Advertisement

Environmental Science and Pollution Research

, Volume 25, Issue 4, pp 3765–3774 | Cite as

Metabolomic analysis of the toxic effect of chronic exposure of cadmium on rat urine

  • Shuai Chen
  • Meiyan Zhang
  • Lu Bo
  • Siqi Li
  • Liyan Hu
  • Xiujuan ZhaoEmail author
  • Changhao SunEmail author
Research Article

Abstract

This study aimed to assess the toxic effect of chronic exposure to cadmium through a metabolomic approach based on ultra-performance liquid chromatography/mass spectrometry (UPLC–MS). Forty male Sprague–Dawley rats were randomly assigned to the following groups: control, low-dose cadmium chloride (CdCl2) (0.13 mg/kg body weight (bw)), middle-dose CdCl2 (0.8/kg bw), and high-dose CdCl2 (4.9 mg/kg bw). The rats continuously received CdCl2 via drinking water for 24 weeks. Rat urine samples were then collected at different time points to establish the metabolomic profiles. Multiple statistical analyses with principal component analysis and partial least squares–discriminant analysis were used to investigate the metabolomic profile changes in the urine samples and screen for potential biomarkers. Thirteen metabolites were identified from the metabolomic profiles of rat urine after treatment. Compared with the control group, the treated groups showed significantly increased intensities of phenylacetylglycine, guanidinosuccinic acid, 4-pyridoxic acid, 4-aminohippuric acid, 4-guanidinobutanoic acid, allantoic acid, dopamine, LysoPC(18:2(9Z,12Z)), and L-urobilinogen. By contrast, the intensities of creatinine, L-carnitine, taurine, and pantothenic acid in the treated groups were significantly decreased. These results indicated that Cd disrupts energy and lipid metabolism. Meanwhile, Cd causes liver and kidney damage via induction of oxidative stress; serum biochemical indices (e.g., creatinine and urea nitrogen) also support the aforementioned results.

Keywords

Cadmium Metabolomics Chronic exposure Toxicity Rat urine UPLC–MS 

Notes

Acknowledgements

The laboratory of nutrition and food hygiene in Harbin Medical University is the key laboratory of Helongjiang Province and Helongjiang Higher Education Institutions.

Funding information

Financial support from China National Center for Food Safety Risk Assessment is acknowledged.

Compliance with ethical standards

Conflict of interest statement

The authors declare that they have no conflicts of interest.

Supplementary material

11356_2017_774_MOESM1_ESM.pdf (668 kb)
ESM 1 (PDF 667 kb).

References

  1. (JECFA) JFWECoFA (2004) Cadmium (addendum). INCHEM. http://www.inchem.org/documents/jecfa/jecmono/v52je22.htm. Accessed 15 Jan 2016
  2. Adefegha SA, Omojokun OS, Oboh G (2015) Modulatory effect of protocatechuic acid on cadmium induced nephrotoxicity and hepatoxicity in rats in vivo. Spring 4(1):619.  https://doi.org/10.1186/s40064-015-1408-6 CrossRefGoogle Scholar
  3. Boets P, Lock K, Goethals PL, Janssen CR, De Schamphelaere KA (2012) A comparison of the short-term toxicity of cadmium to indigenous and alien gammarid species. Ecotoxicology 21(4):1135–1144.  https://doi.org/10.1007/s10646-012-0868-5 CrossRefGoogle Scholar
  4. Chemek M, Mimouna SB, Boughammoura S, Delbes G, Messaoudi I (2016) Protective role of zinc against the toxicity induced by exposure to cadmium during gestation and lactation on testis development. Reprod Toxicol 63:151–160.  https://doi.org/10.1016/j.reprotox.2016.06.005 CrossRefGoogle Scholar
  5. Coen M, Holmes E, Lindon JC, Nicholson JK (2008) NMR-based metabolic profiling and metabonomic approaches to problems in molecular toxicology. Chem Res Toxicol 21(1):9–27.  https://doi.org/10.1021/tx700335d CrossRefGoogle Scholar
  6. Cojocel C, Thomson MS (2004) Protective effect of resveratrol against 6-hydroxydopamine-induced impairment of renal p-aminohippurate transport. Arch Toxicol 78(9):525–532.  https://doi.org/10.1007/s00204-004-0566-z CrossRefGoogle Scholar
  7. De Deyn PP, D’Hooge R, Van Bogaert PP, Marescau B (2001) Endogenous guanidino compounds as uremic neurotoxins. Kidney Int Suppl 78:S77–S83.  https://doi.org/10.1046/j.1523-1755.2001.59780077.x CrossRefGoogle Scholar
  8. El-Boshy ME, Risha EF, Abdelhamid FM, Mubarak MS, Hadda TB (2015) Protective effects of selenium against cadmium induced hematological disturbances, immunosuppressive, oxidative stress and hepatorenal damage in rats. J Trace Elem Med Biol 29:104–110.  https://doi.org/10.1016/j.jtemb.2014.05.009 CrossRefGoogle Scholar
  9. El-Kabbany ZA, Hamza RT, Ibrahim SA, Mahmoud NH (2014) Dyslipidemia and hyperinsulinemia in children and adolescents with chronic liver disease: relation to disease severity. Int J Adolesc Med Health 26(2):195–201.  https://doi.org/10.1515/ijamh-2013-0302 CrossRefGoogle Scholar
  10. Erkan E, Zhao X, Setchell K, Devarajan P (2016) Distinct urinary lipid profile in children with focal segmental glomerulosclerosis. Pediatr Nephrol 31(4):581–588.  https://doi.org/10.1007/s00467-015-3239-7 CrossRefGoogle Scholar
  11. Feng Z, Sun X, Yang J, Hao D, Du L, Wang H, Xu W, Zhao X, Sun C (2012) Metabonomics analysis of urine and plasma from rats given long-term and low-dose dimethoate by ultra-performance liquid chromatography-mass spectrometry. Chem Biol Interact 199(3):143–153.  https://doi.org/10.1016/j.cbi.2012.07.004 CrossRefGoogle Scholar
  12. Ferreira DW, Naquet P, Manautou JE (2015) Influence of vanin-1 and catalytic products in liver during normal and oxidative stress conditions. Curr Med Chem 22(20):2407–2416.  https://doi.org/10.2174/092986732220150722124307 CrossRefGoogle Scholar
  13. Fingerle H, Fischer G, Classen HG (1982) Failure to produce hypertension in rats by chronic exposure to cadmium. Food Chem Toxicol 20(3):301–306.  https://doi.org/10.1016/S0278-6915(82)80296-2 CrossRefGoogle Scholar
  14. Guan Y, Wu T, Ye J (2005) Determination of uric acid and p-aminohippuric acid in human saliva and urine using capillary electrophoresis with electrochemical detection: potential application in fast diagnosis of renal disease. J Chromatogr B Analyt Technol Biomed Life Sci 821(2):229–234.  https://doi.org/10.1016/j.jchromb.2005.03.049 CrossRefGoogle Scholar
  15. Haque ME, Asanuma M, Higashi Y, Miyazaki I, Tanaka KI, Ogawa N (2003) Apoptosis-inducing neurotoxicity of dopamine and its metabolites via reactive quinone generation in neuroblastoma cells. Biochim Biophys Acta 1619(1):39–52.  https://doi.org/10.1016/S0304-4165(02)00440-3 CrossRefGoogle Scholar
  16. Hartwig A (2010) Mechanisms in cadmium-induced carcinogenicity: recent insights. Biometals 23(5):951–960.  https://doi.org/10.1007/s10534-010-9330-4 CrossRefGoogle Scholar
  17. Hu L, Bo L, Zhang M, Li S, Zhao X, Sun C (2017) Metabonomics analysis of serum from rats given long-term and low-level cadmium by ultra-performance liquid chromatography-mass spectrometry. Xenobiotica 1–10.  https://doi.org/10.1080/00498254.2017.1397811
  18. Indiveri C, Iacobazzi V, Tonazzi A, Giangregorio N, Infantino V, Convertini P, Console L, Palmieri F (2011) The mitochondrial carnitine/acylcarnitine carrier: function, structure and physiopathology. Mol Asp Med 32(4-6):223–233.  https://doi.org/10.1016/j.mam.2011.10.008 CrossRefGoogle Scholar
  19. Inoue N, Takeshita S, Gao D, Ishida T, Kawashima S, Akita H, Tawa R, Sakurai H, Yokoyama M (2001) Lysophosphatidylcholine increases the secretion of matrix metalloproteinase 2 through the activation of NADH/NADPH oxidase in cultured aortic endothelial cells. Atherosclerosis 155(1):45–52.  https://doi.org/10.1016/S0021-9150(00)00530-X CrossRefGoogle Scholar
  20. Järup L, Hellström L, Alfvén T, Carlsson MD, Grubb A, Persson B, Pettersson C, Spång G, Schütz A, Elinder CG (2000) Low level exposure to cadmium and early kidney damage: the OSCAR study. Occup Environ Med 57(10):668–672.  https://doi.org/10.1136/oem.57.10.668 CrossRefGoogle Scholar
  21. Jahan S, Khan M, Ahmed S, Ullah H (2014) Comparative analysis of antioxidants against cadmium induced reproductive toxicity in adult male rats. Syst Biol Reprod Med 60(1):28–34.  https://doi.org/10.3109/19396368.2013.843039 CrossRefGoogle Scholar
  22. Jarup L (2003) Hazards of heavy metal contamination. Br Med Bull 68(1):167–182.  https://doi.org/10.1093/bmb/ldg032 CrossRefGoogle Scholar
  23. Kaushik S, Kaur J (2003) Chronic cold exposure affects the antioxidant defense system in various rat tissues. Clin Chim Acta 333(1):69–77.  https://doi.org/10.1016/S0009-8981(03)00171-2 CrossRefGoogle Scholar
  24. Kobayashi E, Suwazono Y, Honda R, Dochi M, Nishijo M, Kido T, Nakagawa H (2008) Changes in renal tubular and glomerular functions and biological acid-base balance after soil replacement in Cd-polluted rice paddies calculated with a general linear mixed model. Biol Trace Elem Res 124(2):164–172.  https://doi.org/10.1007/s12011-008-8125-8 CrossRefGoogle Scholar
  25. Lee YK, Park EY, Kim S, Son JY, Kim TH, Kang WG, Jeong TC, Kim KB, Kwack SJ, Lee J, Kim S, Lee BM, Kim HS (2014) Evaluation of cadmium-induced nephrotoxicity using urinary metabolomic profiles in sprague-dawley male rats. J Toxicol Environ Health A 77(22-24):1384–1398.  https://doi.org/10.1080/15287394.2014.951755 CrossRefGoogle Scholar
  26. Levillain O, Marescau B, Possemiers I, Al Banchaabouchi M, De Deyn PP (2001) Influence of 72% injury in one kidney on several organs involved in guanidino compound metabolism: a time course study. Pflugers Arch 442(4):558–569.  https://doi.org/10.1007/s004240100581 CrossRefGoogle Scholar
  27. Liu J, Qu W, Kadiiska MB (2009) Role of oxidative stress in cadmium toxicity and carcinogenesis. Toxicol Appl Pharmacol 238(3):209–214.  https://doi.org/10.1016/j.taap.2009.01.029 CrossRefGoogle Scholar
  28. Lopez E, Arce C, Oset-Gasque MJ, Canadas S, Gonzalez MP (2006) Cadmium induces reactive oxygen species generation and lipid peroxidation in cortical neurons in culture. Free Radic Biol Med 40(6):940–951.  https://doi.org/10.1016/j.freeradbiomed.2005.10.062 CrossRefGoogle Scholar
  29. Lu LT, Chang IC, Hsiao TY, Yu YH, Ma HW (2007) Identification of pollution source of cadmium in soil: application of material flow analysis and a case study in Taiwan. Environ Sci Pollut Res Int 14:49–59Google Scholar
  30. Mertens A, Holvoet P (2001) Oxidized LDL and HDL: antagonists in atherothrombosis. FASEB J 15(12):2073–2084.  https://doi.org/10.1096/fj.01-0273rev CrossRefGoogle Scholar
  31. Morrison L, Baumann HA, Stengel DB (2008) An assessment of metal contamination along the Irish coast using the seaweed Ascophyllum nodosum (Fucales, Phaeophyceae). Environ Pollut 152(2):293–303.  https://doi.org/10.1016/j.envpol.2007.06.052 CrossRefGoogle Scholar
  32. Mortensen OH, Olsen HL, Frandsen L, Nielsen PE, Nielsen FC, Grunnet N, Quistorff B (2010) A maternal low protein diet has pronounced effects on mitochondrial gene expression in offspring liver and skeletal muscle; protective effect of taurine. J Biomed Sci 17(Suppl 1):S38.  https://doi.org/10.1186/1423-0127-17-s1-s38 CrossRefGoogle Scholar
  33. Naiya TK, Bhattacharya AK, Das SK (2009) Adsorption of Cd(II) and Pb(II) from aqueous solutions on activated alumina. J Colloid Interface Sci 333(1):14–26.  https://doi.org/10.1016/j.jcis.2009.01.003 CrossRefGoogle Scholar
  34. Neimark E, LeLeiko NS (2009) Antioxidant effect of bilirubin and pediatric nonalcoholic fatty liver disease. Pediatrics 124(6):e1240–e1241.  https://doi.org/10.1542/peds.2009-2487 CrossRefGoogle Scholar
  35. Nicholson JK, Lindon JC, Holmes E (1999) ‘Metabonomics’: understanding the metabolic responses of living systems to pathophysiological stimuli via multivariate statistical analysis of biological NMR spectroscopic data. Xenobiotica 29(11):1181–1189.  https://doi.org/10.1080/004982599238047 CrossRefGoogle Scholar
  36. Ognjanović BI, Marković SD, Pavlović SZ, Zikić RV, Stajn AS, Saicić ZS (2008) Effect of chronic cadmium exposure on antioxidant defense system in some tissues of rats: protective effect of selenium. Physiol Res 57(3):403–411Google Scholar
  37. Roberts JR (2007) Urine dipstick testing: everything you need to know. E M N 29:24–27Google Scholar
  38. Schepers E, Glorieux G, Dou L, Cerini C, Gayrard N, Louvet L, Maugard C, Preus P, Rodriguez-Ortiz M, Argiles A, Brunet P, Cohen G, Jankowski J, Jankowski V, Massy Z, Rodriguez M, Vanholder R, for the European Uremic Toxin Work Group (EUTox) (2010) Guanidino compounds as cause of cardiovascular damage in chronic kidney disease: an in vitro evaluation. Blood Purif 30(4):277–287.  https://doi.org/10.1159/000320765 CrossRefGoogle Scholar
  39. Sharma AK (2012) Evaluation of certain food additives and contaminants, Seventy-third report of the Joint FAO/WHO Expert Committee on Food Additives. Indian J Med Res 136(6):1004–1010Google Scholar
  40. Szuster-Ciesielska A, Stachura A, Słotwińska M, Kamińska T, Śnieżko R, Paduch R, Abramczyk D, Filar J, Kandefer-Szerszeń M (2000) The inhibitory effect of zinc on cadmium-induced cell apoptosis and reactive oxygen species (ROS) production in cell cultures. Toxicology 145(2-3):159–171.  https://doi.org/10.1016/S0300-483X(00)00144-X CrossRefGoogle Scholar
  41. Takeshita S, Inoue N, Gao D, Rikitake Y, Kawashima S, Tawa R, Sakurai H, Yokoyama M (2000) Lysophosphatidylcholine enhances superoxide anions production via endothelial NADH/NADPH oxidase. J Atheroscler Thromb 7(4):238–246.  https://doi.org/10.5551/jat1994.7.238 CrossRefGoogle Scholar
  42. Tanaka K, Hine DG, West-Dull A, Lynn TB (1981) Gas-chromatographic method of analysis for urinary organic acids. I. Retention indices of 155 metabolically important compounds. Clin Chem 26:1839–1846Google Scholar
  43. Taysi S (2005) Oxidant/antioxidant status in liver tissue of vitamin B6 deficient rats. Clin Nutr 24(3):385–389.  https://doi.org/10.1016/j.clnu.2004.12.001 CrossRefGoogle Scholar
  44. Thangasamy T, Subathra M, Sittadjody S, Jeyakumar P, Joyee AG, Mendoza E, Chinnakkanu P (2008) Role of L-carnitine in the modulation of immune response in aged rats. Clin Chim Acta 389(1-2):19–24.  https://doi.org/10.1016/j.cca.2007.11.013 CrossRefGoogle Scholar
  45. Theodoridis G, Gika HG, Wilson ID (2008) LC-MS-based methodology for global metabolite profiling in metabonomics/metabolomics. TrAC. Trends Anal Chem 27(3):251–260.  https://doi.org/10.1016/j.trac.2008.01.008 CrossRefGoogle Scholar
  46. Torremans A et al (2005) GSA: behavioral, histological, electrophysiological and neurochemical effects. Physiol Behav 84(2):251–264.  https://doi.org/10.1016/j.physbeh.2004.12.001 CrossRefGoogle Scholar
  47. Wang SY, Wang Y, Jin XW, Zhang Y, Chen JS, Ma WW, Wu YH, Wang DC (2015) A urinary metabolomics study of rats after the exposure to acrylamide by ultra performance liquid chromatography coupled with quadrupole time-of-flight tandem mass spectrometry. Mol BioSyst 11(4):1146–1155.  https://doi.org/10.1039/c4mb00682h CrossRefGoogle Scholar
  48. Wang X, Wu M, Ma J, Chen X, Hua L (2016) Modeling of acute cadmium toxicity in solution to barley root elongation using biotic ligand model theory. J Environ Sci (China) 42:112–118.  https://doi.org/10.1016/j.jes.2015.06.019 CrossRefGoogle Scholar
  49. Yardim-Akaydin S, Sepici A, Ozkan Y, Simsek B, Sepici V (2006) Evaluation of allantoin levels as a new marker of oxidative stress in Behcet’s disease. Scand J Rheumatol 35(1):61–64.  https://doi.org/10.1080/03009740510026878 CrossRefGoogle Scholar
  50. Zong L, Xing J, Liu S, Liu Z, Song F (2017) Cell metabolomics reveals the neurotoxicity mechanism of cadmium in PC12 cells. Ecotoxicol Environ Saf 147:26–33.  https://doi.org/10.1016/j.ecoenv.2017.08.028 CrossRefGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2017

Authors and Affiliations

  1. 1.Department of Nutrition and Food Hygiene, Public Health CollegeHarbin Medical UniversityHarbinChina

Personalised recommendations