced a concentration-dependent inhibition of the cell death cascade (IC50 ≈ 1.9 and 0.66 μM, respectively suggesting that the effect of these agents was independent of PLC. Addition of U73343 shortly after MTX, prevented or attenuated the effects of the toxin, but addition at later times had little or no effect. Time-lapse videomicroscopy showed that U73343 dramatically altered the blebbing profile of MTX-treated cells. Specifically, U73343 blocked bleb dilation and converted the initial blebbing event into "zeiosis", a type of membrane blebbing commonly associated with apoptosis. Cells challenged with MTX and rescued by subsequent addition of U73343, showed enhanced caspase-3 activity 48 hr after the initial insult, consistent with activation of the apoptotic program. Conclusions Within minutes of MTX addition, endothelial cells die by oncosis. Rescue by addition of U73343 shortly after MTX showed that a small percentage of cells are destined to die by oncosis, but that a larger percentage survive; cells that survive the initial insult exhibit zeiosis and may ultimately die by apoptotic mechanisms.

Seasonal Arsenic Accumulation in Stream Sediments at a Groundwater Discharge Zone

DEFF Research Database (Denmark)

MacKay, Allison A.; Gan, Ping; Yu, Ran

2014-01-01

Seasonal changes in arsenic and iron accumulation rates were examined in the sediments of a brook that receives groundwater discharges of arsenic and reduced iron. Clean glass bead columns were deployed in sediments for known periods over the annual hydrologic cycle to monitor changes in arsenic...... and iron concentrations in bead coatings. The highest accumulation rates occurred during the dry summer period (July-October) when groundwater discharges were likely greatest at the sample locations. The intermediate flow period (October-March), With higher surface water: levels, was associated with losses...... of arsenic and iron from bead column coatings at. depths below 2-6 cm. Batch incubations indicated iron releases from solids to be induced by biological reduction of iron (oxy)hydroxide solids. Congruent arsenic releases during incubation were limited by the high arsenic sorption capacity (0.536 mg...

Exercise Prevents Memory Impairment Induced by Arsenic Exposure in Mice: Implication of Hippocampal BDNF and CREB

OpenAIRE

Sun, Bao-Fei; Wang, Qing-Qing; Yu, Zi-Jiang; Yu, Yan; Xiao, Chao-Lun; Kang, Chao-Sheng; Ge, Guo; Linghu, Yan; Zhu, Jun-De; Li, Yu-Mei; Li, Qiang-Ming; Luo, Shi-Peng; Yang, Dang; Li, Lin; Zhang, Wen-Yan

2015-01-01

High concentrations of arsenic, which can be occasionally found in drinking water, have been recognized as a global health problem. Exposure to arsenic can disrupt spatial memory; however, the underlying mechanism remains unclear. In the present study, we tested whether exercise could interfere with the effect of arsenic exposure on the long-term memory (LTM) of object recognition in mice. Arsenic (0, 1, 3, and 10 mg/ kg, i.g.) was administered daily for 12 weeks. We found that arsenic at dos...

Mathematical model insights into arsenic detoxification

Directory of Open Access Journals (Sweden)

Nijhout H Frederik

2011-08-01

methyltransferase has been upregulated by a factor of two in this population. Finally, we also show that a modification of the model gives excellent fits to the data on arsenic metabolism in human cultured hepatocytes. Conclusions The analysis of the Bangladesh data using the model suggests that folate supplementation may be more effective at reducing whole body arsenic than previously expected. There is almost no data on the upregulation of arsenic methyltransferase in populations chronically exposed to arsenic. Our model predicts upregulation by a factor of two in the Bangladesh population studied. This prediction should be verified since it could have important public health consequences both for treatment strategies and for setting appropriate limits on arsenic in drinking water. Our model has compartments for the binding of arsenicals to proteins inside of cells and we show that these comparments are necessary to obtain good fits to data. Protein-binding of arsenicals should be explored in future biochemical studies.

Withaferin A Induces Cell Death Selectively in Androgen-Independent Prostate Cancer Cells but Not in Normal Fibroblast Cells.

Directory of Open Access Journals (Sweden)

Yukihiro Nishikawa

Full Text Available Withaferin A (WA, a major bioactive component of the Indian herb Withania somnifera, induces cell death (apoptosis/necrosis in multiple types of tumor cells, but the molecular mechanism underlying this cytotoxicity remains elusive. We report here that 2 μM WA induced cell death selectively in androgen-insensitive PC-3 and DU-145 prostate adenocarcinoma cells, whereas its toxicity was less severe in androgen-sensitive LNCaP prostate adenocarcinoma cells and normal human fibroblasts (TIG-1 and KD. WA also killed PC-3 cells in spheroid-forming medium. DNA microarray analysis revealed that WA significantly increased mRNA levels of c-Fos and 11 heat-shock proteins (HSPs in PC-3 and DU-145, but not in LNCaP and TIG-1. Western analysis revealed increased expression of c-Fos and reduced expression of the anti-apoptotic protein c-FLIP(L. Expression of HSPs such as HSPA6 and Hsp70 was conspicuously elevated; however, because siRNA-mediated depletion of HSF-1, an HSP-inducing transcription factor, reduced PC-3 cell viability, it is likely that these heat-shock genes were involved in protecting against cell death. Moreover, WA induced generation of reactive oxygen species (ROS in PC-3 and DU-145, but not in normal fibroblasts. Immunocytochemistry and immuno-electron microscopy revealed that WA disrupted the vimentin cytoskeleton, possibly inducing the ROS generation, c-Fos expression and c-FLIP(L suppression. These observations suggest that multiple events followed by disruption of the vimentin cytoskeleton play pivotal roles in WA-mediated cell death.

Investigation of biomethylation of arsenic and tellurium during composting

International Nuclear Information System (INIS)

Diaz-Bone, Roland A.; Raabe, Maren; Awissus, Simone; Keuter, Bianca; Menzel, Bernd; Kueppers, Klaus; Widmann, Renatus; Hirner, Alfred V.

2011-01-01

Though the process of composting features a high microbiological activity, its potential to methylate metals and metalloids has been little investigated so far in spite of the high impact of this process on metal(loid) toxicity and mobility. Here, we studied the biotransformation of arsenic, tellurium, antimony, tin and germanium during composting. Time resolved investigation revealed a highly dynamic process during self-heated composting with markedly differing time patterns for arsenic and tellurium species. Extraordinary high concentrations of up to 150 mg kg -1 methylated arsenic species as well as conversion rates up to 50% for arsenic and 5% for tellurium were observed. In contrast, little to no conversion was observed for antimony, tin and germanium. In addition to experiments with metal(loid) salts, composting of arsenic hyperaccumulating ferns Pteris vittata and P. cretica grown on As-amended soils was studied. Arsenic accumulated in the fronds was efficiently methylated resulting in up to 8 mg kg -1 methylated arsenic species. Overall, these studies indicate that metal(loid)s can undergo intensive biomethylation during composting. Due to the high mobility of methylated species this process needs to be considered in organic waste treatment of metal(loid) contaminated waste materials.

Ultramafic-derived arsenic in a fractured bedrock aquifer

International Nuclear Information System (INIS)

Ryan, Peter C.; Kim, Jonathan; Wall, Andrew J.; Moen, Jonathan C.; Corenthal, Lilly G.; Chow, Daniel R.; Sullivan, Colleen M.; Bright, Kevin S.

2011-01-01

Highlights: → Arsenic is elevated in groundwater from a fractured bedrock aquifer system in northern Vermont, USA. → The arsenic source is serpentinized ultramafic rock. → Antigorite, magnetite (MgCO 3 ) and magnetite (Fe 3 O 4 ) appear to be the main mineralogical hosts of arsenic in the ultramafic rock. → Arsenic appears to be introduced to the ultramafic rock when As-bearing fluids are driven out of sediments during subduction. → The occurrence of serpentinized ultramafic rocks in many orogenic belts suggests that similar arsenic anomalies may occur in geologically-similar terranes globally. - Abstract: In the fractured bedrock aquifer of northern Vermont, USA, As concentrations in groundwater range from 3 ) with lesser amounts in magnetite (Fe 3 O 4 ). Hydrochemistry of monitoring wells drilled into fractured ultramafic rock in a groundwater recharge area with no anthropogenic As source reveals above background As (2-9 μg/L) and an Mg-HCO 3 hydrochemical signature that reflects dissolution of antigorite and magnesite, confirming that As in groundwater can be derived from ultramafic rock dissolution. Arsenic mobility in groundwater affected by ultramafic rock dissolution may be enhanced by alkaline pH values and relatively high HCO 3 - concentrations.

Urinary arsenic profiles reveal exposures to inorganic arsenic from private drinking water supplies in Cornwall, UK

Science.gov (United States)

Middleton, D. R. S.; Watts, M. J.; Hamilton, E. M.; Ander, E. L.; Close, R. M.; Exley, K. S.; Crabbe, H.; Leonardi, G. S.; Fletcher, T.; Polya, D. A.

2016-05-01

Private water supplies (PWS) in Cornwall, South West England exceeded the current WHO guidance value and UK prescribed concentration or value (PCV) for arsenic of 10 μg/L in 5% of properties surveyed (n = 497). In this follow-up study, the first of its kind in the UK, volunteers (n = 207) from 127 households who used their PWS for drinking, provided urine and drinking water samples for total As determination by inductively coupled plasma mass spectrometry (ICP-MS) and urinary As speciation by high performance liquid chromatography ICP-MS (HPLC-ICP-MS). Arsenic concentrations exceeding 10 μg/L were found in the PWS of 10% of the volunteers. Unadjusted total urinary As concentrations were poorly correlated (Spearman’s ρ = 0.36 (P < 0.001)) with PWS As largely due to the use of spot urine samples and the dominance of arsenobetaine (AB) from seafood sources. However, the osmolality adjusted sum, U-AsIMM, of urinary inorganic As species, arsenite (AsIII) and arsenate (AsV), and their metabolites, methylarsonate (MA) and dimethylarsinate (DMA), was found to strongly correlate (Spearman’s ρ: 0.62 (P < 0.001)) with PWS As, indicating private water supplies as the dominant source of inorganic As exposure in the study population of PWS users.

Arsenic induced toxicity in broiler chicks and its alleviation with ascorbic acid: a toxico-patho-biochemical study

Science.gov (United States)

Khan, Ahrar; Sharaf, Rabia; Khan, Muhammad Zargham; Saleemi, Muhammad Kashif; Mahmood, Fazal

2013-01-01

To find out toxico-pathological effects of arsenic (As) and ameliorating effect of ascorbic acid (Vit C), broilers birds were administered 50 and 250 mg/kg arsenic and Vit C, respectively alone/in combination. As-treated birds exhibited severe signs of toxicity such as dullness, depression, increased thirst, open mouth breathing and watery diarrhea. All these signs were partially ameliorated with the treatment of Vit C. As-treated birds showed a significant decrease in serum total proteins while serum enzymes, urea and creatinine were significantly increased. Alkaline phosphatase and lactate dehydrogenase completely whereas proteins, aspartate aminotransferase (AST), alanine aminotransferase (ALT), urea and creatinine were partial ameliorated in birds treated with As+Vit C as compared to As-treated and control birds. Pale and hemorrhagic liver and swollen kidneys were observed in As-treated birds. Histopathologically, liver exhibited congestion and cytoplasmic vacuolation while in kidneys, condensation of tubular epithelium nuclei, epithelial necrosis, increased urinary spaces, sloughing of tubules from basement membrane and cast deposition were observed in As-treated birds. Pathological lesions were partially ameliorated with the treatment of Vit C. It can be concluded that arsenic induces biochemical and histopathological alterations in broiler birds; however, these toxic effects can be partially attenuated by Vit C.

Diverse arsenic- and iron-cycling microbial communities in arsenic-contaminated aquifers used for drinking water in Bangladesh.

Science.gov (United States)

Hassan, Zahid; Sultana, Munawar; van Breukelen, Boris M; Khan, Sirajul I; Röling, Wilfred F M

2015-04-01

Subsurface removal of arsenic by injection with oxygenated groundwater has been proposed as a viable technology for obtaining 'safe' drinking water in Bangladesh. While the oxidation of ferrous iron to solid ferric iron minerals, to which arsenic adsorbs, is assumed to be driven by abiotic reactions, metal-cycling microorganisms may potentially affect arsenic removal. A cultivation-independent survey covering 24 drinking water wells in several geographical regions in Bangladesh was conducted to obtain information on microbial community structure and diversity in general, and on specific functional groups capable of the oxidation or reduction of arsenic or iron. Each functional group, targeted by either group-specific 16S rRNA or functional gene amplification, occurred in at least 79% of investigated samples. Putative arsenate reducers and iron-oxidizing Gallionellaceae were present at low diversity, while more variation in potentially arsenite-oxidizing microorganisms and iron-reducing Desulfuromonadales was revealed within and between samples. Relations between community composition on the one hand and hydrochemistry on the other hand were in general not evident, apart from an impact of salinity on iron-cycling microorganisms. Our data suggest widespread potential for a positive contribution of arsenite and iron oxidizers to arsenic removal upon injection with oxygenated water, but also indicate a potential risk for arsenic re-mobilization by anaerobic arsenate and iron reducers once injection is halted. © FEMS 2015. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

An investigation of the health effects caused by exposure to arsenic from drinking water and coal combustion: arsenic exposure and metabolism.

Science.gov (United States)

Wei, Binggan; Yu, Jiangping; Kong, Chang; Li, Hairong; Yang, Linsheng; Guo, Zhiwei; Cui, Na; Xia, Yajuan; Wu, Kegong

2017-11-01

Few studies have been conducted to compare arsenic exposure, metabolism, and methylation in populations exposed to arsenic in drinking water and from coal combustion. Therefore, arsenic concentrations in the environment and arsenic speciation in the urine of subjects exposed to arsenic as a consequence of coal combustion in a rural area in Shaanxi province (CCA) and in drinking water in a rural area in Inner Mongolia (DWA) were investigated. The mean arsenic concentrations in drinking water, indoor air, and soil in CCA were 4.52 μg/L, 0.03 mg/m 3 , and 14.93 mg/kg, respectively. The mean arsenic concentrations in drinking water and soil in DWA were 144.71 μg/L and 10.19 mg/kg, respectively, while the level in indoor air was lower than the limit of detection. The total daily intakes of arsenic in DWA and CCA were 4.47 and 3.13 μg/day·kg, respectively. The mean urinary concentrations of inorganic arsenic (iAs), monomethylarsonic acid (MMA), dimethylarsenic acid (DMA), and total arsenic (TAs) for subjects with skin lesions in DWA were 50.41, 47.01, 202.66, and 300.08 μg/L. The concentrations for subjects without skin lesions were 49.76, 44.20, 195.60, and 289.56 μg/L, respectively. The %iAs, %MMA, and %DMA in the TAs in the urine of subjects from CCA were 12.24, 14.73, and 73.03%, while the corresponding values from DWA were 17.54, 15.57, and 66.89%, respectively. The subjects in DWA typically had a higher %iAs and %MMA, and a lower %DMA, and primary and secondary methylation index (PMI and SMI) than the subjects in CCA. It was concluded that the arsenic methylation efficiency of subjects in DWA and CCA was significantly influenced by chronic exposure to high levels of arsenic in the environment. The lower PMI and SMI values in DWA revealed lower arsenic methylation capacity due to ingestion of arsenic in drinking water. However, it remained unclear if the differences in arsenic metabolism between the two groups were due to differences in exposure levels

Helper T cell subpopulations from women are more susceptible to the toxic effect of sodium arsenite in vitro

International Nuclear Information System (INIS)

Vega, Libia; Montes de Oca, Pavel; Saavedra, Rafael; Ostrosky-Wegman, Patricia

2004-01-01

Arsenic is known to produce inhibition as well as induction of proliferative responses in animal and human cells depending on the doses. Despite the amount of information on the immunotoxic effects of arsenic exposure in different animal models, little is known in humans. Arsenic susceptibility of lymphocyte subpopulations (T helper (Th), CD4+; T cytotoxic (Tc), CD8+) and whether arsenic effects are gender related are still to be determined. This work evaluated the in vitro toxicity of sodium arsenite on human T lymphocyte subpopulations from men and women. Peripheral blood mononuclear cells (PBMC) obtained from healthy young men and women were treated with sodium arsenite (0.01, 0.1, and 1 μM). We assessed cell viability, cell proliferation, and the proportion of Th and Tc cells after 48 or 72 h of arsenic exposure in resting and phytohemagglutinin M (PHA)-activated PBMC. We observed that sodium arsenite at 1 μM was more toxic for Th than for Tc cells in PBMC from women. Besides, T lymphocytes from women were more affected by the cell proliferation inhibition induced by arsenic, suggesting that women could be more susceptible to the toxic and immunotoxic effects caused by arsenic exposure

The polymorphisms of P53 codon 72 and MDM2 SNP309 and renal cell carcinoma risk in a low arsenic exposure area

Energy Technology Data Exchange (ETDEWEB)

Huang, Chao-Yuan [Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan (China); Department of Urology, National Taiwan University Hospital, College of Medicine National Taiwan University, Taipei, Taiwan (China); Su, Chien-Tien [Department of Family Medicine, Taipei Medical University Hospital, Taipei, Taiwan (China); Chu, Jan-Show [Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan (China); Department of Pathology, College of Medicine, Taipei Medical University, Taipei, Taiwan (China); Huang, Shu-Pin [Department of Urology, Kaohsiung Medical University Hospital, College of Medicine Kaohsiung Medical University, Kaohsiung, Taiwan (China); Pu, Yeong-Shiau [Department of Urology, National Taiwan University Hospital, College of Medicine National Taiwan University, Taipei, Taiwan (China); Yang, Hsiu-Yuan [School of Public Health, College of Public Health and Nutrition, Taipei Medical University, Taipei, Taiwan (China); Chung, Chi-Jung [Department of Medical Research, China Medical University Hospital, Taichung, Taiwan (China); Department of Health Risk Management, College of Public Health, China Medical University, Taichung, Taiwan (China); Wu, Chia-Chang [School of Public Health, College of Public Health and Nutrition, Taipei Medical University, Taipei, Taiwan (China); Department of Urology, Taipei Medical Universtiy-Shuang Ho Hospital, Taipei, Taiwan (China); Hsueh, Yu-Mei, E-mail: ymhsueh@tmu.edu.tw [School of Public Health, College of Public Health and Nutrition, Taipei Medical University, Taipei, Taiwan (China); Department of Public Health, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan (China)

2011-12-15

Our recent study demonstrated the increased risk of renal cell carcinoma (RCC) associated with high urinary total arsenic levels among people living in a low arsenic exposure area. Genomic instability is important in arsenic carcinogenesis. This study evaluated the relationship between the polymorphisms of p53, p21, and MDM2, which plays a role in gene stability, and the arsenic-related RCC risk. Here, we found that p53 Pro/Pro genotype and MDM2 SNP309 GG genotype significantly increased RCC risk compared to the p53 Arg/Arg genotype and MDM2 SNP309 TT genotype. RCC patients with the p53Arg/Arg genotype had a signicantly low percentage of inorganic arsenic, a low percentage of monomethylarsonic acid (MMA), and a high percentage of dimethylarsinic acid (DMA), which indicates efcient arsenic methylation capacity. Subjects with the p53 Arg/Pro + Pro/Pro genotype or MDM2 SNP309 TG + GG genotype, in conjunction with high urinary total arsenic ({>=} 14.02 {mu}g/L), had a signicantly higher RCC risk than those with the p53 Arg/Arg or MDM2 SNP309 TT genotypes and low urinary total arsenic. Taken together, this is the first study to show that a variant genotype of p53 Arg{sup 72}Pro or MDM2 SNP309 may modify the arsenic-related RCC risk even in a non-obvious arsenic exposure area. -- Highlights: Black-Right-Pointing-Pointer Subjects with p53 Pro/Pro or MDM2 GG genotype significantly increased RCC risk. Black-Right-Pointing-Pointer A significant multiplicative joint effect of p53 and p21 on RCC risk. Black-Right-Pointing-Pointer RCC patients with p53 Arg/Arg genotype had efficient arsenic methylation capacity. Black-Right-Pointing-Pointer Joint effect of p53 or MDM2 genotype and high urinary total arsenic on RCC risk.

Evaluating the cement stabilization of arsenic-bearing iron wastes from drinking water treatment.

Science.gov (United States)

Clancy, Tara M; Snyder, Kathryn V; Reddy, Raghav; Lanzirotti, Antonio; Amrose, Susan E; Raskin, Lutgarde; Hayes, Kim F

2015-12-30

Cement stabilization of arsenic-bearing wastes is recommended to limit arsenic release from wastes following disposal. Such stabilization has been demonstrated to reduce the arsenic concentration in the Toxicity Characteristic Leaching Procedure (TCLP), which regulates landfill disposal of arsenic waste. However, few studies have evaluated leaching from actual wastes under conditions similar to ultimate disposal environments. In this study, land disposal in areas where flooding is likely was simulated to test arsenic release from cement stabilized arsenic-bearing iron oxide wastes. After 406 days submersed in chemically simulated rainwater, wastes. Presenting the first characterization of cement stabilized waste using μXRF, these results revealed the majority of arsenic in cement stabilized waste remained associated with iron. This distribution of arsenic differed from previous observations of calcium-arsenic solid phases when arsenic salts were stabilized with cement, illustrating that the initial waste form influences the stabilized form. Overall, cement stabilization is effective for arsenic-bearing wastes when acidic conditions can be avoided. Copyright © 2015 Elsevier B.V. All rights reserved.

Nickel induces transcriptional down-regulation of DNA repair pathways in tumorigenic and non-tumorigenic lung cells.

Science.gov (United States)

Scanlon, Susan E; Scanlon, Christine D; Hegan, Denise C; Sulkowski, Parker L; Glazer, Peter M

2017-06-01

The heavy metal nickel is a known carcinogen, and occupational exposure to nickel compounds has been implicated in human lung and nasal cancers. Unlike many other environmental carcinogens, however, nickel does not directly induce DNA mutagenesis, and the mechanism of nickel-related carcinogenesis remains incompletely understood. Cellular nickel exposure leads to signaling pathway activation, transcriptional changes and epigenetic remodeling, processes also impacted by hypoxia, which itself promotes tumor growth without causing direct DNA damage. One of the mechanisms by which hypoxia contributes to tumor growth is the generation of genomic instability via down-regulation of high-fidelity DNA repair pathways. Here, we find that nickel exposure similarly leads to down-regulation of DNA repair proteins involved in homology-dependent DNA double-strand break repair (HDR) and mismatch repair (MMR) in tumorigenic and non-tumorigenic human lung cells. Functionally, nickel induces a defect in HDR capacity, as determined by plasmid-based host cell reactivation assays, persistence of ionizing radiation-induced DNA double-strand breaks and cellular hypersensitivity to ionizing radiation. Mechanistically, we find that nickel, in contrast to the metalloid arsenic, acutely induces transcriptional repression of HDR and MMR genes as part of a global transcriptional pattern similar to that seen with hypoxia. Finally, we find that exposure to low-dose nickel reduces the activity of the MLH1 promoter, but only arsenic leads to long-term MLH1 promoter silencing. Together, our data elucidate novel mechanisms of heavy metal carcinogenesis and contribute to our understanding of the influence of the microenvironment on the regulation of DNA repair pathways. © The Author 2017. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Detection of trace amount of arsenic in groundwater by laser-induced breakdown spectroscopy and adsorption

Science.gov (United States)

Haider, A. F. M. Y.; Hedayet Ullah, M.; Khan, Z. H.; Kabir, Firoza; Abedin, K. M.

2014-03-01

LIBS technique coupled with adsorption has been applied for the efficient detection of arsenic in liquid. Several adsorbents like tea leaves, bamboo slice, charcoal and zinc oxide have been used to enable sensitive detection of arsenic presence in water using LIBS. Among these, zinc oxide and charcoal show the better results. The detection limits for arsenic in water were 1 ppm and 8 ppm, respectively, when ZnO and charcoal were used as adsorbents of arsenic. To date, the determination of 1 ppm of As in water is the lowest concentration of detected arsenic in water by the LIBS technique. The detection limit of As was lowered to even less than 100 ppb by a combination of LIBS technique, adsorption by ZnO and concentration enhancement technique. Using the combination of these three techniques the ultimate concentration of arsenic was found to be 0.083 ppm (83 ppb) for arsenic polluted water collected from a tube-well of Farajikandi union (longitude 90.64°, latitude 23.338° north) of Matlab Upozila of Chandpur district in Bangladesh. This result compares fairly well with the finding of arsenic concentration of 0.078 ppm in the sample by the AAS technique at the Bangladesh Council of Scientific and Industrial Research (BCSIR) lab. Such a low detection limit (1 ppm) of trace elements in liquid matrix has significantly enhanced the scope of LIBS as an analytical tool.

Phytoremediation of arsenic contaminated soil by arsenic accumulators: a three year study.

Science.gov (United States)

Raj, Anshita; Singh, Nandita

2015-03-01

To investigate whether phytoremediation can remove arsenic from the contaminated area, a study was conducted for three consecutive years to determine the efficiency of Pteris vittata, Adiantum capillus veneris, Christella dentata and Phragmites karka, on arsenic removal from the arsenic contaminated soil. Arsenic concentrations in the soil samples were analysed after harvesting in 2009, 2010 and 2011 at an interval of 6 months. Frond arsenic concentrations were also estimated in all the successive harvests. Fronds resulted in the greatest amount of arsenic removal. Root arsenic concentrations were analysed in the last harvest. Approximately 70 % of arsenic was removed by P. vittata which was recorded as the highest among the four plant species. However, 60 % of arsenic was removed by A. capillus veneris, 55.1 % by C. dentata and 56.1 % by P. karka of arsenic was removed from the contaminated soil in 3 years.

Polyphosphate induces matrix metalloproteinase-3-mediated proliferation of odontoblast-like cells derived from induced pluripotent stem cells

Energy Technology Data Exchange (ETDEWEB)

Ozeki, Nobuaki; Hase, Naoko; Yamaguchi, Hideyuki; Hiyama, Taiki; Kawai, Rie [Department of Endodontics, School of Dentistry, Aichi Gakuin University, 2-11 Suemori-dori, Chikusa-ku, Nagoya, Aichi 464-8651 (Japan); Kondo, Ayami [Department of Medicinal Biochemistry, School of Pharmacy, Aichi Gakuin University, 1-100 Kusumoto, Chikusa-ku, Nagoya 464-8650 (Japan); Nakata, Kazuhiko [Department of Endodontics, School of Dentistry, Aichi Gakuin University, 2-11 Suemori-dori, Chikusa-ku, Nagoya, Aichi 464-8651 (Japan); Mogi, Makio, E-mail: makio@dpc.agu.ac.jp [Department of Medicinal Biochemistry, School of Pharmacy, Aichi Gakuin University, 1-100 Kusumoto, Chikusa-ku, Nagoya 464-8650 (Japan)

2015-05-01

Inorganic polyphosphate [Poly(P)] may represent a physiological source of phosphate and has the ability to induce bone differentiation in osteoblasts. We previously reported that cytokine-induced matrix metalloproteinase (MMP)-3 accelerates the proliferation of purified odontoblast-like cells. In this study, MMP-3 small interfering RNA (siRNA) was transfected into odontoblast-like cells derived from induced pluripotent stem cells to investigate whether MMP-3 activity is induced by Poly(P) and/or is associated with cell proliferation and differentiation into odontoblast-like cells. Treatment with Poly(P) led to an increase in both cell proliferation and additional odontoblastic differentiation. Poly(P)-treated cells showed a small but significant increase in dentin sialophosphoprotein (DSPP) and dentin matrix protein-1 (DMP-1) mRNA expression, which are markers of mature odontoblasts. The cells also acquired additional odontoblast-specific properties including adoption of an odontoblastic phenotype typified by high alkaline phosphatase (ALP) activity and a calcification capacity. In addition, Poly(P) induced expression of MMP-3 mRNA and protein, and increased MMP-3 activity. MMP-3 siRNA-mediated disruption of the expression of these effectors potently suppressed the expression of odontoblastic biomarkers ALP, DSPP, and DMP-1, and blocked calcification. Interestingly, upon siRNA-mediated silencing of MMP-3, we noted a potent and significant decrease in cell proliferation. Using specific siRNAs, we revealed that a unique signaling cascade, Poly(P)→MMP-3→DSPP and/or DMP-1, was intimately involved in the proliferation of odontoblast-like cells. - Highlights: • Polyphosphate increases proliferation of iPS cell-derived odontoblast-like cells. • Polyphosphate-induced MMP-3 results in an increase of cell proliferation. • Induced cell proliferation involves MMP-3, DSPP, and/or DMP-1 sequentially. • Induced MMP-3 also results in an increase of odontoblastic

Arsenic and diabetes and hypertension in human populations: A review

International Nuclear Information System (INIS)

Chen, C.-J.; Wang, S.-L.; Chiou, J.-M.; Tseng, C.-H.; Chiou, H.-Y.; Hsueh, Y.-M.; Chen, S.-Y.; Wu, M.-M.; Lai, M.-S.

2007-01-01

Long-term exposure to ingested arsenic from drinking water has been well documented to be associated with an increased risk of diabetes mellitus and hypertension in a dose-response relationship among residents of arseniasis-endemic areas in southwestern Taiwan and Bangladesh. An increased risk of self-reported hypertension but not diabetes was reported in a community-based study of residents who consumed drinking water with a low level of arsenic. Increased glycosylated hemoglobin level and systolic blood pressure were observed in workers occupationally exposed to arsenic. Inconsistent findings of arsenic and diabetes in occupational studies may result from the healthy worker effect and the variation in exposure measurement, age composition, number of patients, accuracy in diagnosis and classification of underlying causes of death, competing causes of death, and method to detect diabetes. The dose-response relationship and toxicological mechanisms of arsenic-induced diabetes and hypertension need further elucidation

Analytical artefacts in the speciation of arsenic in clinical samples

International Nuclear Information System (INIS)

Slejkovec, Zdenka; Falnoga, Ingrid; Goessler, Walter; Elteren, Johannes T. van; Raml, Reingard; Podgornik, Helena; Cernelc, Peter

2008-01-01

Urine and blood samples of cancer patients, treated with high doses of arsenic trioxide were analysed for arsenic species using HPLC-HGAFS and, in some cases, HPLC-ICPMS. Total arsenic was determined with either flow injection-HGAFS in urine or radiochemical neutron activation analysis in blood fractions (in serum/plasma, blood cells). The total arsenic concentrations (during prolonged, daily/weekly arsenic trioxide therapy) were in the μg mL -1 range for urine and in the ng g -1 range for blood fractions. The main arsenic species found in urine were As(III), MA and DMA and in blood As(V), MA and DMA. With proper sample preparation and storage of urine (no preservation agents/storage in liquid nitrogen) no analytical artefacts were observed and absence of significant amounts of alleged trivalent metabolites was proven. On the contrary, in blood samples a certain amount of arsenic can get lost in the speciation procedure what was especially noticeable for the blood cells although also plasma/serum gave rise to some disappearance of arsenic. The latter losses may be attributed to precipitation of As(III)-containing proteins/peptides during the methanol/water extraction procedure whereas the former losses were due to loss of specific As(III)-complexing proteins/peptides (e.g. cysteine, metallothionein, reduced GSH, ferritin) on the column (Hamilton PRP-X100) during the separation procedure. Contemporary analytical protocols are not able to completely avoid artefacts due to losses from the sampling to the detection stage so that it is recommended to be careful with the explanation of results, particularly regarding metabolic and pharmacokinetic interpretations, and always aim to compare the sum of species with the total arsenic concentration determined independently

Matrix metalloproteinase-9 is involved in chronic lymphocytic leukemia cell response to fludarabine and arsenic trioxide.

Directory of Open Access Journals (Sweden)

Irene Amigo-Jiménez

Full Text Available Matrix metalloproteinase-9 (MMP-9 contributes to chronic lymphocytic leukemia (CLL pathology by regulating cell migration and preventing spontaneous apoptosis. It is not known if MMP-9 is involved in CLL cell response to chemotherapy and we address this in the present study, using arsenic trioxide (ATO and fludarabine as examples of cytotoxic drugs.We used primary cells from the peripheral blood of CLL patients and MEC-1 cells stably transfected with an empty vector or a vector containing MMP-9. The effect of ATO and fludarabine was determined by flow cytometry and by the MTT assay. Expression of mRNA was measured by RT-PCR and qPCR. Secreted and cell-bound MMP-9 was analyzed by gelatin zymography and flow cytometry, respectively. Protein expression was analyzed by Western blotting and immunoprecipitation. Statistical analyses were performed using the two-tailed Student's t-test.In response to ATO or fludarabine, CLL cells transcriptionally upregulated MMP-9, preceding the onset of apoptosis. Upregulated MMP-9 primarily localized to the membrane of early apoptotic cells and blocking apoptosis with Z-VAD prevented MMP-9 upregulation, thus linking MMP-9 to the apoptotic process. Culturing CLL cells on MMP-9 or stromal cells induced drug resistance, which was overcome by anti-MMP-9 antibodies. Accordingly, MMP-9-MEC-1 transfectants showed higher viability upon drug treatment than Mock-MEC-1 cells, and this effect was blocked by silencing MMP-9 with specific siRNAs. Following drug exposure, expression of anti-apoptotic proteins (Mcl-1, Bcl-xL, Bcl-2 and the Mcl-1/Bim, Mcl-1/Noxa, Bcl-2/Bax ratios were higher in MMP-9-cells than in Mock-cells. Similar results were obtained upon culturing primary CLL cells on MMP-9.Our study describes for the first time that MMP-9 induces drug resistance by modulating proteins of the Bcl-2 family and upregulating the corresponding anti-apoptotic/pro-apoptotic ratios. This is a novel role for MMP-9 contributing to CLL