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Kaiser CS, Lubisch M, Schröder E, Ressmann L, Nicolaus M, Leusder D, Moyzio S, Peuss R, Miranda-Vizuete A, Liebau E. Unraveling the functional dynamics of Caenorhabditis elegans stress-responsive omega class GST-44. FEBS J 2025. [PMID: 40186509 DOI: 10.1111/febs.70088] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2024] [Revised: 02/24/2025] [Accepted: 03/06/2025] [Indexed: 04/07/2025]
Abstract
Glutathione transferases from the omega class are notable for their roles in redox regulation and cellular stress response. In this study, we conducted a comprehensive functional characterization of GST-44, an omega-class glutathione S-transferase (GSTO), in Caenorhabditis elegans, focusing on its role in cellular defense mechanisms against stress. Biochemical analysis revealed GSTO-specific enzymatic activities of recombinant GST-44, including dehydroascorbate reductase, thioltransferase, and arsenate reductase activities. Using transgenic GFP reporter strains, we identified predominant expression of GST-44 in the intestine and excretory H-cell, with significant upregulation observed under diverse stress conditions. Induction of GST-44 was particularly pronounced in the intestine in response to pathogen-, oxidative-, and endoplasmic reticulum stress. Notably, under arsenic stress, the expression of gst-44 was significantly upregulated in the excretory system of the worm, underscoring its critical role in mediating arsenic detoxification. Moreover, we demonstrated the induction of GST-44 using dimethyl fumarate, a highly specific mammalian Nrf-2 activator. The upregulation of GST-44 during arsenic stress was dependent not only on the oxidative stress response transcription factor SKN-1/Nrf2 but also on PHA-4. The deletion mutant strain gst-44(tm6133) exhibited reduced stress resistance and a shortened lifespan, with a highly diminished survival rate under arsenic stress compared to other CRISPR-generated C. elegans GSTO deletion mutants. Our findings highlight the essential role of GST-44 in mediating arsenic detoxification, as well as in stress adaptation and defense mechanisms in C. elegans.
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Affiliation(s)
| | - Milena Lubisch
- Institute of Integrative Cell Biology and Physiology, University of Münster, Germany
| | - Emma Schröder
- Institute of Integrative Cell Biology and Physiology, University of Münster, Germany
| | - Luka Ressmann
- Institute of Integrative Cell Biology and Physiology, University of Münster, Germany
| | - Marie Nicolaus
- Institute of Integrative Cell Biology and Physiology, University of Münster, Germany
| | - Dustin Leusder
- Institute of Integrative Cell Biology and Physiology, University of Münster, Germany
| | - Sven Moyzio
- Institute of Integrative Cell Biology and Physiology, University of Münster, Germany
| | - Robert Peuss
- Institute of Integrative Cell Biology and Physiology, University of Münster, Germany
| | - Antonio Miranda-Vizuete
- Redox Homeostasis Group, Instituto de Biomedicina de Sevilla (IBIS), Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, Spain
| | - Eva Liebau
- Institute of Integrative Cell Biology and Physiology, University of Münster, Germany
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Ran X, Yan X, Ma G, Liang Z, Zhuang H, Tang X, Chen X, Cao X, Liu X, Huang Y, Wang Y, Zhang X, Luo P, Shen L. Integration of proteomics and metabolomics analysis investigate mechanism of As-induced immune injury in rat spleen. ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY 2024; 284:116913. [PMID: 39208582 DOI: 10.1016/j.ecoenv.2024.116913] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/05/2024] [Revised: 08/12/2024] [Accepted: 08/20/2024] [Indexed: 09/04/2024]
Abstract
Arsenic (As) is a widespread metalloid and human carcinogen found in the natural environment, and multiple toxic effects have been shown to be associated with As exposure. As can be accumulated in the spleen, the largest peripheral lymphatic organ, and long-term exposure to As can lead to splenic injury. In this study, a Sprague-Dawley (SD) rat model of As-poisoned was established, aiming to explore the molecular mechanism of As-induced immune injury through the combined analysis of proteomics and metabolomics of rats' spleen. After feeding the rats with As diet (50 mg/kg) for 90 days, the spleen tissue of the rats in the As-poisoned group was damaged, the level of As was significantly higher than that of the control group (P < 0.001), and the level of inflammatory cytokine interleukin-6 (IL-6) was decreased (P < 0.01). Proteomics and metabolomics results showed that a total of 134 differentially expressed proteins (DEPs) (P < 0.05 and fold change > 1.2) and 182 differentially expressed metabolites (DEMs) (VIP >1 and P < 0.05) were identified in the spleens of the As poisoned group compared to the control group (As/Ctrl). The proteomic results highlight the role of hypoxia-inducible factors (HIF), natural killer cell mediated cytotoxicity, and ribosomes. The major pathways of metabolic disruption included arachidonic acid (AA) metabolism, glycerophospholipid metabolism and folate single-carbon pool. The integrated analysis of these two omics suggested that Hmox1, Stat3, arachidonic acid, phosphatidylcholine and leukotriene B4 may play key roles in the mechanism of immune injury to the spleen by As exposure. The results indicate that As exposure can cause spleen damage in rats. Through proteomic and metabolomic analysis, the key proteins and metabolites and their associated mechanisms were obtained, which provided a basis for further understanding of the molecular mechanism of spleen immune damage caused by As exposure.
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Affiliation(s)
- Xiaoqian Ran
- School of Public Health, the Key Laboratory of Environmental Pollution Monitoring and Disease Control, Ministry of Education, Guizhou Medical University, Guiyang 561113, PR China
| | - Xi Yan
- School of Public Health, the Key Laboratory of Environmental Pollution Monitoring and Disease Control, Ministry of Education, Guizhou Medical University, Guiyang 561113, PR China
| | - Guanwei Ma
- School of Public Health, the Key Laboratory of Environmental Pollution Monitoring and Disease Control, Ministry of Education, Guizhou Medical University, Guiyang 561113, PR China
| | - Zhiyuan Liang
- College of Life Science and Oceanography, Shenzhen University, Shenzhen 518060, PR China
| | - Hongbin Zhuang
- College of Life Science and Oceanography, Shenzhen University, Shenzhen 518060, PR China
| | - Xiaoxiao Tang
- College of Life Science and Oceanography, Shenzhen University, Shenzhen 518060, PR China
| | - Xiaolu Chen
- School of Public Health, the Key Laboratory of Environmental Pollution Monitoring and Disease Control, Ministry of Education, Guizhou Medical University, Guiyang 561113, PR China
| | - Xueshan Cao
- College of Life Science and Oceanography, Shenzhen University, Shenzhen 518060, PR China
| | - Xukun Liu
- College of Life Science and Oceanography, Shenzhen University, Shenzhen 518060, PR China
| | - Yuhan Huang
- College of Life Science and Oceanography, Shenzhen University, Shenzhen 518060, PR China
| | - Yi Wang
- School of Public Health, the Key Laboratory of Environmental Pollution Monitoring and Disease Control, Ministry of Education, Guizhou Medical University, Guiyang 561113, PR China
| | - Xinglai Zhang
- School of Public Health, the Key Laboratory of Environmental Pollution Monitoring and Disease Control, Ministry of Education, Guizhou Medical University, Guiyang 561113, PR China
| | - Peng Luo
- School of Public Health, the Key Laboratory of Environmental Pollution Monitoring and Disease Control, Ministry of Education, Guizhou Medical University, Guiyang 561113, PR China; Collaborative Innovation Center for Prevention and Control of Endemic and Ethnic Regional Diseases Co-constructed by the Province and Ministry, Guizhou Medical University, Guiyang 561113, China; Guizhou Ecological Food Innovation Engineering Research Center, Guiyang 561113, China; State Key Laboratory of Functions and Applications of Medicinal Plants, Guizhou Medical University, Guiyang 550014, China.
| | - Liming Shen
- School of Public Health, the Key Laboratory of Environmental Pollution Monitoring and Disease Control, Ministry of Education, Guizhou Medical University, Guiyang 561113, PR China; College of Life Science and Oceanography, Shenzhen University, Shenzhen 518060, PR China.
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Schrenk D, Bignami M, Bodin L, Chipman JK, del Mazo J, Grasl‐Kraupp B, Hogstrand C, Hoogenboom L(R, Leblanc J, Nebbia CS, Nielsen E, Ntzani E, Petersen A, Sand S, Vleminckx C, Wallace H, Barregård L, Benford D, Dogliotti E, Francesconi K, Gómez Ruiz JÁ, Steinkellner H, Tauriainen T, Schwerdtle T. Risk assessment of small organoarsenic species in food. EFSA J 2024; 22:e8844. [PMID: 38957748 PMCID: PMC11217773 DOI: 10.2903/j.efsa.2024.8844] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 07/04/2024] Open
Abstract
The European Commission asked EFSA for a risk assessment on small organoarsenic species in food. For monomethylarsonic acid MMA(V), decreased body weight resulting from diarrhoea in rats was identified as the critical endpoint and a BMDL10 of 18.2 mg MMA(V)/kg body weight (bw) per day (equivalent to 9.7 mg As/kg bw per day) was calculated as a reference point (RP). For dimethylarsinic acid DMA(V), increased incidence in urinary bladder tumours in rats was identified as the critical endpoint. A BMDL10 of 1.1 mg DMA(V)/kg bw per day (equivalent to 0.6 mg As/kg bw per day) was calculated as an RP. For other small organoarsenic species, the toxicological data are insufficient to identify critical effects and RPs, and they could not be included in the risk assessment. For both MMA(V) and DMA(V), the toxicological database is incomplete and a margin of exposure (MOE) approach was applied for risk characterisation. The highest chronic dietary exposure to DMA(V) was estimated in 'Toddlers', with rice and fish meat as the main contributors across population groups. For MMA(V), the highest chronic dietary exposures were estimated for high consumers of fish meat and processed/preserved fish in 'Infants' and 'Elderly' age class, respectively. For MMA(V), an MOE of ≥ 500 was identified not to raise a health concern. For MMA(V), all MOEs were well above 500 for average and high consumers and thus do not raise a health concern. For DMA(V), an MOE of 10,000 was identified as of low health concern as it is genotoxic and carcinogenic, although the mechanisms of genotoxicity and its role in carcinogenicity of DMA(V) are not fully elucidated. For DMA(V), MOEs were below 10,000 in many cases across dietary surveys and age groups, in particular for some 95th percentile exposures. The Panel considers that this would raise a health concern.
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Yan X, Zhang J, Li J, Zhang X, Wang Y, Chen X, Luo P, Hu T, Cao X, Zhuang H, Tang X, Yao F, He Z, Ma G, Ran X, Shen L. Effects of arsenic exposure on trace element levels in the hippocampus and cortex of rats and their gender differences. J Trace Elem Med Biol 2023; 80:127289. [PMID: 37660573 DOI: 10.1016/j.jtemb.2023.127289] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/31/2023] [Revised: 08/09/2023] [Accepted: 08/21/2023] [Indexed: 09/05/2023]
Abstract
BACKGROUND Exposure to arsenic (As) is a major public health challenge worldwide. Chronic exposure to As can cause various human health effects, including skin diseases, cardiovascular disease, neurological disorders, and cancer. Studies have shown that As exposure can lead to disturbances in the balance of trace elements in the body. Moreover, As readily crosses the blood-brain barrier and can be enriched in the hippocampus and cortex, causing neurotoxic damage. At present, there are few reports on the effect of As on trace element levels in the central nervous system (CNS). Therefore, we sought to explore As-induced neurotoxicity and the effects of As on CNS trace element levels. METHODS An As-induced neurological injury model in rats was established by feeding As chow for 90 days of continuous exposure, and 19 elements were detected in the hippocampus and cortex of As-exposed rats by inductively coupled plasma mass spectrometry. RESULTS The results showed that the As levels in the hippocampus and cortex of As-exposed rats were significantly higher than those in the control group, The As levels in the cortex were significantly higher than in the hippocampus group. The levels of Cd, Ho, and Rb were increased in the hippocampus and decreased in Au, Ba, Ce, Cs, Pd, Se, Sr, and Tl in the As-exposed group, while the levels of Cd and Rb were increased and Se and Au were decreased in the cortex. Significant gender differences in the effects of As on hippocampal Cd, Ba, Rb, and Sr, and cortical Cd and Mo. CONCLUSION It is suggested that elemental imbalance may be a risk factor for developing As toxicity plays a synergistic or antagonistic role in As-induced toxicity and is closely related to As-induced CNS damage.
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Affiliation(s)
- Xi Yan
- College of Life Science and Oceanography, Shenzhen University, Shenzhen 518060, PR China; School of Public Health, the key Laboratory of Environmental Pollution Monitoring and Disease Control, Ministry of Education, Guizhou Medical University, Guiyang 550025, PR China
| | - Jun Zhang
- College of Life Science and Oceanography, Shenzhen University, Shenzhen 518060, PR China; School of Public Health, the key Laboratory of Environmental Pollution Monitoring and Disease Control, Ministry of Education, Guizhou Medical University, Guiyang 550025, PR China
| | - Junyu Li
- Shenzhen Customs Food Inspection and Quarantine Technology Centre, Shenzhen 518000, PR China
| | - Xinglai Zhang
- College of Life Science and Oceanography, Shenzhen University, Shenzhen 518060, PR China; School of Public Health, the key Laboratory of Environmental Pollution Monitoring and Disease Control, Ministry of Education, Guizhou Medical University, Guiyang 550025, PR China
| | - Yi Wang
- College of Life Science and Oceanography, Shenzhen University, Shenzhen 518060, PR China; School of Public Health, the key Laboratory of Environmental Pollution Monitoring and Disease Control, Ministry of Education, Guizhou Medical University, Guiyang 550025, PR China
| | - Xiaolu Chen
- College of Life Science and Oceanography, Shenzhen University, Shenzhen 518060, PR China; School of Public Health, the key Laboratory of Environmental Pollution Monitoring and Disease Control, Ministry of Education, Guizhou Medical University, Guiyang 550025, PR China
| | - Peng Luo
- School of Public Health, the key Laboratory of Environmental Pollution Monitoring and Disease Control, Ministry of Education, Guizhou Medical University, Guiyang 550025, PR China
| | - Ting Hu
- School of Public Health, the key Laboratory of Environmental Pollution Monitoring and Disease Control, Ministry of Education, Guizhou Medical University, Guiyang 550025, PR China
| | - Xueshan Cao
- College of Life Science and Oceanography, Shenzhen University, Shenzhen 518060, PR China
| | - Hongbin Zhuang
- College of Life Science and Oceanography, Shenzhen University, Shenzhen 518060, PR China
| | - Xiaoxiao Tang
- College of Life Science and Oceanography, Shenzhen University, Shenzhen 518060, PR China
| | - Fang Yao
- College of Life Science and Oceanography, Shenzhen University, Shenzhen 518060, PR China
| | - Zhijun He
- College of Life Science and Oceanography, Shenzhen University, Shenzhen 518060, PR China
| | - Guanwei Ma
- College of Life Science and Oceanography, Shenzhen University, Shenzhen 518060, PR China; School of Public Health, the key Laboratory of Environmental Pollution Monitoring and Disease Control, Ministry of Education, Guizhou Medical University, Guiyang 550025, PR China
| | - Xiaoqian Ran
- College of Life Science and Oceanography, Shenzhen University, Shenzhen 518060, PR China; School of Public Health, the key Laboratory of Environmental Pollution Monitoring and Disease Control, Ministry of Education, Guizhou Medical University, Guiyang 550025, PR China
| | - Liming Shen
- College of Life Science and Oceanography, Shenzhen University, Shenzhen 518060, PR China; Shenzhen-Hong Kong Institute of Brain Science-Shenzhen Fundamental Research Institutions, Shenzhen 518055, PR China.
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Gao C, Lin L, Li J, Wu M, Lv J, Tian S, Hai X. Monomethylarsonous acid binds to Cys-104α and Cys-112β of hemoglobin in acute promyelocytic leukemia patients treated with arsenic trioxide. Toxicol Lett 2023; 380:31-39. [PMID: 37024065 DOI: 10.1016/j.toxlet.2023.04.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2022] [Revised: 01/29/2023] [Accepted: 04/03/2023] [Indexed: 04/08/2023]
Abstract
Arsenic trioxide (As2O3) has prominent effect in treating acute promyelocytic leukemia (APL). Identification of arsenic-binding proteins has gained attention for their important biological functions. However, none has been published concerning the binding mechanism of arsenic with hemoglobin (Hb) in APL patients after treatment of As2O3. The present study discloses the binding sites of arsenic on Hb in APL patients. Concentrations of inorganic arsenic (iAs), monomethyl arsenic (MMA), and dimethyl arsenic (DMA) in erythrocytes of APL patients were quantified using HPLC-inductively coupled plasma-mass spectroscopy (HPLC-ICP-MS). Hb-bound arsenic was identified by size-exclusion chromatography ICP-MS. The binding sites of arsenic on Hb were determined by mass spectrometry (MS). The concentration trend of arsenic species in erythrocytes of 9 APL patients treated with As2O3 was iAs>MMA>DMA, and MMA was the predominant methylated arsenic metabolite. Size-exclusion chromatography separation of free and protein-bound arsenic by simultaneous monitoring of 57Fe and 75As demonstrated the presence of Hb-bound arsenic. MS information suggested monomethylarsonous (MMAIII) was the dominant arsenic bound to Hb, and further identified that Cys-104α and Cys-112β were two binding sites of MMAIII in Hb. MMAIII binding to Cys-104α and Cys-112β was responsible for arsenic accumulation in erythrocytes of APL patients. This interaction may contribute to understand the therapeutic effect of As2O3 as an anticancer drug and its toxicity on APL patients.
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Affiliation(s)
- Chunlu Gao
- Department of Pharmacy, First Affiliated Hospital of Harbin Medical University, 23 Youzheng Street, Nangang District, Harbin, 150001, China
| | - Liwang Lin
- Department of Pharmacy, First Affiliated Hospital of Harbin Medical University, 23 Youzheng Street, Nangang District, Harbin, 150001, China
| | - Jing Li
- Department of Pharmacy, First Affiliated Hospital of Guangxi Medical University, Nanning, 530021, China
| | - Mengliang Wu
- Heilongjiang University of Chinese Medicine, 24 Heping Road, Xiangfang District, Harbin, 150040, China
| | - Jian Lv
- Department of Pharmacy, First Affiliated Hospital of Harbin Medical University, 23 Youzheng Street, Nangang District, Harbin, 150001, China
| | - Shuo Tian
- Heilongjiang University of Chinese Medicine, 24 Heping Road, Xiangfang District, Harbin, 150040, China
| | - Xin Hai
- Department of Pharmacy, First Affiliated Hospital of Harbin Medical University, 23 Youzheng Street, Nangang District, Harbin, 150001, China.
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El-Ghiaty MA, El-Kadi AO. Arsenic: Various species with different effects on cytochrome P450 regulation in humans. EXCLI JOURNAL 2021; 20:1184-1242. [PMID: 34512225 PMCID: PMC8419240 DOI: 10.17179/excli2021-3890] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/17/2021] [Accepted: 07/02/2021] [Indexed: 11/22/2022]
Abstract
Arsenic is well-recognized as one of the most hazardous elements which is characterized by its omnipresence throughout the environment in various chemical forms. From the simple inorganic arsenite (iAsIII) and arsenate (iAsV) molecules, a multitude of more complex organic species are biologically produced through a process of metabolic transformation with biomethylation being the core of this process. Because of their differential toxicity, speciation of arsenic-based compounds is necessary for assessing health risks posed by exposure to individual species or co-exposure to several species. In this regard, exposure assessment is another pivotal factor that includes identification of the potential sources as well as routes of exposure. Identification of arsenic impact on different physiological organ systems, through understanding its behavior in the human body that leads to homeostatic derangements, is the key for developing strategies to mitigate its toxicity. Metabolic machinery is one of the sophisticated body systems targeted by arsenic. The prominent role of cytochrome P450 enzymes (CYPs) in the metabolism of both endobiotics and xenobiotics necessitates paying a great deal of attention to the possible effects of arsenic compounds on this superfamily of enzymes. Here we highlight the toxicologically relevant arsenic species with a detailed description of the different environmental sources as well as the possible routes of human exposure to these species. We also summarize the reported findings of experimental investigations evaluating the influence of various arsenicals on different members of CYP superfamily using human-based models.
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Affiliation(s)
- Mahmoud A. El-Ghiaty
- Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Alberta, Canada
| | - Ayman O.S. El-Kadi
- Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Alberta, Canada
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BOO induces fibrosis and EMT in urothelial cells which can be recapitulated in vitro through elevated storage and voiding pressure cycles. Int Urol Nephrol 2021; 53:2007-2018. [PMID: 34232473 DOI: 10.1007/s11255-021-02942-3] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2021] [Accepted: 06/30/2021] [Indexed: 10/20/2022]
Abstract
PURPOSE To determine the unique contributions from elevated voiding and storage pressures in the development of fibrosis and the epithelial-to-mesenchymal transition (EMT) in urothelial cells, and how progressive BOO pressure cycling is an important mechanical cue leading to these pathological changes. MATERIALS AND METHODS Urothelial cells isolated from control, SHAM, 2 (acute)- or 6 (chronic)-week BOO rats treated with an inflammasome inhibitor or no drug. Total RNA was isolated and RT-PCR was conducted with custom primers for pro-fibrotic and EMT genes. In separate experiments, a rat urothelial cell line was exposed to cyclic pressure regimes characteristic of acute and chronic BOO in the presence or absence of an inflammasome inhibitor. Following exposure, RT-PCR was conducted, collagen content was determined and intracellular caspase-1 activity was measured. RESULTS Urothelial cells isolated from acute and chronic BOO rat models demonstrated expression of pro-fibrotic and EMT genes. Similarly, MYP3 rat urothelial cells subjected to pressure cycling regimes that reflect intravesical pressures in the acute or chronic BOO bladder also demonstrated increased expression of pro-fibrotic and EMT genes, along with elevated soluble collagen. Treatment with inflammasome inhibitors reduced expression of pro-fibrotic genes in the rat model and pressure cycling model but had a limited effect on EMT. CONCLUSION These results indicate that acute and chronic BOO pressure cycling are essential in the initiation and progression of fibrosis in the bladder via the NLRP3 inflammasome, but also provide new evidence that there is also an alternative NLRP3-independent pathway leading to EMT and fibrosis.
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Stýblo M, Venkatratnam A, Fry RC, Thomas DJ. Origins, fate, and actions of methylated trivalent metabolites of inorganic arsenic: progress and prospects. Arch Toxicol 2021; 95:1547-1572. [PMID: 33768354 PMCID: PMC8728880 DOI: 10.1007/s00204-021-03028-w] [Citation(s) in RCA: 41] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2021] [Accepted: 03/11/2021] [Indexed: 12/16/2022]
Abstract
The toxic metalloid inorganic arsenic (iAs) is widely distributed in the environment. Chronic exposure to iAs from environmental sources has been linked to a variety of human diseases. Methylation of iAs is the primary pathway for metabolism of iAs. In humans, methylation of iAs is catalyzed by arsenic (+ 3 oxidation state) methyltransferase (AS3MT). Conversion of iAs to mono- and di-methylated species (MAs and DMAs) detoxifies iAs by increasing the rate of whole body clearance of arsenic. Interindividual differences in iAs metabolism play key roles in pathogenesis of and susceptibility to a range of disease outcomes associated with iAs exposure. These adverse health effects are in part associated with the production of methylated trivalent arsenic species, methylarsonous acid (MAsIII) and dimethylarsinous acid (DMAsIII), during AS3MT-catalyzed methylation of iAs. The formation of these metabolites activates iAs to unique forms that cause disease initiation and progression. Taken together, the current evidence suggests that methylation of iAs is a pathway for detoxification and for activation of the metalloid. Beyond this general understanding of the consequences of iAs methylation, many questions remain unanswered. Our knowledge of metabolic targets for MAsIII and DMAsIII in human cells and mechanisms for interactions between these arsenicals and targets is incomplete. Development of novel analytical methods for quantitation of MAsIII and DMAsIII in biological samples promises to address some of these gaps. Here, we summarize current knowledge of the enzymatic basis of MAsIII and DMAsIII formation, the toxic actions of these metabolites, and methods available for their detection and quantification in biomatrices. Major knowledge gaps and future research directions are also discussed.
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Affiliation(s)
- Miroslav Stýblo
- Department of Nutrition, Gillings School of Global Public Health, The University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA.
| | - Abhishek Venkatratnam
- Department of Nutrition, Gillings School of Global Public Health, The University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA
- Department of Environmental Science and Engineering, Gillings School of Global Public Health, The University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA
| | - Rebecca C Fry
- Department of Environmental Science and Engineering, Gillings School of Global Public Health, The University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA
| | - David J Thomas
- Chemical Characterization and Exposure Division, Center for Computational Toxicology and Exposure, Office of Research and Development, U.S. Environmental Protection Agency, Research Triangle Park, NC, 27709, USA.
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Ahn J, Boroje IJ, Ferdosi H, Kramer ZJ, Lamm SH. Prostate Cancer Incidence in U.S. Counties and Low Levels of Arsenic in Drinking Water. INTERNATIONAL JOURNAL OF ENVIRONMENTAL RESEARCH AND PUBLIC HEALTH 2020; 17:ijerph17030960. [PMID: 32033184 PMCID: PMC7036874 DOI: 10.3390/ijerph17030960] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/21/2019] [Revised: 01/27/2020] [Accepted: 01/30/2020] [Indexed: 12/20/2022]
Abstract
Background: Although inorganic arsenic in drinking water at high levels (100s–1000s μg/L [ppb]) increases cancer risk (skin, bladder, lung, and possibly prostate), the evidence at lower levels is limited. Methods: We conducted an ecologic analysis of the dose-response relationship between prostate cancer incidence and low arsenic levels in drinking water in a large study of U.S. counties (N = 710). County arsenic levels were <200 ug/L with median <100 ug/L and dependency greater than 10%. Groundwater well usage, water arsenic levels, prostate cancer incidence rates (2009–2013), and co-variate data were obtained from various U.S. governmental agencies. Poisson and negative-binomial regression analyses and stratified analysis were performed. Results: The best fitting polynomial analysis yielded a J-shaped linear-quadratic model. Linear and quadratic terms were significant (p < 0.001) in the Poisson model, and the quadratic term was significant (p < 0.05) in the negative binomial model. This model indicated a decreasing risk of prostate cancer with increasing arsenic level in the low range and increasing risk above. Conclusions: This study of prostate cancer incidence in US counties with low levels of arsenic in their well-water arsenic levels finds a j-shaped model with decreasing risk at very low levels and increasing risk at higher levels.
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Affiliation(s)
- Jaeil Ahn
- Department of Biostatistics, Bioinformatics, and Biomathematics, Georgetown University School of Medicine, Washington, DC 20007, USA;
| | - Isabella J. Boroje
- Center for Epidemiology and Environmental Health (CEOH, LLC), Washington, DC 20016, USA; (I.J.B.); (H.F.); (Z.J.K.)
- Department of Epidemiology and Biostatistics, Milken Institute School of Public Health, George Washington University, Washington, DC 20052, USA
- Department of Global Health, Milken Institute School of Public Health, George Washington University, Washington, DC 20052, USA
| | - Hamid Ferdosi
- Center for Epidemiology and Environmental Health (CEOH, LLC), Washington, DC 20016, USA; (I.J.B.); (H.F.); (Z.J.K.)
- Department of Epidemiology and Biostatistics, Milken Institute School of Public Health, George Washington University, Washington, DC 20052, USA
| | - Zachary J. Kramer
- Center for Epidemiology and Environmental Health (CEOH, LLC), Washington, DC 20016, USA; (I.J.B.); (H.F.); (Z.J.K.)
| | - Steven H. Lamm
- Center for Epidemiology and Environmental Health (CEOH, LLC), Washington, DC 20016, USA; (I.J.B.); (H.F.); (Z.J.K.)
- Department of Health Policy and Management, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD 21205, USA
- Department of Pediatrics, Georgetown University School of Medicine, Washington, DC 20007, USA
- Correspondence:
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Tsuji JS, Chang ET, Gentry PR, Clewell HJ, Boffetta P, Cohen SM. Dose-response for assessing the cancer risk of inorganic arsenic in drinking water: the scientific basis for use of a threshold approach. Crit Rev Toxicol 2019; 49:36-84. [DOI: 10.1080/10408444.2019.1573804] [Citation(s) in RCA: 34] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Affiliation(s)
| | - Ellen T. Chang
- Exponent, Inc., Menlo Park, CA and Stanford Cancer Institute, Stanford, CA, USA
| | | | | | - Paolo Boffetta
- Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Samuel M. Cohen
- Havlik-Wall Professor of Oncology, Department of Pathology and Microbiology and the Fred and Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE, USA
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11
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Mac Monagail M, Morrison L. Arsenic speciation in a variety of seaweeds and associated food products. ARSENIC SPECIATION IN ALGAE 2019. [DOI: 10.1016/bs.coac.2019.03.005] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
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12
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Zhou Q, Xi S. A review on arsenic carcinogenesis: Epidemiology, metabolism, genotoxicity and epigenetic changes. Regul Toxicol Pharmacol 2018; 99:78-88. [PMID: 30223072 DOI: 10.1016/j.yrtph.2018.09.010] [Citation(s) in RCA: 130] [Impact Index Per Article: 18.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2018] [Revised: 09/08/2018] [Accepted: 09/12/2018] [Indexed: 12/19/2022]
Abstract
Long-term exposure to arsenic (inorganic arsenic) is a world-wide environmental health concern. Arsenic is classified as the Group 1 human carcinogen by the International Agency for Research on Cancer (IARC). Epidemiological studies have established a strong association between inorganic arsenic (iAs) exposure in drinking water and an increased incidence of cancer including bladder, liver, lung, prostate, and skin cancer. iAs also increases the risk of other diseases such as cardiovascular disease, hypertension and diabetes. The molecular mechanisms of carcinogenesis of iAs remain poorly defined, several mechanisms have been proposed, including genotoxicity, altered cell proliferation, oxidative stress, changes to the epigenome, disturbances of signal transduction pathways, cytotoxicity and regenerative proliferation. In this article, we will summarize current knowledge on the mechanisms of arsenic carcinogenesis and focus on integrating all these issues to garner a broader perspective.
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Affiliation(s)
- Qing Zhou
- Department of Environmental and Occupational Health, Liaoning Provincial Key Laboratory of Arsenic Biological Effect and Poisoning, School of Public Health, China Medical University, No.77 Puhe Road, Shenyang North New Area, Shenyang 110122, Liaoning Province, People's Republic of China
| | - Shuhua Xi
- Department of Environmental and Occupational Health, Liaoning Provincial Key Laboratory of Arsenic Biological Effect and Poisoning, School of Public Health, China Medical University, No.77 Puhe Road, Shenyang North New Area, Shenyang 110122, Liaoning Province, People's Republic of China.
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13
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Dunton CL, Purves JT, Hughes FM, Jin H, Nagatomi J. Elevated hydrostatic pressure stimulates ATP release which mediates activation of the NLRP3 inflammasome via P2X 4 in rat urothelial cells. Int Urol Nephrol 2018; 50:1607-1617. [PMID: 30099658 PMCID: PMC6129973 DOI: 10.1007/s11255-018-1948-0] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2018] [Accepted: 07/30/2018] [Indexed: 02/06/2023]
Abstract
Partial bladder outlet obstruction (pBOO) is a prevalent urological condition commonly accompanied by increased intravesical pressure, inflammation, and fibrosis. Studies have demonstrated that pBOO results in increased NLRP3 inflammasome and caspase-1 activation and that ATP is released from urothelial cells in response to elevated pressure. In the present study, we investigated the role of elevated pressure in triggering caspase-1 activation via purinergic receptors activation in urothelial cells. Rat urothelial cell line, MYP3 cells, was subjected to hydrostatic pressures of 15 cmH2O for 60 min, or 40 cmH2O for 1 min to simulate elevated storage and voiding pressure conditions, respectively. ATP concentration in the supernatant media and intracellular caspase-1 activity in cell lysates were measured. Pressure experiments were repeated in the presence of antagonists for purinergic receptors to determine the mechanism for pressure-induced caspase-1 activation. Exposure of MYP3 cells to both pressure conditions resulted in an increase in extracellular ATP levels and intracellular caspase-1 activity. Treatment with P2X7 antagonist led to a decrease in pressure-induced ATP release by MYP3 cells, while P2X4 antagonist had no effect but both antagonists inhibited pressure-induced caspase-1 activation. Moreover, when MYP3 cells were treated with extracellular ATP (500 µM), P2X4 antagonist inhibited ATP-induced caspase-1 activation, but not P2X7 antagonist. We concluded that pressure-induced extracellular ATP in urothelial cells is amplified by P2X7 receptor activation and ATP-induced-ATP release. The amplified ATP signal then activates P2X4 receptors, which mediate activation of the caspase-1 inflammatory response.
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Affiliation(s)
- Cody L Dunton
- Department of Bioengineering, Clemson University, Clemson, SC, USA
| | - J Todd Purves
- Department of Bioengineering, Clemson University, Clemson, SC, USA.,Division of Urology, Department of Surgery, Duke University Medical Center, Durham, NC, USA.,Department of Pediatrics, Duke University Medical Center, Durham, NC, USA
| | - Francis M Hughes
- Department of Bioengineering, Clemson University, Clemson, SC, USA.,Division of Urology, Department of Surgery, Duke University Medical Center, Durham, NC, USA
| | - Huixia Jin
- Division of Urology, Department of Surgery, Duke University Medical Center, Durham, NC, USA
| | - Jiro Nagatomi
- Department of Bioengineering, Clemson University, Clemson, SC, USA.
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14
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15
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Li J, Duan X, Dong D, Zhang Y, Zhao L, Li W, Chen J, Sun G, Li B. Tissue-specific distributions of inorganic arsenic and its methylated metabolites, especially in cerebral cortex, cerebellum and hippocampus of mice after a single oral administration of arsenite. J Trace Elem Med Biol 2017; 43:15-22. [PMID: 27745987 DOI: 10.1016/j.jtemb.2016.10.002] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/15/2016] [Revised: 09/28/2016] [Accepted: 10/02/2016] [Indexed: 11/26/2022]
Abstract
Groundwater contaminated with inorganic arsenic (iAs) is the main source of human exposure to arsenic and generates a global health issue. In this study, the urinary excretion, as well as the time-course distributions of various arsenic species in murine tissues, especially in different brain regions were determined after a single oral administration of 2.5, 5, 10 and 20mg/kg sodium arsenite (NaAsO2). Our data showed that the peak times of urinary, hepatic and nephritic total arsenic (TAs) were happened at about 1h, then TAs levels decreased gradually and almost could not be observed after 72h. On contrast, the time course of TAs in lung, urinary bladder and different brain regions exhibited an obvious process of accumulation and elimination,and the peak times were nearly at 6h to 9h. TAs levels of 10 and 20mg/kg NaAsO2 groups were significantly higher than 2.5 and 5mg/kg groups, and the amounts of TAs in 5mg/kg groups were in the order of liver>lung>kidney>urinary bladder>hippocampus>cerebral cortex>cerebellum. In addition, iAs was the most abundant species in liver and kidney, while lung and urinary bladder accumulated the highest concentrations of dimethylated arsenicals (DMA). What's more, the distributions of arsenic species were not homogeneous among different brain regions, as DMA was the sole species in cerebral cortex and cerebellum, while extremely high concentrations and percentages of monomethylated arsenicals (MMA) were found in hippocampus. These results demonstrated that distributions of iAs and its methylated metabolites were tissue-specific and even not homogeneous among different brain regions, which must be considered as to the tissue- and region-specific toxicity of iAs exposure. Our results thus provide useful information for clarifying and reducing the uncertainty in the risk assessment for this metalloid.
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Affiliation(s)
- Jinlong Li
- Department of Occupational and Environmental Health, Key Laboratory of Arsenic-related Biological Effects and Prevention and Treatment in Liaoning Province, School of Public Health, China Medical University, Shenyang, 110013, China
| | - Xiaoxu Duan
- Department of Toxicology, School of Public Health, Shenyang Medical College, Shenyang, 110034, Liaoning, China
| | - Dandan Dong
- Cao County Center for Disease Control and Prevention, Heze City, Shandong Province, 274400, China
| | - Yang Zhang
- Chengde City Center for Disease Prevention and Control, Chengde City, Hebei Province, 069000, China
| | - Lu Zhao
- Department of Occupational and Environmental Health, Key Laboratory of Arsenic-related Biological Effects and Prevention and Treatment in Liaoning Province, School of Public Health, China Medical University, Shenyang, 110013, China
| | - Wei Li
- Department of Occupational and Environmental Health, Key Laboratory of Arsenic-related Biological Effects and Prevention and Treatment in Liaoning Province, School of Public Health, China Medical University, Shenyang, 110013, China
| | - Jinli Chen
- Department of Occupational and Environmental Health, Key Laboratory of Arsenic-related Biological Effects and Prevention and Treatment in Liaoning Province, School of Public Health, China Medical University, Shenyang, 110013, China
| | - Guifan Sun
- Environment and Non-Communicable Diseases Research Center, School of Public Health, China Medical University, Shenyang, 110013, China
| | - Bing Li
- Department of Occupational and Environmental Health, Key Laboratory of Arsenic-related Biological Effects and Prevention and Treatment in Liaoning Province, School of Public Health, China Medical University, Shenyang, 110013, China.
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16
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Rezaei M, Khodayar MJ, Seydi E, Soheila A, Parsi IK. Acute, but not Chronic, Exposure to Arsenic Provokes Glucose Intolerance in Rats: Possible Roles for Oxidative Stress and the Adrenergic Pathway. Can J Diabetes 2017; 41:273-280. [DOI: 10.1016/j.jcjd.2016.10.008] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/28/2015] [Revised: 09/06/2016] [Accepted: 10/17/2016] [Indexed: 12/12/2022]
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17
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Khairul I, Wang QQ, Jiang YH, Wang C, Naranmandura H. Metabolism, toxicity and anticancer activities of arsenic compounds. Oncotarget 2017; 8:23905-23926. [PMID: 28108741 PMCID: PMC5410354 DOI: 10.18632/oncotarget.14733] [Citation(s) in RCA: 201] [Impact Index Per Article: 25.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2016] [Accepted: 01/11/2017] [Indexed: 01/17/2023] Open
Abstract
A variety of studies indicated that inorganic arsenic and its methylated metabolites have paradoxical effects, namely, carcinogenic and anticancer effects. Epidemiological studies have shown that long term exposure to arsenic can increase the risk of cancers of lung, skin or bladder in man, which is probably associated with the arsenic metabolism. In fact, the enzymatic conversion of inorganic arsenic by Arsenic (+3 oxidation state) methyltransferase (AS3MT) to mono- and dimethylated arsenic species has long been considered as a major route for detoxification. However, several studies have also indicated that biomethylation of inorganic arsenic, particularly the production of trivalent methylated metabolites, is a process that activates arsenic as a toxin and a carcinogen. On the other hand, arsenic trioxide (As2O3) has recently been recognized as one of the most effective drugs for the treatment of APL. However, elaboration of the cytotoxic mechanisms of arsenic and its methylated metabolites in eradicating cancer is sorely lacking. To provide a deeper understanding of the toxicity and carcinogenicity along with them use of arsenic in chemotherapy, caution is required considering the poor understanding of its various mechanisms of exerting toxicity. Thereby, in this review, we have focused on arsenic metabolic pathway, the roles of the methylated arsenic metabolites in toxicity and in the therapeutic efficacy for the treatments of solid tumors, APL and/or non-APL malignancies.
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Affiliation(s)
- Islam Khairul
- Department of Toxicology, School of Medicine and Public Health, Zhejiang University, Hangzhou, China
| | - Qian Qian Wang
- Department of Toxicology, School of Medicine and Public Health, Zhejiang University, Hangzhou, China
- College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China
| | - Yu Han Jiang
- Department of Toxicology, School of Medicine and Public Health, Zhejiang University, Hangzhou, China
- Ocean College, Zhejiang University, Hangzhou, China
| | - Chao Wang
- Department of Toxicology, School of Medicine and Public Health, Zhejiang University, Hangzhou, China
| | - Hua Naranmandura
- Department of Toxicology, School of Medicine and Public Health, Zhejiang University, Hangzhou, China
- College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China
- Ocean College, Zhejiang University, Hangzhou, China
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18
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Cohen SM, Chowdhury A, Arnold LL. Inorganic arsenic: A non-genotoxic carcinogen. J Environ Sci (China) 2016; 49:28-37. [PMID: 28007178 DOI: 10.1016/j.jes.2016.04.015] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2016] [Revised: 04/21/2016] [Accepted: 04/22/2016] [Indexed: 05/02/2023]
Abstract
Inorganic arsenic induces a variety of toxicities including cancer. The mode of action for cancer and non-cancer effects involves the metabolic generation of trivalent arsenicals and their reaction with sulfhydryl groups within critical proteins in various cell types which leads to the biological response. In epithelial cells, the response is cell death with consequent regenerative proliferation. If this continues for a long period of time, it can result in an increased risk of cancer. Arsenicals do not react with DNA. There is evidence for indirect genotoxicity in various in vitro and in vivo systems, but these involve exposures at cytotoxic concentrations and are not the basis for cancer development. The resulting markers of genotoxicity could readily be due to the cytotoxicity rather than an effect on the DNA itself. Evidence for genotoxicity in humans has involved detection of chromosomal aberrations, sister chromatid exchanges in lymphocytes and micronucleus formation in lymphocytes, buccal mucosal cells, and exfoliated urothelial cells in the urine. Numerous difficulties have been identified in the interpretation of such results, including inadequate assessment of exposure to arsenic, measurement of micronuclei, and potential confounding factors such as tobacco exposure, folate deficiency, and others. Overall, the data strongly supports a non-linear dose response for the effects of inorganic arsenic. In various in vitro and in vivo models and in human epidemiology studies there appears to be a threshold for biological responses, including cancer.
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Affiliation(s)
- Samuel M Cohen
- Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE 68198-3135, USA.
| | - Aparajita Chowdhury
- Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE 68198-3135, USA
| | - Lora L Arnold
- Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE 68198-3135, USA
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19
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Hughes FM, Turner DP, Todd Purves J. The potential repertoire of the innate immune system in the bladder: expression of pattern recognition receptors in the rat bladder and a rat urothelial cell line (MYP3 cells). Int Urol Nephrol 2015; 47:1953-64. [PMID: 26490556 DOI: 10.1007/s11255-015-1126-6] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2015] [Accepted: 09/24/2015] [Indexed: 12/21/2022]
Abstract
PURPOSE The urothelium is a frontline sensor of the lower urinary tract, sampling the bladder lumen and stimulating an immune response to infectious and noxious agents. Pattern recognition receptors (PRRs) recognize such agents and coordinate the innate response, often by forming inflammasomes that activate caspase-1 and the release of interleukin-1. We have shown the presence of one PRR (NLRP3) in the urothelia and its central role in the inflammatory response to cyclophosphamide. The purpose of this study was to (1) assess the likely range of the PPR response by assessing the repertoire present in the rat bladder and (2) determine the utility of the MYP3 rat urothelia cell line for in vitro studies by assessing its PPR repertoire and functional responsiveness. METHODS Immunohistochemistry was performed for seven PPRs (NLRP1, NLRP3, NLRP6, NLRP7, NLRP12, NLRC4 and AIM2) on bladder sections and MYP3 cells. For functionality, MYP3 cells were challenged with the quintessential NLRP3 activator ATP and assessed for caspase-1 activation. RESULTS All PPRs examined were expressed in the bladder and localized to the urothelial layer with several also in the detrusor (none in the interstitia). MYP3 cells also expressed all PRRs with a variable intracellular location. ATP-stimulated caspase-1 activity in MYP3 cells in a dose-dependent manner was reduced by knockdown of NLRP3 expression. CONCLUSION The results suggest that the bladder possesses the capacity to initiate an innate immune response to a wide array of uropathological agents and the MYP3 cells will provide an excellent investigational tool for this field.
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Affiliation(s)
- Francis M Hughes
- Division of Urology, Department of Surgery, Duke University Medical Center, DUMC Box 3831, Durham, NC, 27710, USA. .,Department of Urology, Medical University of South Carolina, Charleston, SC, USA.
| | - David P Turner
- Department of Pathology and Lab Medicine, Medical University of South Carolina, Charleston, SC, USA
| | - J Todd Purves
- Division of Urology, Department of Surgery, Duke University Medical Center, DUMC Box 3831, Durham, NC, 27710, USA.,Department of Urology, Medical University of South Carolina, Charleston, SC, USA.,Department of Pediatrics, Medical University of South Carolina, Charleston, SC, USA.,Department of Regenerative Medicine and Cell Biology, Medical University of South Carolina, Charleston, SC, USA
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20
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Dodmane PR, Arnold LL, Pennington KL, Singh RK, Cardoso APF, Cohen SM. Effect of trivalent arsenicals on cell proliferation in mouse and human microvascular endothelial cells. Toxicol Rep 2015; 2:833-837. [PMID: 28962419 PMCID: PMC5598208 DOI: 10.1016/j.toxrep.2015.05.009] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2015] [Revised: 04/28/2015] [Accepted: 05/18/2015] [Indexed: 12/17/2022] Open
Abstract
Chronic exposure to high levels of inorganic arsenic (iAs) has been associated with cancerous and non-cancerous health effects, including cardiovascular effects. However, the mechanism for a presumed toxic effect of arsenic on vascular tissue is not clear. Our working hypothesis is that inorganic trivalent arsenic and its methylated metabolites react with cysteine-containing cellular proteins and alter their function leading to adverse events such as cytotoxicity or proliferation. In this study, human microvascular endothelial cells (HMEC1) and mouse microvascular endothelial cells (MFP-MVEC) were exposed to arsenite (iAsIII), monomethylarsonous acid (MMAIII), or dimethylarsinous acid (DMAIII) for 72 h to evaluate cytotoxicity, and for 24, 48 or 72 h to evaluate cell proliferation. Both cell lines showed similar LC50 values, from 0.1 to 2.4 μM, for all three trivalent arsenicals. The endothelial cells treated with1 nM to 1 μM concentrations of the three trivalent arsenicals did not show increased cell proliferation at 24, 48 or 72 h or increased rate of proliferation at 72 h of exposure. Overall, cytotoxicity of trivalent arsenicals to microvascular endothelial cells is similar to their cytotoxicity to epithelial cells, and that these compounds are not mitogenic.
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Affiliation(s)
- Puttappa R Dodmane
- Department of Pathology and Microbiology, University of Nebraska Medical Center, 983135 Nebraska Medical Center Omaha, NE 68198-3135, USA
| | - Lora L Arnold
- Department of Pathology and Microbiology, University of Nebraska Medical Center, 983135 Nebraska Medical Center Omaha, NE 68198-3135, USA
| | - Karen L Pennington
- Department of Pathology and Microbiology, University of Nebraska Medical Center, 983135 Nebraska Medical Center Omaha, NE 68198-3135, USA
| | - Rakesh K Singh
- Department of Pathology and Microbiology, University of Nebraska Medical Center, 983135 Nebraska Medical Center Omaha, NE 68198-3135, USA
| | - Ana Paula Ferragut Cardoso
- Department of Pathology and Microbiology, University of Nebraska Medical Center, 983135 Nebraska Medical Center Omaha, NE 68198-3135, USA
| | - Samuel M Cohen
- Department of Pathology and Microbiology, University of Nebraska Medical Center, 983135 Nebraska Medical Center Omaha, NE 68198-3135, USA
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Shimoda Y, Kurosawa H, Kato K, Endo Y, Yamanaka K, Endo G. Proposal for novel metabolic pathway of highly toxic dimethylated arsenics accompanied by enzymatic sulfuration, desulfuration and oxidation. J Trace Elem Med Biol 2015; 30:129-36. [PMID: 25559201 DOI: 10.1016/j.jtemb.2014.12.006] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/26/2014] [Revised: 11/27/2014] [Accepted: 12/13/2014] [Indexed: 11/19/2022]
Abstract
The International Agency for Research on Cancer (IARC) has concluded that dimethylarsinic acid [(CH3)2AsO(OH), DMA(V)], a main metabolite of inorganic arsenic, is responsible for carcinogenesis in urinary bladder and lung in rodents, and various modes of carcinogenic action have been proposed. One theory concerning the mode of action is that the biotransformation of dimethylarsinous acid [(CH3)2AsOH, DMA(III)] from DMA(V) plays an important role in the carcinogenesis by way of reactive oxygen species (ROS) production. Furthermore, dimethylmonothioarsinic acid [(CH3)2AsS(OH), DMMTA(V)], a metabolite of DMA(V), has also been noted because of its higher toxicity. However, the metabolic mechanisms of formation and disappearance of DMA(III) and DMMTA(V), and their toxicity are not fully understood. Thus, the purpose of the present study was to clarify the mechanism of metabolic formation of DMMTA(V) and DMA(V) from DMA(III). The in vitro transformation of arsenicals by treatment with liver homogenate from rodents and sulfur transferase was detected by HPLC-ICP-MS and HPLC-tandem MS. DMMTA(V) is produced from DMA(III) but not DMA(V) by cellular fractions from mouse liver homogenates and by rhodanese from bovine liver in the presence of thiosulfate, a sulfur donor. Not only DMMTA(V) thus produced but also DMA(III) are re-converted into DMA(V) by an in vitro addition of S9 mix. These findings indicate that the metabolic process not only of DMA(III) to DMA(V) or DMMTA(V) but also of DMMTA(V) to DMA(V) consists of a complicated mode of interaction between monooxygenase including cytochrome P450 (CYP) and/or sulfur transferase.
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Affiliation(s)
- Yasuyo Shimoda
- Laboratory of Environmental Toxicology and Carcinogenesis, Nihon University School of Pharmacy, 7-7-1 Narashinodai, Funabashi, Chiba 274-8555, Japan
| | - Hidetoshi Kurosawa
- Laboratory of Environmental Toxicology and Carcinogenesis, Nihon University School of Pharmacy, 7-7-1 Narashinodai, Funabashi, Chiba 274-8555, Japan
| | - Koichi Kato
- Laboratory of Environmental Toxicology and Carcinogenesis, Nihon University School of Pharmacy, 7-7-1 Narashinodai, Funabashi, Chiba 274-8555, Japan
| | - Yoko Endo
- Research Center for Occupational Poisoning, Kansai Rosai Hospital, Hyogo 660-8511, Japan
| | - Kenzo Yamanaka
- Laboratory of Environmental Toxicology and Carcinogenesis, Nihon University School of Pharmacy, 7-7-1 Narashinodai, Funabashi, Chiba 274-8555, Japan.
| | - Ginji Endo
- Department of Preventive Medicine and Environmental Health, Graduate School of Medicine, Osaka City University, Osaka 545-8585, Japan
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Liu S, Zhang L, Sun Q, Wang F, Xi S, Sun G. The distribution in tissues and urine of arsenic metabolites after subchronic exposure to dimethylarsinic acid (DMAV) in rats. Biol Trace Elem Res 2015; 164:219-25. [PMID: 25575662 DOI: 10.1007/s12011-014-0208-0] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/13/2014] [Accepted: 12/10/2014] [Indexed: 01/01/2023]
Abstract
Dimethylarsinic acid (DMA(V)) acted as cancer promoter promoted urinary bladder, liver, and lung carcinogenesis in rats. Understanding of the distribution of arsenicals in critical sites will aid to define the action of DMA(V)-induced toxicity and carcinogenicity. The present experiment was conducted to compare the accumulated levels of arsenicals in the liver, kidney, and bladder of both male and female rats after subchronic exposure to DMA(V). After exposure to DMA(V) in drinking water for 10 weeks, urinary DMA concentrations of 100 and 200 ppm DMA(V)-treated rats increased significantly compared with those of the control rats. Smaller amount of trimethylarsinic acid (TMA) was detected in urine, but not in liver, kidney, and bladder muscle. In the liver and kidney, the levels of DMA in DMA(V)-treated rats significantly increased compared with those of the control group, but there was no difference between 100 and 200 ppm DMA(V)-treated rats. DMA did not accumulate in bladder muscle. There was no difference for DMA concentrations between male and female rats. Our results suggest that the accumulation of DMA in the liver and kidney was saturated above 100 ppm DMA(V) treatment concentration, and DMA(V) was a little partly metabolized to TMA, and TMA was rapidly excreted into urine.
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Affiliation(s)
- Shengnan Liu
- Department of Environmental and Occupational Health, Liaoning Provincial Key Laboratory of Arsenic Biological Effect and Poisoning, School of Public Health, China Medical University, No. 77 Puhe Road, Shenyang North New Area, Shenyang City, 110013, China,
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Wang QQ, Thomas DJ, Naranmandura H. Importance of being thiomethylated: formation, fate, and effects of methylated thioarsenicals. Chem Res Toxicol 2015; 28:281-9. [PMID: 25531277 DOI: 10.1021/tx500464t] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Although inorganic arsenic has long been recognized as a potent toxicant and carcinogen in humans, recent evidence shows that at least some of its effects are mediated by methylated metabolites. Elucidating the conversion of inorganic arsenic to mono-, di-, and trimethylated species has provided insights into the enzymology of this pathway and identified genetic and environmental factors that influence the susceptibility of individuals to this metalloid's adverse health effects. Notably, almost all work on the formation, fate, and effects of methylated arsenicals has focused on oxoarsenicals in which arsenic is bound to one or more oxygen atoms. However, thioarsenicals are a class of arsenicals in which a sulfur atom has replaced one or more oxygens that are bound to arsenic. Thioarsenicals have been identified as urinary metabolites in humans and other animals following exposure to inorganic arsenic. Studies find that methylated thioarsenicals exhibit kinetic behavior and toxicological properties that distinguish them from methylated oxoarsenicals. This perspective considers that formation, fate, and effects of methylated thioarsenicals with an emphasis on examining the linkages between the molecular processes that underlie both methylation and thiolation reactions. Integrating this information will provide a more comprehensive view of the relationship between the metabolism of arsenic and the risk posed by chronic exposure to this environmental contaminant.
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Affiliation(s)
- Qian Qian Wang
- Department of Toxicology, School of Medicine and Public Health, ‡College of Pharmaceutical Sciences, Zhejiang University , Hangzhou 310058, China
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25
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Lynch HN, Greenberg GI, Pollock MC, Lewis AS. A comprehensive evaluation of inorganic arsenic in food and considerations for dietary intake analyses. THE SCIENCE OF THE TOTAL ENVIRONMENT 2014; 496:299-313. [PMID: 25089691 DOI: 10.1016/j.scitotenv.2014.07.032] [Citation(s) in RCA: 38] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/04/2014] [Revised: 07/09/2014] [Accepted: 07/09/2014] [Indexed: 06/03/2023]
Abstract
Arsenic (As) can exist in the environment in several different forms, each having unique chemical characteristics that influence its toxicity and potential for human and ecological exposure. Within the last decade or so, the focus on speciated As (both the inorganic and organic forms) and its potential toxicity has led to an increased availability of data on speciated As in different food types. To gain an understanding of these developments and the current science, we evaluated the state of knowledge regarding As speciation in food and calculated the average levels of several species of As measured in food. Because inorganic arsenic (inAs) is considered the most toxicologically important form of As, we focused our analysis on papers presenting information on total inAs and speciated inAs (inAs(3+) or inAs(5+)). We also evaluated speciated As forms (e.g., monomethylarsonic and dimethylarsinic acid) when presented with inAs information. Publications were drawn from the peer-reviewed literature and reports by authoritative health agencies. While a great deal of speciation data were identified, including over 6500 unique inAs data points, unclear study methodology and inconsistencies between studies introduced uncertainty into the analysis of these data. Despite these limitations, our analysis demonstrates that inAs in foods can vary widely by type and even by sample, with mean inAs concentrations ranging from undetectable (in milk) to 11,000 μg/kg (in seaweed/algae). We found a high percentage of non-measurable As in many food types, suggesting that the limits of detection of speciated As must be considered to accurately estimate dietary As exposure. The applicability of our analysis is limited by the inconsistencies and uncertainties in the available data; calculations of inAs dietary intake should be tailored to the study population of interest and should consider study quality.
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Affiliation(s)
| | | | | | - Ari S Lewis
- Gradient, 20 University Road, Cambridge, MA 02138 USA.
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Kulshrestha A, Jarouliya U, Prasad GBKS, Flora SJS, Bisen PS. Arsenic-induced abnormalities in glucose metabolism: Biochemical basis and potential therapeutic and nutritional interventions. World J Transl Med 2014; 3:96-111. [DOI: 10.5528/wjtm.v3.i2.96] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/06/2014] [Revised: 06/21/2014] [Accepted: 07/17/2014] [Indexed: 02/05/2023] Open
Abstract
Health hazards due to the consumption of heavy metals such as arsenic have become a worldwide problem. Metabolism of arsenic produces various intermediates which are more toxic and cause toxicity. Arsenic exposure results in impairment of glucose metabolism, insulin secretion in pancreatic β-cells, altered gene expressions and signal transduction, and affects insulin-stimulated glucose uptake in adipocytes or skeletal muscle cells. Arsenic toxicity causes abnormalities in glucose metabolism through an increase in oxidative stress. Arsenic interferes with the sulfhydryl groups and phosphate groups present in various enzymes involved in glucose metabolism including pyruvate dehydrogenase and α-ketoglutarate dehydrogenase, and contributes to their impairment. Arsenic inhibits glucose transporters present in the cell membrane, alters expression of genes involved in glucose metabolism, transcription factors and inflammatory cytokines which stimulate oxidative stress. Some theories suggest that arsenic exposure under diabetic conditions inhibits hyperglycemia. However, the exact mechanism behind the behavior of arsenic as an antagonist or synergist on glucose homeostasis and insulin secretion is not yet fully understood. The present review delineates the relationship between arsenic and the biochemical basis of its relationship to glucose metabolism. This review also addresses potential therapeutic and nutritional interventions for attenuating arsenic toxicity. Several other potential nutritional supplements are highlighted in the review that could be used to combat arsenic toxicity.
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O'Neill A, Gupta BS, Phillips DH. Distribution of arsenic and risk assessment of activities on a golf course fertilised with arsenic-containing Ascophyllum nodosum seaweed. THE SCIENCE OF THE TOTAL ENVIRONMENT 2014; 482-483:252-9. [PMID: 24657370 DOI: 10.1016/j.scitotenv.2014.03.006] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/06/2013] [Revised: 02/25/2014] [Accepted: 03/02/2014] [Indexed: 06/03/2023]
Abstract
The use of seaweed fertilisers in sports green maintenance has become a common practice across the globe due to its image as an "eco-friendly" alternative to chemical fertilisers. The aim of this study was to characterise the risk of human exposure to arsenic (As), via dermal absorption, from golfing activities on a private golf course in the UK, where As contaminated seaweed fertiliser (~100mg/kg d.wt.) is applied. This was fulfilled by, 1) determining As concentrations in shallow soils with GIS geo-statistical analysis, 2) measuring As concentrations from an on-site borehole groundwater well, and (3) developing a risk assessment calculation for golfing activities based on field and questionnaire data. Total As concentrations in shallow soils were less than the UK threshold for domestic soils, however, frequent and sustained dermal contact between site-users and surface soil attributed to a maximum carcinogenic risk value of 2.75×10(-4), which is in the upper limit of the acceptable risk range. Arsenic concentrations in underlying groundwater exceeded the WHO's permissible drinking water standard, demonstrating the risk of groundwater contamination following the application of seaweed fertiliser to golf course soils. This is the first risk study on dermal As absorption via the application of a seaweed fertiliser.
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Affiliation(s)
- Antonia O'Neill
- Environmental Engineering Research Centre, School of Planning, Architecture and Civil Engineering, Queen's University of Belfast, Belfast BT9 5AG, Northern Ireland, UK
| | - Bhaskar Sen Gupta
- Environmental Engineering Research Centre, School of Planning, Architecture and Civil Engineering, Queen's University of Belfast, Belfast BT9 5AG, Northern Ireland, UK.
| | - Debra H Phillips
- Environmental Engineering Research Centre, School of Planning, Architecture and Civil Engineering, Queen's University of Belfast, Belfast BT9 5AG, Northern Ireland, UK
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The impact of recent advances in research on arsenic cancer risk assessment. Regul Toxicol Pharmacol 2014; 69:91-104. [DOI: 10.1016/j.yrtph.2014.02.006] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2012] [Revised: 02/05/2014] [Accepted: 02/07/2014] [Indexed: 11/23/2022]
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Lawley SD, Yun J, Gamble MV, Hall MN, Reed MC, Nijhout HF. Mathematical modeling of the effects of glutathione on arsenic methylation. Theor Biol Med Model 2014; 11:20. [PMID: 24885596 PMCID: PMC4041632 DOI: 10.1186/1742-4682-11-20] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2014] [Accepted: 04/30/2014] [Indexed: 02/06/2023] Open
Abstract
Background Arsenic is a major environmental toxin that is detoxified in the liver by biochemical mechanisms that are still under study. In the traditional metabolic pathway, arsenic undergoes two methylation reactions, each followed by a reduction, after which it is exported and released in the urine. Recent experiments show that glutathione plays an important role in arsenic detoxification and an alternative biochemical pathway has been proposed in which arsenic is first conjugated by glutathione after which the conjugates are methylated. In addition, in rats arsenic-glutathione conjugates can be exported into the plasma and removed by the liver in the bile. Methods We have developed a mathematical model for arsenic biochemistry that includes three mechanisms by which glutathione affects arsenic methylation: glutathione increases the speed of the reduction steps; glutathione affects the activity of arsenic methyltranferase; glutathione sequesters inorganic arsenic and its methylated downstream products. The model is based as much as possible on the known biochemistry of arsenic methylation derived from cellular and experimental studies. Results We show that the model predicts and helps explain recent experimental data on the effects of glutathione on arsenic methylation. We explain why the experimental data imply that monomethyl arsonic acid inhibits the second methylation step. The model predicts time course data from recent experimental studies. We explain why increasing glutathione when it is low increases arsenic methylation and that at very high concentrations increasing glutathione decreases methylation. We explain why the possible temporal variation of the glutathione concentration affects the interpretation of experimental studies that last hours. Conclusions The mathematical model aids in the interpretation of data from recent experimental studies and shows that the Challenger pathway of arsenic methylation, supplemented by the glutathione effects described above, is sufficient to understand and predict recent experimental data. More experimental studies are needed to explicate the detailed mechanisms of action of glutathione on arsenic methylation. Recent experimental work on the effects of glutathione on arsenic methylation and our modeling study suggest that supplements that increase hepatic glutathione production should be considered as strategies to reduce adverse health effects in affected populations.
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Affiliation(s)
| | | | | | | | - Michael C Reed
- Department of Mathematics, Duke University, Durham, NC 27708, USA.
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Da Rocha MS, Arnold LL, De Oliveira MLCS, Catalano SMI, Cardoso APF, Pontes MGN, Ferrucio B, Dodmane PR, Cohen SM, De Camargo JLV. Diuron-induced rat urinary bladder carcinogenesis: Mode of action and human relevance evaluations using the International Programme on Chemical Safety framework. Crit Rev Toxicol 2014; 44:393-406. [DOI: 10.3109/10408444.2013.877870] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
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Medeiros M, Le TM, Troup D, Novak P, Gandolfi AJ. Expression Of Selected Pathway-Marker Genes In Human Urothelial Cells Exposed Chronically To A Non-Cytotoxic Concentration Of Monomethylarsonous Acid. Toxicol Rep 2014; 1:421-434. [PMID: 25177542 PMCID: PMC4144464 DOI: 10.1016/j.toxrep.2014.07.004] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2014] [Revised: 07/01/2014] [Accepted: 07/01/2014] [Indexed: 11/28/2022] Open
Abstract
Bladder cancer has been associated with chronic arsenic exposure. Monomethylarsonous acid [MMA(III)] is a metabolite of inorganic arsenic and has been shown to transform an immortalized urothelial cell line (UROtsa) at concentrations 20-fold less than arsenite. MMA(III) was used as a model arsenical to examine the mechanisms of arsenical-induced transformation of urothelium. A previous microarray analysis revealed only minor changes in gene expression at one and two months of chronic exposure to MMA(III), contrasting with substantial changes observed at three months of exposure. To address the lack of information between two and three months of exposure (the critical period of transformation), the expression of select pathway marker genes was measured by PCR array analysis on a weekly basis. Cell proliferation rate, anchorage-independent growth, and tumorigenicity in SCID mice were also assessed to determine the early, persistent phenotypic changes and their association with the changes in expression of these selected marker genes. A very similar pattern of alterations in these genes was observed when compared to the microarray results, and suggested that early perturbations in cell signaling cascades, immunological pathways, cytokine expression, and MAPK pathway are particularly important in driving malignant transformation. These results showed a strong association between the acquired phenotypic changes that occurred as early as one to two months of chronic MMA(III) exposure, and the observed gene expression pattern that is indicative of the earliest stages in carcinogenesis.
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Affiliation(s)
- Matthew Medeiros
- Department of Pharmacology and Toxicology, University of Arizona, Tucson, AZ 85721, United States
| | - Tam Minh Le
- Department of Pharmacology and Toxicology, University of Arizona, Tucson, AZ 85721, United States
| | - Daniel Troup
- Department of Pharmacology and Toxicology, University of Arizona, Tucson, AZ 85721, United States
| | - Petr Novak
- Biology Centre ASCR, Institute of Plant Molecular Biology, Ceske Budejovice, 37005, Czech Republic
| | - A. Jay Gandolfi
- Department of Pharmacology and Toxicology, University of Arizona, Tucson, AZ 85721, United States
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Kotyzová D, Bludovská M, Eybl V. Differential influences of various arsenic compounds on antioxidant defense system in liver and kidney of rats. ENVIRONMENTAL TOXICOLOGY AND PHARMACOLOGY 2013; 36:1015-1021. [PMID: 24095718 DOI: 10.1016/j.etap.2013.09.003] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/27/2013] [Revised: 08/08/2013] [Accepted: 09/04/2013] [Indexed: 06/02/2023]
Abstract
In this study, oxidative stress-related parameters and As retention were examined in liver and kidneys of male Wistar rats exposed to arsenic trioxide, sodium arsenite (iAsIII), sodium arsenate (iAsV), and dimethylarsinic acid (DMAsV) at a single ip dose of 3.8 mgAs/kgbw, at 24h post-exposure. In liver, lipid peroxidation increased in iAsIII-exposed rats, glutathione peroxidase activity decreased in inorganic arsenic (iAs)-exposed rats, and catalase and thioredoxin reductase activities decreased significantly in all As-exposed groups. Both As(III) and As(V) exposure elevated GSH level with no effect on glutathione reductase activity. In kidneys, catalase activity decreased significantly in iAs-exposed, rats; GSH level, glutathione reductase and thioredoxin reductase activity decreased in DMAsV-treated, rats. The tissue As retention was higher in kidneys compared to liver and was also higher in As(III)-exposed compared to As(V)-exposed rats. The results demonstrate similar potency of inorganic As(III) and As(V) compounds to inhibit/induce antioxidant defense system, with liver being more vulnerable to acute As(III)- and As(V)-induced oxidative stress.
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Affiliation(s)
- Dana Kotyzová
- Department of Pharmacology and Toxicology, Charles University in Prague, Faculty of Medicine in Pilsen, Czech Republic.
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Dose–response of diuron [3-(3,4-dichlorophenyl)-1,1-dimethylurea] in the urothelial mucosa of Wistar rats. Toxicology 2013; 312:1-5. [DOI: 10.1016/j.tox.2013.07.007] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2013] [Revised: 07/02/2013] [Accepted: 07/10/2013] [Indexed: 11/17/2022]
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Cohen SM, Arnold LL, Beck BD, Lewis AS, Eldan M. Evaluation of the carcinogenicity of inorganic arsenic. Crit Rev Toxicol 2013; 43:711-52. [DOI: 10.3109/10408444.2013.827152] [Citation(s) in RCA: 123] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
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Cytotoxicity and gene expression changes induced by inorganic and organic trivalent arsenicals in human cells. Toxicology 2013; 312:18-29. [PMID: 23876855 DOI: 10.1016/j.tox.2013.07.008] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2013] [Revised: 07/08/2013] [Accepted: 07/11/2013] [Indexed: 02/03/2023]
Abstract
Inorganic arsenic (iAs) is a human urinary bladder, skin and lung carcinogen. iAs is metabolized to methylated arsenicals, with trivalent arsenicals more cytotoxic than pentavalent forms in vitro. In this study, cytotoxicity and gene expression changes for arsenite (iAs(III)), monomethylarsonous acid (MMA(III)) and dimethylarsinous acid (DMA(III)) were evaluated in three human cell types, urothelial (1T1), keratinocyte (HEK001) and bronchial epithelial (HBE) cells, corresponding to target organs for iAs-induced cancer. Cells were exposed to arsenicals to determine cytotoxicity and to study gene expression changes. Affymetrix chips were used to determine differentially expressed genes (DEGs) by statistical analysis. Lethal concentrations (LC50) for trivalent arsenicals in all cells ranged from 1.6 to 10μM. MMA(III) and DMA(III) had 4-12-fold greater potency compared to iAs. Increasing concentrations of iAs(III) induced more genes and additional signaling pathways in HBE cells. At equivalent cytotoxic concentrations, greater numbers of DEGs were induced in 1T1 cells compared to the other cells. Each arsenical altered slightly different signaling pathways within and between cell types, but when altered pathways from all three arsenicals were combined, they were similar between cell types. The major signaling pathways altered included NRF2-mediated stress response, interferon, p53, cell cycle regulation and lipid peroxidation. These results show a similar process qualitatively and quantitatively for all three cell types, and support a mode of action involving cytotoxicity and regenerative proliferation.
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Chen B, Lu X, Shen S, Arnold LL, Cohen SM, Le XC. Arsenic Speciation in the Blood of Arsenite-Treated F344 Rats. Chem Res Toxicol 2013; 26:952-62. [DOI: 10.1021/tx400123q] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/24/2023]
Affiliation(s)
- Baowei Chen
- Division of Analytical and Environmental
Toxicology, Department of Laboratory Medicine and Pathology, Faculty
of Medicine and Dentistry, University of Alberta, Edmonton, Alberta T6G 2G3, Canada
| | - Xiufen Lu
- Division of Analytical and Environmental
Toxicology, Department of Laboratory Medicine and Pathology, Faculty
of Medicine and Dentistry, University of Alberta, Edmonton, Alberta T6G 2G3, Canada
| | - Shengwen Shen
- Division of Analytical and Environmental
Toxicology, Department of Laboratory Medicine and Pathology, Faculty
of Medicine and Dentistry, University of Alberta, Edmonton, Alberta T6G 2G3, Canada
| | - Lora L. Arnold
- Department of Pathology and
Microbiology, University of Nebraska Medical Center, Omaha, Nebraska 68198-3135, United States
| | - Samuel M. Cohen
- Department of Pathology and
Microbiology, University of Nebraska Medical Center, Omaha, Nebraska 68198-3135, United States
| | - X. Chris Le
- Division of Analytical and Environmental
Toxicology, Department of Laboratory Medicine and Pathology, Faculty
of Medicine and Dentistry, University of Alberta, Edmonton, Alberta T6G 2G3, Canada
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Currier J, Saunders RJ, Ding L, Bodnar W, Cable P, Matoušek T, Creed JT, Stýblo M. Comparative oxidation state specific analysis of arsenic species by high-performance liquid chromatography-inductively coupled plasma-mass spectrometry and hydride generation-cryotrapping-atomic absorption spectrometry. JOURNAL OF ANALYTICAL ATOMIC SPECTROMETRY 2013; 28:843-852. [PMID: 23687401 PMCID: PMC3655785 DOI: 10.1039/c3ja30380b] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/12/2023]
Abstract
The formation of methylarsonous acid (MAsIII) and dimethylarsinous acid (DMAsIII) in the course of inorganic arsenic (iAs) metabolism plays an important role in the adverse effects of chronic exposure to iAs. High-performance liquid chromatography-inductively coupled plasma-mass spectrometry (HPLC-ICP-MS) and hydride generation-cryotrapping-atomic absorption spectrometry (HG-CT-AAS) have been frequently used for the analysis of MAsIII and DMAsIII in biological samples. While HG-CT-AAS has consistently detected MAsIII and DMAsIII, HPLC-ICP-MS analyses have provided inconsistent and contradictory results. This study compares the capacities of both methods to detect and quantify MAsIII and DMAsIII in an in vitro methylation system consisting of recombinant human arsenic (+3 oxidation state) methyltransferase (AS3MT), S-adenosylmethionine as a methyl donor, a non-thiol reductant tris(2-carboxyethyl)phosphine, and arsenite (iAsIII) or MAsIII as substrate. The results show that reversed-phase HPLC-ICP-MS can identify and quantify MAsIII and DMAsIII in aqueous mixtures of biologically relevant arsenical standards. However, HPLC separation of the in vitro methylation mixture resulted in significant losses of MAsIII, and particularly DMAsIII with total arsenic recoveries below 25%. Further analyses showed that MAsIII and DMAsIII bind to AS3MT or interact with other components of the methylation mixture, forming complexes that do not elute from the column. Oxidation of the mixture with H2O2 which converted trivalent arsenicals to their pentavalent analogs prior to HPLC separation increased total arsenic recoveries to ~95%. In contrast, HG-CT-AAS analysis found large quantities of methylated trivalent arsenicals in mixtures incubated with either iAsIII or MAsIII and provided high (>72%) arsenic recoveries. These data suggest that an HPLC-based analysis of biological samples can underestimate MAsIII and DMAsIII concentrations and that controlling for arsenic species recovery is essential to avoid artifacts.
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Affiliation(s)
- Jenna Currier
- Curriculum in Toxicology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7461, USA
| | - R. Jesse Saunders
- Department of Nutrition, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7461, USA
| | - Lan Ding
- Department of Nutrition, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7461, USA
| | - Wanda Bodnar
- Department of Environmental Sciences and Engineering, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7461, USA
| | - Peter Cable
- Department of Environmental Sciences and Engineering, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7461, USA
| | - Tomáš Matoušek
- Institute of Analytical Chemistry of the ASCR, v.v.i., Veveří 97, 602 00 Brno, Czech Republic
| | - John T. Creed
- Microbiological and Chemical Exposure Assessment Research Division, NERL, US EPA, Cincinnati, OH 45628, USA
| | - Miroslav Stýblo
- Curriculum in Toxicology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7461, USA
- Department of Nutrition, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7461, USA
- Corresponding Author: Tel: (+1) 919-966-5721; Fax: (+1) 919-843-0776;
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Muñiz Ortiz JG, Wallace KA, Leinisch F, Kadiiska MB, Mason RP, Kligerman AD. Catalase has a key role in protecting cells from the genotoxic effects of monomethylarsonous acid: a highly active metabolite of arsenic. ENVIRONMENTAL AND MOLECULAR MUTAGENESIS 2013; 54:317-326. [PMID: 23640787 DOI: 10.1002/em.21780] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/07/2013] [Revised: 03/20/2013] [Accepted: 03/24/2013] [Indexed: 06/02/2023]
Abstract
Although it is widely known that arsenic-contaminated drinking water causes many diseases, arsenic's exact mode of action (MOA) is not fully understood. Induction of oxidative stress has been proposed as an important key event in the toxic MOA of arsenic. The authors' studies are centered on identifying a reactive species involved in the genotoxicity of arsenic using a catalase (CAT) knockout mouse model that is impaired in its ability to breakdown hydrogen peroxide (H2 O2 ). The authors assessed the induction of DNA damage using the Comet assay following exposure of mouse Cat(+/) (+) and Cat(-) (/) (-) primary splenic lymphocytes to monomethylarsonous acid (MMA(III) ) to identify the potential role of H2 O2 in mediating cellular effects of this metalloid. The results showed that the Cat(-) (/) (-) lymphocytes are more susceptible to MMA(III) than the Cat(+/) (+) lymphocytes by a small (1.5-fold) but statistically significant difference. CAT activity assays demonstrated that liver tissue has approximately three times more CAT activity than lymphocytes. Therefore, Comet assays were performed on primary Cat(+/) (+) , Cat(+/) (-) , and Cat(-) (/) (-) hepatocytes to determine if the Cat(-) (/) (-) cells were more susceptible to MMA(III) than lymphocytes. The results showed that the Cat(-) (/) (-) hepatocytes exhibit higher levels of DNA strand breakage than the Cat(+/) (+) (approximately fivefold) and Cat(+/) (-) (approximately twofold) hepatocytes exposed to MMA(III) . Electron spin resonance using 5,5-dimethyl-1-pyrroline-N-oxide as the spin-trap agent detected the generation of ·OH via MMA(III) when H2 O2 was present. These experiments suggest that CAT is involved in protecting cells against the genotoxic effects of the ·OH generated by MMA(III) .
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Affiliation(s)
- Jorge G Muñiz Ortiz
- Integrated Systems Toxicology Division, National Health and Environmental Effects Research Laboratory, Office of Research and Development, U.S. Environmental Protection Agency, Research Triangle Park, North Carolina 27711, USA
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Zhao FJ, Zhu YG, Meharg AA. Methylated arsenic species in rice: geographical variation, origin, and uptake mechanisms. ENVIRONMENTAL SCIENCE & TECHNOLOGY 2013; 47:3957-66. [PMID: 23521218 DOI: 10.1021/es304295n] [Citation(s) in RCA: 214] [Impact Index Per Article: 17.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/21/2023]
Abstract
Rice is a major source of inorganic arsenic (iAs) in the human diet because paddy rice is efficient at accumulating As. Rice As speciation is dominated by iAs and dimethylarsinic acid (DMA). Here we review the global pattern in rice As speciation and the factors causing the variation. Rice produced in Asia shows a strong linear relationship between iAs and total As concentration with a slope of 0.78. Rice produced in Europe and the United States shows a more variable, but generally hyperbolic relationship with DMA being predominant in U.S. rice. Although there is significant genotypic variation in grain As speciation, the regional variations are primarily attributed to environmental factors. Emerging evidence also indicates that methylated As species in rice are derived from the soil, while rice plants lack the As methylation ability. Soil flooding and additions of organic matter increase microbial methylation of As, although the microbial community responsible for methylation is poorly understood. Compared with iAs, methylated As species are taken up by rice roots less efficiently but are transported to the grain much more efficiently, which may be an important factor responsible for the spikelet sterility disorder (straight-head disease) in rice. DMA is a weak carcinogen, but the level of ingestion from rice consumption is much lower than that of concern. Questions that require further investigations are identified.
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Affiliation(s)
- Fang-Jie Zhao
- College of Resources and Environmental Sciences, Nanjing Agricultural University, Nanjing 210095, China.
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Dodmane PR, Arnold LL, Pennington KL, Thomas DJ, Cohen SM. Effect of dietary treatment with dimethylarsinous acid (DMAIII) on the urinary bladder epithelium of arsenic (+3 oxidation state) methyltransferase (As3mt) knockout and C57BL/6 wild type female mice. Toxicology 2013; 305:130-5. [DOI: 10.1016/j.tox.2013.01.015] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2012] [Revised: 01/08/2013] [Accepted: 01/22/2013] [Indexed: 10/27/2022]
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Suzuki S, Arnold LL, Pennington KL, Kakiuchi-Kiyota S, Chen B, Lu X, Le XC, Cohen SM. Effects of co-administration of dietary sodium arsenate and 2,3-dimercaptopropane-1-sulfonic acid (DMPS) on the rat bladder epithelium. Toxicology 2012; 299:155-9. [PMID: 22664484 DOI: 10.1016/j.tox.2012.05.019] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2012] [Revised: 05/18/2012] [Accepted: 05/22/2012] [Indexed: 12/31/2022]
Abstract
Inorganic arsenic is a known human carcinogen, inducing tumors of the skin, urinary bladder and lung. It is metabolized to organic methylated arsenicals. 2,3-Dimercaptopropane-1-sulfonic acid (DMPS), a chelating agent, is capable of reducing pentavalent arsenicals to the trivalent state and binding to the trivalent species, and it has been used in the treatment of heavy metal poisoning in humans. Therefore, we investigated the ability of DMPS to inhibit the cytotoxicity and regenerative urothelial cell proliferation induced by arsenate administration in vivo. Female rats were treated for 4 weeks with 100 ppm As(V). DMPS (2800 ppm) co-administered in the diet significantly reduced the As(V)-induced cytotoxicity of superficial cells detected by scanning electron microscopy (SEM), and the incidence of simple hyperplasia observed by light microscopy and the bromodeoxyuridine (BrdU) labeling index. It also reduced the total concentration of arsenicals in the urine and the methylation of arsenic. There were no differences in oxidative stress as assessed by immunohistochemical staining for 8-hydroxy-2'-deoxyguanosine (8OHdG) of the bladder urothelium. No differences were detected in urine sediments between groups. These data suggest that DMPS has the ability to inhibit both arsenate-induced acute toxicity and regenerative proliferation of the rat bladder epithelium, most likely by decreasing exposure of the urothelium to trivalent arsenicals excreted in the urine. These data provide additional evidence that the effects of arsenate exposure in vivo do not appear to be related to oxidative effects on dG in DNA.
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Affiliation(s)
- Shugo Suzuki
- Department of Pathology and Microbiology and the Eppley Institute for Cancer Research, University of Nebraska Medical Center, Omaha, NE 68198-3135, United States
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Bailey KA, Wallace K, Smeester L, Thai SF, Wolf DC, Edwards SW, Fry RC. Transcriptional Modulation of the ERK1/2 MAPK and NF-κB Pathways in Human Urothelial Cells After Trivalent Arsenical Exposure: Implications for Urinary Bladder Cancer. JOURNAL OF CANCER RESEARCH UPDATES 2012; 1:57-68. [PMID: 23487506 PMCID: PMC3593739] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Subscribe] [Scholar Register] [Indexed: 06/01/2023]
Abstract
Chronic exposure to drinking water contaminated with inorganic arsenic (iAs) is associated with an increased risk of urinary bladder (UB) cancers in humans. The exact role of specific iAs metabolite(s) in As-mediated carcinogenesis remains largely unknown. Experimental evidence suggests that trivalent arsenicals, namely arsenite (iAsIII) and two of its metabolites, monomethylarsonous acid (MMAIII) and dimethylarsinous acid (DMAIII), are possible proximate UB carcinogens. Here, we used a transcriptomics approach to examine perturbed molecular pathways in a human urothelial cell line (UROtsa) after short-term exposure to iAsIII, MMAIII and DMAIII. Molecular pathways containing genes that encode proteins implicated in UB cancer development were perturbed by both MMAIII and DMAIII. These pathways included those of the extracellular signal-regulated kinase 1/2 mitogen-activated protein kinase (ERK 1/2 MAPK) and nuclear factor kappa beta (NF-κB). Together, these results may inform the current understanding of effects in the UB induced by acute As exposure and the relationship of these effects with As-mediated carcinogenesis.
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Affiliation(s)
- Kathryn A. Bailey
- Department of Environmental Sciences and Engineering, UNC Gillings School of Global Public Health, University of North Carolina at Chapel Hill, NC 27599, USA
| | - Kathleen Wallace
- National Health and Environmental Effects Research Laboratory, Office of Research and Development, U.S. Environmental Protection Agency, Research Triangle Park, NC 27711, USA
| | - Lisa Smeester
- Department of Environmental Sciences and Engineering, UNC Gillings School of Global Public Health, University of North Carolina at Chapel Hill, NC 27599, USA
| | - Sheau-Fung Thai
- National Health and Environmental Effects Research Laboratory, Office of Research and Development, U.S. Environmental Protection Agency, Research Triangle Park, NC 27711, USA
| | - Douglas C. Wolf
- National Health and Environmental Effects Research Laboratory, Office of Research and Development, U.S. Environmental Protection Agency, Research Triangle Park, NC 27711, USA
| | - Stephen W. Edwards
- National Health and Environmental Effects Research Laboratory, Office of Research and Development, U.S. Environmental Protection Agency, Research Triangle Park, NC 27711, USA
| | - Rebecca C. Fry
- Department of Environmental Sciences and Engineering, UNC Gillings School of Global Public Health, University of North Carolina at Chapel Hill, NC 27599, USA
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Lewis AS, Reid KR, Pollock MC, Campleman SL. Speciated arsenic in air: measurement methodology and risk assessment considerations. JOURNAL OF THE AIR & WASTE MANAGEMENT ASSOCIATION (1995) 2012; 62:2-17. [PMID: 22393805 DOI: 10.1080/10473289.2011.608620] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/31/2023]
Abstract
Accurate measurement of arsenic (As) in air is critical to providing a more robust understanding of arsenic exposures and associated human health risks. Although there is extensive information available on total arsenic in air, less is known on the relative contribution of each arsenic species. To address this data gap, the authors conducted an in-depth review of available information on speciated arsenic in air. The evaluation included the type of species measured and the relative abundance, as well as an analysis of the limitations of current analytical methods. Despite inherent differences in the procedures, most techniques effectively separated arsenic species in the air samples. Common analytical techniques such as inductively coupled plasma mass spectrometry (ICP-MS) and/or hydride generation (HG)- or quartz furnace (GF)-atomic absorption spectrometry (AAS) were used for arsenic measurement in the extracts, and provided some of the most sensitive detection limits. The current analysis demonstrated that, despite limited comparability among studies due to differences in seasonal factors, study duration, sample collection methods, and analytical methods, research conducted to date is adequate to show that arsenic in air is mainly in the inorganic form. Reported average concentrations of As(III) and As(V) ranged up to 7.4 and 10.4 ng/m3, respectively, with As(V) being more prevalent than As(III) in most studies. Concentrations of the organic methylated arsenic compounds are negligible (in the pg/m3 range). However because of the variability in study methods and measurement methodology, the authors were unable to determine the variation in arsenic composition as a function of source or particulate matter (PM) fraction. In this work, the authors include the implications of arsenic speciation in air on potential exposure and risks. The authors conclude that it is important to synchronize sample collection, preparation, and analytical techniques in order to generate data more useful for arsenic inhalation risk assessment, and a more robust documentation of quality assurance/quality control (QA/QC) protocols is necessary to ensure accuracy, precision, representativeness, and comparability.
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Hughes MF, Beck BD, Chen Y, Lewis AS, Thomas DJ. Arsenic exposure and toxicology: a historical perspective. Toxicol Sci 2011; 123:305-32. [PMID: 21750349 PMCID: PMC3179678 DOI: 10.1093/toxsci/kfr184] [Citation(s) in RCA: 755] [Impact Index Per Article: 53.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2011] [Accepted: 06/30/2011] [Indexed: 12/23/2022] Open
Abstract
The metalloid arsenic is a natural environmental contaminant to which humans are routinely exposed in food, water, air, and soil. Arsenic has a long history of use as a homicidal agent, but in the past 100 years arsenic, has been used as a pesticide, a chemotherapeutic agent and a constituent of consumer products. In some areas of the world, high levels of arsenic are naturally present in drinking water and are a toxicological concern. There are several structural forms and oxidation states of arsenic because it forms alloys with metals and covalent bonds with hydrogen, oxygen, carbon, and other elements. Environmentally relevant forms of arsenic are inorganic and organic existing in the trivalent or pentavalent state. Metabolism of arsenic, catalyzed by arsenic (+3 oxidation state) methyltransferase, is a sequential process of reduction from pentavalency to trivalency followed by oxidative methylation back to pentavalency. Trivalent arsenic is generally more toxicologically potent than pentavalent arsenic. Acute effects of arsenic range from gastrointestinal distress to death. Depending on the dose, chronic arsenic exposure may affect several major organ systems. A major concern of ingested arsenic is cancer, primarily of skin, bladder, and lung. The mode of action of arsenic for its disease endpoints is currently under study. Two key areas are the interaction of trivalent arsenicals with sulfur in proteins and the ability of arsenic to generate oxidative stress. With advances in technology and the recent development of animal models for arsenic carcinogenicity, understanding of the toxicology of arsenic will continue to improve.
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Affiliation(s)
- Michael F Hughes
- Office of Research and Development, National Health and Environmental Effects Research Laboratory, U.S. Environmental Protection Agency, Research Triangle Park, North Carolina 27711, USA.
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Yokohira M, Arnold LL, Lautraite S, Sheets L, Wason S, Stahl B, Eigenberg D, Pennington KL, Kakiuchi-Kiyota S, Cohen SM. The effects of oral treatment with transfluthrin on the urothelium of rats and its metabolite, tetrafluorobenzoic acid on urothelial cells in vitro. Food Chem Toxicol 2011; 49:1215-23. [DOI: 10.1016/j.fct.2011.02.022] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2011] [Revised: 02/24/2011] [Accepted: 02/26/2011] [Indexed: 10/18/2022]
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Gómez-Ariza JL, Jahromi EZ, González-Fernández M, García-Barrera T, Gailer J. Liquid chromatography-inductively coupled plasma-based metallomic approaches to probe health-relevant interactions between xenobiotics and mammalian organisms. Metallomics 2011; 3:566-77. [PMID: 21614343 DOI: 10.1039/c1mt00037c] [Citation(s) in RCA: 36] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
In mammals, the transport of essential elements from the gastrointestinal tract to organs is orchestrated by biochemical mechanisms which have evolved over millions of years. The subsequent organ-based assembly of sufficient amounts of metalloproteins is a prerequisite to maintain mammalian health and well-being. The chronic exposure of various human populations to environmentally abundant toxic metals/metalloid compounds and/or the deliberate administration of medicinal drugs, however, can adversely affect these processes which may eventually result in disease. A better understanding of the perturbation of these processes has the potential to advance human health, but their visualization poses a major problem. Nonetheless, liquid chromatography-inductively coupled plasma-based 'metallomics' methods, however, can provide much needed insight. Size-exclusion chromatography-inductively coupled plasma atomic emission spectrometry, for example, can be used to visualize changes that toxic metals/medicinal drugs exert at the metalloprotein level when they are added to plasma in vitro. In addition, size-exclusion chromatography-inductively coupled plasma mass spectrometry can be employed to analyze organs from toxic metal/medicinal drug-exposed organisms for metalloproteins to gain insight into the biochemical changes that are associated with their acute or chronic toxicity. The execution of such studies-from the selection of an appropriate model organism to the generation of accurate analytical data-is littered with potential pitfalls that may result in artifacts. Drawing on recent lessons that were learned by two research groups, this tutorial review is intended to provide relevant information with regard to the experimental design and the practical application of these aforementioned metallomics tools in applied health research.
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Affiliation(s)
- José Luis Gómez-Ariza
- Department of Chemistry and Material Sciences, Faculty of Experimental Science, University of Huelva, Campus de El Carmen, 21007 Huelva, Spain
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Yokohira M, Arnold LL, Pennington KL, Suzuki S, Kakiuchi-Kiyota S, Herbin-Davis K, Thomas DJ, Cohen SM. Effect of sodium arsenite dose administered in the drinking water on the urinary bladder epithelium of female arsenic (+3 oxidation state) methyltransferase knockout mice. Toxicol Sci 2011; 121:257-66. [PMID: 21385732 DOI: 10.1093/toxsci/kfr051] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/14/2022] Open
Abstract
The enzyme arsenic (+3 oxidation state) methyltransferase (As3mt) catalyzes reactions converting inorganic arsenic to methylated metabolites, some of which are highly cytotoxic. In a previous study, female As3mt knockout (KO) mice treated with diet containing 100 or 150 ppm arsenic as arsenite showed systemic toxicity and significant effects on the urothelium. In the present study, we showed that the cytotoxic and proliferative effects of arsenite administration on the urothelium are dose dependent. Female wild-type C57BL/6 mice and As3mt KO mice were divided into five groups (n = 7) with free access to drinking water containing 0, 1, 10, 25, or 50 ppm arsenic as arsenite for 4 weeks. At sacrifice, urinary bladders of both As3mt KO and wild-type mice showed hyperplasia by light microscopy; however, the hyperplasia was more severe in the As3mt KO mice. Intracytoplasmic granules were detected in the urothelium of As3mt KO and wild-type mice at arsenic doses ≥ 10 ppm but were more numerous, more extensive, and larger in the KO mice. A no effect level for urothelial effects was identified at 1 ppm arsenic in the wild-type and As3mt KO mice. In As3mt KO mice, livers showed mild acute inflammation and kidneys showed hydronephrosis. The present study shows a dose-response for the effects of orally administered arsenite on the bladder urothelium of wild-type and As3mt KO mice, with greater effects in the KO strain but with a no effect level of 1 ppm for both.
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Affiliation(s)
- Masanao Yokohira
- Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, Nebraska 68198-3135, USA
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Bailey KA, Hester SD, Knapp GW, Owen RD, Thai SF. Gene expression of normal human epidermal keratinocytes modulated by trivalent arsenicals. Mol Carcinog 2011; 49:981-98. [PMID: 20886546 DOI: 10.1002/mc.20677] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/01/2023]
Abstract
Chronic exposure to inorganic arsenic (iAs) is associated with the development of benign and malignant human skin lesions including nonmelanoma skin cancers. The precise arsenical form(s) responsible for this carcinogenic effect are unknown, although trivalent inorganic arsenic (iAs(III)) and two of its toxic metabolites, monomethylarsonous acid (MMA(III)) and methylarsinous acid (DMA(III)), are attractive candidates. In an effort to better understand and compare their toxic effects in the skin, we compared the global gene expression profiles of normal human epidermal keratinocytes (NHEKs) exposed to varying noncytotoxic/slightly cytotoxic concentrations of iAs(III), MMA(III), and DMA(III) for 24 h. Exposure to each arsenical treatment group exhibited a dose effect in the number of altered genes and the magnitude of expression change in NHEKs. The most significant gene expression changes associated with iAs(III) and MMA(III) exposure were consistent with several key events believed to be important to As-driven skin carcinogenesis, namely induction of oxidative stress, increased transcript levels of keratinocyte growth factors, and modulation of MAPK and NF-κB pathways. At both comparable arsenical concentrations and comparable NHEK toxicity, greater potential carcinogenic effects were observed in MMA(III)-exposed NHEKs than those exposed to iAs(III), including involvement of more proinflammatory signals and increased transcript levels of more growth factor genes. In contrast, none of these above-mentioned transcriptional trends were among the most significantly altered functions in the DMA(III) treatment group. This study suggests the relative capacity of each of the tested arsenicals to drive suspected key events in As-mediated skin carcinogenesis is MMA(III) > iAs(III) with little contribution from DMA(III).
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Affiliation(s)
- Kathryn A Bailey
- US Environmental Protection Agency, Research Triangle Park, North Carolina, USA
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Hughes MF, Edwards BC, Herbin-Davis KM, Saunders J, Styblo M, Thomas DJ. Arsenic (+3 oxidation state) methyltransferase genotype affects steady-state distribution and clearance of arsenic in arsenate-treated mice. Toxicol Appl Pharmacol 2010; 249:217-23. [PMID: 20887743 DOI: 10.1016/j.taap.2010.09.017] [Citation(s) in RCA: 59] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2010] [Revised: 09/20/2010] [Accepted: 09/22/2010] [Indexed: 11/18/2022]
Abstract
Arsenic (+3 oxidation state) methyltransferase (As3mt) catalyzes formation of mono-, di-, and tri-methylated metabolites of inorganic arsenic. Distribution and retention of arsenic were compared in adult female As3mt knockout mice and wild-type C57BL/6 mice using a regimen in which mice received daily oral doses of 0.5mg of arsenic as arsenate per kilogram of body weight. Regardless of genotype, arsenic body burdens attained steady state after 10 daily doses. At steady state, arsenic body burdens in As3mt knockout mice were 16 to 20 times greater than in wild-type mice. During the post dosing clearance period, arsenic body burdens declined in As3mt knockout mice to ~35% and in wild-type mice to ~10% of steady-state levels. Urinary concentration of arsenic was significantly lower in As3mt knockout mice than in wild-type mice. At steady state, As3mt knockout mice had significantly higher fractions of the body burden of arsenic in liver, kidney, and urinary bladder than did wild-type mice. These organs and lung had significantly higher arsenic concentrations than did corresponding organs from wild-type mice. Inorganic arsenic was the predominant species in tissues of As3mt knockout mice; tissues from wild-type mice contained mixtures of inorganic arsenic and its methylated metabolites. Diminished capacity for arsenic methylation in As3mt knockout mice prolongs retention of inorganic arsenic in tissues and affects whole body clearance of arsenic. Altered retention and tissue tropism of arsenic in As3mt knockout mice could affect the toxic or carcinogenic effects associated with exposure to this metalloid or its methylated metabolites.
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Affiliation(s)
- Michael F Hughes
- Pharmacokinetics Branch, Integrated Systems Toxicology Division, National Health and Environmental Effects Research Laboratory, Office of Research and Development, US Environmental Protection Agency, Research Triangle Park, NC 27711, USA
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Naranmandura H, Bu N, Suzuki KT, Lou Y, Ogra Y. Distribution and speciation of arsenic after intravenous administration of monomethylmonothioarsonic acid in rats. CHEMOSPHERE 2010; 81:206-213. [PMID: 20594576 DOI: 10.1016/j.chemosphere.2010.06.043] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/16/2010] [Revised: 05/30/2010] [Accepted: 06/09/2010] [Indexed: 05/29/2023]
Abstract
Quite a few new thioarsenicals have recently been found in urine of arsenic-exposed humans and animals, and some of them have been shown to be highly toxic to cells. However, little is known about their toxic effects and metabolism in the body. In order to elucidate the toxic mechanism of thioarsenicals, we further focused on the distribution and metabolism of monomethylmonothioarsonic acid (MMMTA(V)) in rats. MMMTA(V) was synthesized chemically and injected intravenously into rats at the dose of 0.5mg As/kg, followed by speciation analysis of selected organs and body fluids at 10 min and 12h after the injection. MMMTA(V) was excreted into urine in its intact form, and approximately 35% of the dose was recovered in urine at 12h after the injection, suggesting that MMMTA(V) was taken up more effectively by organs/tissues than non-thiolated, monomethylarsonous acid (MMA(V)) previously studied. On the other hand, the liver and kidneys contained arsenic that was in a protein-binding form with free forms of DMA(V) or DMDTA(V) at 10 min, and disappeared at 12h after the injection. Moreover, these bound arsenic species in kidneys were converted back to MMA(V) after oxidation with H(2)O(2), suggesting that the arsenic bound to proteins had been reduced within the body and was in a trivalent oxidation state. In red blood cells (RBCs), most of the arsenic was in the form of DMA(III) bound to hemoglobin (Hb), and approximately 40% of the dose was recovered in RBCs at 12h after injection. These results indicate that arsenic accumulated preferentially in RBCs after being transformed to DMA(III). In addition, we have also discussed the effect of MMMTA(V) on viability of human bladder cancer T24 cells in comparison with MMA(V). Consequently, MMMTA(V) was assumed to be a more toxic arsenic metabolite than non-thiolated MMA(V).
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Affiliation(s)
- Hua Naranmandura
- Institute of Pharmacology & Toxicology and Biochemical Pharmaceutics, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China.
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