Environmental Science and Pollution Research

, Volume 24, Issue 21, pp 17485–17492 | Cite as

Differential toxicity of arsenic on renal oxidative damage and urinary metabolic profiles in normal and diabetic mice

  • Jinbao Yin
  • Su Liu
  • Jing Yu
  • Bing WuEmail author
Research Article


Diabetes is a common metabolic disease, which might influence susceptibility of the kidney to arsenic toxicity. However, relative report is limited. In this study, we compared the influence of inorganic arsenic (iAs) on renal oxidative damage and urinary metabolic profiles of normal and diabetic mice. Results showed that iAs exposure increased renal lipid peroxidation in diabetic mice and oxidative DNA damage in normal mice, meaning different effects of iAs exposure on normal and diabetic individuals. Nuclear magnetic resonance (NMR)-based metabolome analyses found that diabetes significantly changed urinary metabolic profiles of mice. Oxidative stress-related metabolites, such as arginine, glutamine, methionine, and β-hydroxybutyrate, were found to be changed in diabetic mice. The iAs exposure altered amino acid metabolism, lipid metabolism, carbohydrate metabolism, and energy metabolism in normal and diabetic mice, but had higher influence on metabolic profiles of diabetic mice than normal mice, especially for oxidative stress-related metabolites and metabolisms. Above results indicate that diabetes increased susceptibility to iAs exposure. This study provides basic information on differential toxicity of iAs on renal toxicity and urinary metabolic profiles in normal and diabetic mice and suggests that diabetic individuals should be considered as susceptible population in toxicity assessment of arsenic.


Arsenic Diabetes Oxidative damage Metabolic profiles Kidney Mouse 



This work was supported by Natural Science Foundation of Jiangsu Province (BK20131270), Foundation of State Key Laboratory of Pollution Control and Resource Reuse, and Fundamental Research Funds for the Central Universities of Nanjing University.

Compliance with ethical standards

Compliance with the NIH Guide for the Care and Use of Laboratory Animals. And the protocol was approved by the Committee on the Ethics of Animal Experiments of the Nanjing Military General Hospital.

Supplementary material

11356_2017_9391_MOESM1_ESM.docx (20 kb)
ESM 1 (DOCX 20 kb)


  1. Ajala O, English P, Pinkney J (2013) Systematic review and meta-analysis of different dietary approaches to the management of type 2 diabetes. Am J Clin Nutr 97:505–516. doi: 10.3945/ajcn.112.042457 CrossRefGoogle Scholar
  2. Albina ML, Alonso V, Linares V, Bellés M, Sirvent JJ, Domingo JL, Sánchez DJ (2010) Effects of exposure to BDE-99 on oxidative status of liver and kidney in adult rats. Toxicology 271:51–56CrossRefGoogle Scholar
  3. Apel K, Hirt H (2004) Reactive oxygen species: metabolism, oxidative stress, and signal transduction. Annu rev Plant Biol 55:373–399CrossRefGoogle Scholar
  4. Birkenfeld AL, Shulman GI (2014) Nonalcoholic fatty liver disease, hepatic insulin resistance, and type 2 diabetes. Hepatology 59:713–723. doi: 10.1002/hep.26672 CrossRefGoogle Scholar
  5. Butte NF (2000) Carbohydrate and lipid metabolism in pregnancy: normal compared with gestational diabetes mellitus. Am J Clin Nutr 71:1256s–1261sGoogle Scholar
  6. Chen CJ, Chen CW, Wu MM, Kuo TL (1992) Cancer potential in liver, lung, bladder and kidney due to ingested inorganic arsenic in drinking-water. J Cancer 66:888–892. doi: 10.1038/bjc.1992.380 CrossRefGoogle Scholar
  7. Coskun O, Kanter M, Korkmaz A, Oter S (2005) Quercetin, a flavonoid antioxidant, prevents and protects streptozotocin-induced oxidative stress and β-cell damage in rat pancreas. Pharmacol Res 51:117–123CrossRefGoogle Scholar
  8. Dheer R, Patterson J, Dudash M, Stachler EN, Bibby KJ, Stolz DB, Shiva S, Wang Z, Hazen SL, Barchowsky A, Stolza JF (2015) Arsenic induces structural and compositional colonic microbiome change and promotes host nitrogen and amino acid metabolism. Toxicol Appl Pharmacol 289:397–408. doi: 10.1016/j.taap.2015.10.020 CrossRefGoogle Scholar
  9. El-Missiry M, Othman A, Amer M (2004) L-arginine ameliorates oxidative stress in alloxan-induced experimental diabetes mellitus. J Appl Toxicol 24:93–97CrossRefGoogle Scholar
  10. Emwas AH, Luchinat C, Turano P, Tenori L, Roy R, Salek RM, Ryan D, Merzaban JS, Kaddurah-Daouk R, Zeri AC, Gowda GAN, Raftery D, Wang Y, Brennan L, Wishart DS (2015) Standardizing the experimental conditions for using urine in NMR-based metabolomic studies with a particular focus on diagnostic studies: a review. Metabolomics 11:872–894. doi: 10.1007/s11306-014-0746-7 CrossRefGoogle Scholar
  11. Flora SJ (2011) Arsenic-induced oxidative stress and its reversibility. Free Radical Bio Med 51:257–281CrossRefGoogle Scholar
  12. Flora SJ, Bhadauria S, Pant SC, Dhaked RK (2005) Arsenic induced blood and brain oxidative stress and its response to some thiol chelators in rats. Life Sci 77:2324–2337CrossRefGoogle Scholar
  13. Forbes JM, Coughlan MT, Cooper ME (2008) Oxidative stress as a major culprit in kidney disease in diabetes. Diabetes 57:1446–1454CrossRefGoogle Scholar
  14. Fowler BA, Whittaker MH, Lipsky M, Wang G, Chen X-Q (2004) Oxidative stress induced by lead, cadmium and arsenic mixtures: 30-day, 90-day, and 180-day drinking water studies in rats: an overview. Biometals 17:567–568CrossRefGoogle Scholar
  15. Friedrich N (2012) Metabolomics in diabetes research. J Endocrinol 215:29–42. doi: 10.1530/joe-12-0120 CrossRefGoogle Scholar
  16. Fu JZ, Schoeman JC, Harms AC, van Wietmarschen HA, Vreeken RJ, Berger R, Cuppen BVJ, Lafeber FPJG, van der Greef J, Hankemeier T (2016) Metabolomics profiling of the free and total oxidised lipids in urine by LC-MS/MS: application in patients with rheumatoid arthritis. Anal Bioanal Chem 408:6307–6319. doi: 10.1007/s00216-016-9742-2 CrossRefGoogle Scholar
  17. Ganti S, Weiss RH (2011) Urine metabolomics for kidney cancer detection and biomarker discovery. Urol Oncol -Semin Ori 29(5):551–557CrossRefGoogle Scholar
  18. Garcia-Sevillano MA, Contreras-Acuna M, Garcia-Barrera T, Navarro F, Gomez-Ariza JL (2014) Metabolomic study in plasma, liver and kidney of mice exposed to inorganic arsenic based on mass spectrometry. Anal Bioanal Chem 406:1455–1469. doi: 10.1007/s00216-013-7564-z CrossRefGoogle Scholar
  19. Guha Mazumder DN (2008) Chronic arsenic toxicity & human health. Indian J Med res 128:436–447Google Scholar
  20. Kelley DE, McKolanis TM, Hegazi RAF, Kuller LH, Kalhan SC (2003) Fatty liver in type 2 diabetes mellitus: relation to regional adiposity, fatty acids, and insulin resistance. Am J Physiol Endocrinol Metab 285:E906–E916. doi: 10.1152/ajpendo.00117.2003 CrossRefGoogle Scholar
  21. Kim K, Taylor SL, Ganti S, Guo L, Osier MV, Weiss RH (2011) Urine metabolomic analysis identifies potential biomarkers and pathogenic pathways in kidney cancer. Omics 15:293–303CrossRefGoogle Scholar
  22. Kurata M, Suzuki M, Agar NS (1993) Antioxidant systems and erythrocyte life-span in mammals comp. Biochem Physiol B Comp Biochem 106:477–487CrossRefGoogle Scholar
  23. Lass A, Suessenbacher A, Wölkart G, Mayer B, Brunner F (2002) Functional and analytical evidence for scavenging of oxygen radicals by L-arginine. Mol Pharmacol 61:1081–1088CrossRefGoogle Scholar
  24. Lindon JC, Nicholson JK, Everett JR (1999) NMR spectroscopy of biofluids. Annual Reports on NMR Spectroscopy 38:1–88CrossRefGoogle Scholar
  25. Liu S, Guo X, Zhang X, Cui Y, Zhang Y, Wu B (2013) Impact of iron precipitant on toxicity of arsenic in water: a combined in vivo and in vitro study. Environ Sci Technol 47:3432–3438. doi: 10.1021/es400176m Google Scholar
  26. Liu S, Guo X, Wu B, Yu H, Zhang X, Li M (2014) Arsenic induces diabetic effects through beta-cell dysfunction and increased gluconeogenesis in mice. Sci Rep 4:6894. doi: 10.1038/srep06894 CrossRefGoogle Scholar
  27. Lowry OH, Rosebrough NJ, Farr AL, Randall RJ (1951) Protein measurement with the Folin phenol reagent. J Biol Chem 193:265–275Google Scholar
  28. Matés JM, Pérez-Gómez C, de Castro IN, Asenjo M, Márquez J (2002) Glutamine and its relationship with intracellular redox status, oxidative stress and cell proliferation/death. Int J Biochem Cell Biol 34:439–458CrossRefGoogle Scholar
  29. Matsuda M, Shimomura I (2013) Increased oxidative stress in obesity: implications for metabolic syndrome, diabetes, hypertension, dyslipidemia, atherosclerosis, and cancer. Obes Res Clin Pract 7:e330–e341. doi: 10.1016/j.orcp.2013.05.004 CrossRefGoogle Scholar
  30. Meister A (1981) On the cycles of glutathione metabolism and transport. Curr top Cell Regul 18:21–58CrossRefGoogle Scholar
  31. Nandi D, Patra RC, Swarup D (2006) Oxidative stress indices and plasma biochemical parameters during oral exposure to arsenic in rats. Food Chem Toxicol 44:1579–1584. doi: 10.1016/j.fct.2006.04.013 CrossRefGoogle Scholar
  32. Navas-Acien A, Silbergeld EK, Streeter RA, Clark JM, Burke TA, Guallar E (2006) Arsenic exposure and type 2 diabetes: a systematic review of the experimental and epidemiologic evidence. Environ Health Perspect 114:641–648. doi: 10.1289/ehp.8551 CrossRefGoogle Scholar
  33. Oberley LW, Spitz DR (1984) [61] assay of superoxide dismutase activity in tumor tissue. Methods Enzymol 105:457–464CrossRefGoogle Scholar
  34. Patel A (2007) Effects of a fixed combination of perindopril and indapamide on macrovascular and microvascular outcomes in patients with type 2 diabetes mellitus (the ADVANCE trial): a randomised controlled trial. Lancet 370:829–840. doi: 10.1016/S0140-6736(07)61303-8 CrossRefGoogle Scholar
  35. Patel HV, Kalia K (2010) Sub-chronic arsenic exposure aggravates nephrotoxicity in experimental diabetic rats. Indian J Exp Biol 48:762–768Google Scholar
  36. Patra R, Swarup D, Dwivedi S (2001) Antioxidant effects of α tocopherol, ascorbic acid and L-methionine on lead induced oxidative stress to the liver, kidney and brain in rats. Toxicology 162:81–88CrossRefGoogle Scholar
  37. Pavlik M, Pavlikova D, Staszkova L, Neuberg M, Kaliszova R, Szakova J, Tlustos P (2010) The effect of arsenic contamination on amino acids metabolism in Spinacia oleracea. L Ecotox Environ Safe 73:1309–1313. doi: 10.1016/j.ecoenv.2010.07.008 CrossRefGoogle Scholar
  38. Pisarenko OI (1996) Mechanisms of myocardial protection by amino acids: facts and hypotheses. Clin Exp Pharmacol Physiol 23:627–633CrossRefGoogle Scholar
  39. Prabu SM, Muthumani M (2012) Silibinin ameliorates arsenic induced nephrotoxicity by abrogation of oxidative stress, inflammation and apoptosis in rats. Mol Biol Rep 39:11201–11216CrossRefGoogle Scholar
  40. Rahman MM, Rahman F, Sansom L, Naidu R, Schmidt O (2009) Arsenic interactions with lipid particles containing iron. Environ Geochem Health 31:201–206. doi: 10.1007/s10653-008-9236-z CrossRefGoogle Scholar
  41. Scheuermann-Freestone M, Madsen PL, Manners D, Blamire AM, Buckingham RE, Styles P, Radda GK, Neubauer S, Clarke K (2003) Abnormal cardiac and skeletal muscle energy metabolism in patients with type 2 diabetes. Circulation 107:3040–3046. doi: 10.1161/01.cir.0000072789.89096.10 CrossRefGoogle Scholar
  42. Shimazu T, Hirschey MD, Newman J, He WJ, Shirakawa K, Le Moan N, Grueter CA, Lim H, Saunders LR, Stevens RD, Newgard CB, Farese RV, de Cabo R, Ulrich S, Akassoglou K, Verdin E (2013) Suppression of oxidative stress by β-hydroxybutyrate, an endogenous histone deacetylase inhibitor. Science 339:211–214CrossRefGoogle Scholar
  43. Tannahill GM, Curtis AM, Adamik J, Palsson-McDermott EM, McGettrick AF, Goel G, Frezza C, Bernard NJ, Kelly B, Foley NH, Zheng L, Gardet A, Tong Z, Jany SS, Corr SC, Haneklaus M, Caffrey BE, Pierce K, Walmsley S, Beasley FC, Cummins E, Nizet V, Whyte M, Taylor CT, Lin H, Masters SL, Gottlieb E, Kelly VP, Clish C, Auron PE, Xavier RJ, O'Neill LAJ (2013) Succinate is an inflammatory signal that induces IL-1 beta through HIF-1 alpha. Nature 496:238–242CrossRefGoogle Scholar
  44. Tchounwou PB, Patlolla AK, Centeno JA (2003) Carcinogenic and systemic health effects associated with arsenic exposure - a critical review. Toxicol Pathol 31:575–588. doi: 10.1080/01926230390242007 Google Scholar
  45. Toyokuni S, Tanaka T, Hatton Y, Nishiyama Y, Yoshida A, Uchida K, Hiai H, Ochi H, Osawa (1997) Quantitative immunohistochemical determination of 8-hydroxy-2′-deoxyguanosine by a monoclonal antibody N45. 1: its application to ferric nitrilotriacetate-induced renal carcinogenesis model. Lab Investig 76:365–374Google Scholar
  46. Wang XN, Zhao HY, Shao YL, Wang P, Wei YR, Zhang WQ, Jiang J, Chen Y, Zhang ZG (2014) Nephroprotective effect of astaxanthin against trivalent inorganic arsenic-induced renal injury in wistar rats. Nutr Res Pract 8:46–53. doi: 10.4162/nrp.2014.8.1.46 CrossRefGoogle Scholar
  47. Wang XX, Mu XL, Zhang J, Huang QY, Alamdar AV, Tian MP, Liua LP, Shen HQ (2015) Serum metabolomics reveals that arsenic exposure disrupted lipid and amino acid metabolism in rats: a step forward in understanding chronic arsenic toxicity. Metallomics 7:544–552. doi: 10.1039/c5mt00002e CrossRefGoogle Scholar
  48. Yagi K (1998) Simple assay for the level of total lipid peroxides in serum or plasma. Free Radic Antioxid Protocol 108:101–106Google Scholar
  49. Yin J, Zhang X-X, Wu B, Xian Q (2015) Metagenomic insights into tetracycline effects on microbial community and antibiotic resistance of mouse gut. Ecotoxicology 24:2125–2132. doi: 10.1007/s10646-015-1540-7 CrossRefGoogle Scholar
  50. Zhang Y, Zhang X, Wu B, Cheng S (2012) Evaluating the transcriptomic and metabolic profile of mice exposed to source drinking water. Environ Sci Technol 46:78–83. doi: 10.1021/es201369x CrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2017

Authors and Affiliations

  1. 1.State Key Laboratory of Pollution Control and Resource ReuseSchool of the Environment, Nanjing University, Xianlin CampusNanjingPeople’s Republic of China

Personalised recommendations