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Researchers found new sulfur-containing metabolites in the urine of rats exposed to arsenite


Inorganic arsenic is a well-recognized Class I human carcinogen. Numerous epidemiological studies have demonstrated that chronic exposure of humans to inorganic arsenic via drinking water is linked to skin, bladder, and lung cancer as well as other health hazards such as diabetes and cardiovascular effects. While arsenic is often named the classical poison, the toxicities of different arsenicals vary drastically with their chemical forms and oxidation state. Therefore, in order to understand the arsenic metabolism, the toxicity of the produced metabolites and the underlying mechanisms of action responsible for their toxicity, speciation analysis identifying and quantifying the different arsenicals in the biological samples is especially important.

Arsenic mainly enters the environment in the form of inorganic species, released from rocks and minerals in contact with the aquatic environment. Taken up by organisms, the inorganic arsenic can be transformed into various organic species through a series of biological processes including redox reactions and methylation. The major arsenic metabolites commonly identified are monomethylarsonic acid (MMAv) and dimethylarsinic acid. Since these pentavalent arsenic species are less toxic than the inorganic arsenite, the metabolic processes leading to the methylated species have often been discussed as a detoxification route. However, more recently it was recognized that the trivalent methylated arsenicals are also produced. This is of particular concern, since these trivalent methylarsenicals are even more potent cytotoxins than inorganic arsenic. Recently, another type of arsenicals, thio-containing methylated species have also been identified in various biological samples. Although many efforts have been made to understand the metabolism of arsenic, the metabonomics of arsenic has yet to be fully elucidated.

The new study:
Aiming to improve our understanding of metabolism of inorganic arsenic in animals, the researchers conducted an animal feeding study with an emphasis on identifying new arsenic metabolites. Female rats were exposed to arsenite via the diet. Arsenic species in rat urine where then determined by high performance liquid chromatography (HPLC) coupled with either inductively coupled plasma mass spectrometry (ICPMS) or electrospray ionization tandem mass spectrometry (ESI MS/MS).  Out of the nine arsenic species detected, seven were previously reported, including iAsIII, arsenate, monomethylarsonic acid, dimethylarsinic acid, trimethylarsine oxide, monomethylmonothioarsonic acid, and dimethylmonothioarsinic acid.  Two new methyldithioarsenicals, monomethyldithioarsonic acid (MMDTAv) and dimethyldithioarsinic acid (DMDTAv), were identified for the first time in the urine of rats treated with iAsIII. Their concentration increased with increasing dosage of inorganic arsenic in the diet. MMDTAv has not been identified in any biological samples of animals before. Its concentration in the rats urine was approximately 1/5 of DMDTAv.

The authors speculate, that the microbiome in the rats could contribute to the formation of these new thioarsenicals. In order to investigate the contribution of the microbiome, further research, e.g., using the rat microbiome and germ-free rats, is proposed by them.

The cited study:

Baowei Chen, Xiufen Lu, Lora L. Arnold, Samuel M. Cohen, X. Chris Le, Identification of Methylated Dithioarsenicals in the Urine of Rats Fed with Sodium Arsenite, Chem. Res. Toxicol. 2016. DOI: 10.1021/acs.chemrestox.6b00151

Used analytical techniques (and instruments):

Agilent 7500-CE ICP-MS

Related studies (newest first):

Q.Q. Wang, D.J. Thomas, H. Naranmandura, Importance of being thiomethylated: formation, fate, and effects of methylated thioarsenicals. Chem. Res. Toxicol., 28 (2015) 281-289. doi: 10.1021/tx500464t

S.S.C.D. Rubin, P. Alava, I. Zekker, G. Du Laing, T. Van de Wiele, Arsenic Thiolation and the Role of Sulfate-Reducing Bacteria from the Human Intestinal Tract. Environ. Health Perspect., 122 (2014) 817-822. doi: 10.1289/ehp.1307759

M. Contreras-Acuna, T. Garcia-Barrera, M. Garcia-Sevillano, J.L. Gomez-Ariza, Arsenic metabolites in human serum and urine after seafood (Anemonia sulcata) consumption and bioaccessibility assessment using liquid chromatography coupled to inorganic and organic mass spectrometry. Microchem. J.,  112 (2014) 56-64. doi: 10.1016/j.microc.2013.09.007

H. Naranmandura, K. Rehman, X.C. Le, D.J. Thomas, Formation of methylated oxyarsenicals and thioarsenicals in wild-type and arsenic (+3 oxidation state) methyltransferase knockout mice exposed to arsenate. Anal. Bioanal. Chem., 405 (2013) 1885-1891. doi: 10.1007/s00216-012-6207-0

N. Bu, H.Y. Wang, W.H. Hao, X. Liu, S. Xu, B. Wu, Y. Anan, Y. Ogra, N.J. Lou, H. Naranmandura, Generation of thioarsenicals is dependent on the enterohepatic circulation in rats. Metallomics, 3 (2011) 1064-1073. doi: 10.1039/c1mt00036e

H. Naranmandura, M.W. Carew, S. Xu, J. Lee, E.M. Leslie, M. Weinfeld, X.C. Le, Comparative Toxicity of Arsenic Metabolites in Human Bladder Cancer EJ-1 Cells. Chem. Res. Toxicol., 24 (2011) 1586-1596. doi: 10.1021/tx200291p

T.S. Pinyayev, M.J. Kohan, K. Herbin-Davis, J.T. Creed, D.J. Thomas,  Preabsorptive metabolism of sodium arsenate by anaerobic microbiota of mouse cecum forms a variety of methylated and thiolated arsenicals. Chem. Res. Toxicol., 24 (2011) 475-477. doi. 10.1021/tx200040w

H. Naranmandura, N. Bu, K.T. Suzuki, Y. Lou, Y. Ogra, Distribution and speciation of arsenic after intravenous administration of monomethylmonothioarsonic acid in rats. Chemosphere, 81 (2010) 206-213. doi: 10.1016/j.chemosphere.2010.06.043

T. Van de Wiele, C.M. Gallawa, K.M. Kubachka, J.T. Creed, N. Basta, E.A. Dayton, S. Whitacre, G. Du Laing, K. Bradham, Arsenic Metabolism by Human Gut Microbiota upon in Vitro Digestion of Contaminated Soils. Environ. Health Perspect., 118 (2010) 1004-1009. doi: 10.1289/ehp.0901794

S. Suzuki, L.L. Arnold, K.L. Pennington, B.W. Chen, H. Naranmandura, X.C. Le, S.M. Cohen, Dietary administration of sodium arsenite to rats: Relations between dose and urinary concentrations of methylated and thio-metabolites and effects on the rat urinary bladder epithelium. Toxicol. Appl. Pharmacol. 244 (2010) 99-105. doi: 10.1016/j.taap.2009.12.026

H. Naranmandura, Y. Ogra, K. Iwata, J. Lee, K.T. Suzuki, M. Weinfeld, X.C. Le, Evidence for toxicity differences between inorganic arsenite and thioarsenicals in human bladder cancer cells. Toxicol. Appl. Pharmacol., 238 (2009) 133-140. doi: 10.1016/j.taap.2009.05.006

K.M. Kubachka, M.C. Kohan, K. Herbin-Davis, J.T. Creed, D.J. Thomas, Exploring the in vitro formation of trimethylarsine sulfide from dimethylthioarsinic acid in anaerobic microflora of mouse cecum using HPLC-ICP-MS and HPLC-ESI-MS. Toxicol. Appl. Pharmacol., 239 (2009) 137-143. doi: 10.1016/j.taap.2008.12.008

K.M. Kubachka, M.C. Kohan, S.D Conklin, K. Herbin-Davis, J.T. Creed, D.J. Thomas, In vitro biotransformation of dimethylarsinic acid and trimethylarsine oxide by anaerobic microflora of mouse cecum analyzed by HPLC-ICP-MS and HPLC ESI-MS. J. Anal. At. Spectrom., 24 (2009) 1062-1068. doi: 10.1039/b817820h

S.K.V. Yathavakilla, M. Fricke, P.A. Creed, D.T. Heitkemper, N.V. Shockey, C. Schwegel, J.A. Caruso, J.T. Creed, Arsenic speciation and identification of monomethylarsonous acid and monomethylthioarsonic acid in a complex matrix. Anal. Chem., 80 (2008) 775-782. doi: 10.1021/ac0714462

T. Ochi, K. Kita, T. Suzuki, A. Rumpler, W. Goessler, K.A. FrancesconiCytotoxic, genotoxic and cell-cycle disruptive effects of thio-dimethylarsinate in cultured human cells and the role of glutathione. Toxicol. Appl. Pharmacol., 228 (2008) 59-67. doi: 10.1016/j.taap.2007.11.023

B.K. Mandal, K.T. Suzuki, K. Anzai, K. Yamaguchi, Y. Sei, A SEC-HPLC-ICP MS hyphenated technique for identification of sulfur-containing arsenic metabolites in biological samples. J. Chromatogr. B: Anal. Technol. Biomed. Life Sci., 874 (2008) 64-76. doi: 10.1016/j.jchromb.2008.09.004

H. Naranmandura, K.T. Suzuki, Formation of dimethylthioarsenicals in red blood cells. Toxicol. Appl. Pharmacol., 227 (2008) 390-399. doi: 10.1016/j.taap.2007.11.008

H. Naranmandura, K. Ibata, K.T. Suzuki, Toxicity of dimethylmonothioarsinic acid toward human epidermoid carcinoma A431 cells. Chem. Res. Toxicol., 20 (2007) 1120-1125. doi: 10.1021/tx700103y

A. Raml, A. Rumpler, W. Goessler, M. Vahter, L. Li, T. Ochi, K.A. Francesconi, Thio-dimethylarsinate is a common metabolite in urine samples from arsenic-exposed women in Bangladesh. Toxicol. Appl. Pharmacol., 222 (2007) 374-380. doi: 10.1016/j.taap.2006.12.014

H. Naranmandura, N. Suzuki, K. Iwata, S. Hirano, K.T. Suzuki, Arsenic metabolism and thioarsenicals in hamsters and rats, Chem. Res. Toxicol., 20 (2007) 616-624. doi: 10.1021/tx700038x

K.T. Suzuki, K. Iwata, H. Naranmandura, N. Suzuki, Metabolic differences between two dimethylthioarsenicals in rats. Toxicol. Appl. Pharmacol., 218 (2007) 166-173. doi: 10.1016/j.taap.2006.10.027

K.T. Suzuki, B.K. Mandal, A. Katagiri, Y. Sakuma, A. Kawakami, Y. Ogra, K. Yamaguchi, Y. Sei, K. Yamanaka, K. Anzai, M. Ohmichi, H. Takayama, N. Aimi, Dimethylthioarsenicals as arsenic metabolites and their chemical preparations. Chem. Res. Toxicol., 17 (2004) 914-921. doi: 10.1021/tx049963s

K. Yoshida, K. Kuroda, X. Zhou, Y. Inoue, Y. Date, H. Wanibuchi, S. Fukushima, G. Endo,  Urinary sulfurcontaining metabolite produced by intestinal bacteria following oral
administration of dimethylarsinic acid to rats
. Chem. Res. Toxicol., 16 (2003) 1124-1129. doi: 10.1021/tx030008x

M.J. Mass, A. Tennant, B.C. Roop, W.R. Cullen, M. Styblo, D.J. Thomas, A.D.  Kligerman, Methylated trivalent arsenic species are genotoxic. Chem. Res. Toxicol., 14 (2001) 355-361. doi: 10.1021/tx000251l

M. Styblo, L.M. Del Razo, L. Vega, D.R. Germolec, E.L. LeCluyse, G.A. Hamilton, W. Reed, C. Wang, W.R. Cullen, D.J. Thomas, Comparative toxicity of trivalent and pentavalent inorganic and methylated arsenicals in rat and human cells. Arch. Toxicol., 74 (2000) 289-299. doi: 10.1007/s002040000134

Related EVISA Resources

Brief summary: Speciation and Toxicity
Brief summary: Standard methods for arsenic speciation analysis
Brief summary: ICP-MS: A versatile detection system for speciation analysis
Brief summary: LC-ICP-MS: The most often used hyphenated system for speciation analysis
Brief summary: ESI-MS: The tool for the identification of species
Link database: Toxicity of organic arsenic species
Link database: Toxicity of inorganic Arsenic
Link database: Human exposure from arsenic in the diet
Link database: Analytical Methods for Arsenic Speciation Analysis
Link Page: All about food science
Material database: Materials for Arsenic speciation analysis

Related EVISA News (newest first)

April 16, 2016: Arsenic-Containing Phosphatidylcholines Discovered in Herring Caviar
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August 2, 2010: Gut bacteria transform inorganic arsenate leading to more toxic arsenic species
September 5, 2008: Exposure to inorganic arsenic may increase diabetes risk
August 8, 2008: Arsenolipids in Fish Oil by Arsenic Speciation Analysis

last time modified: August 12,2016


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