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Accumulation Patterns of Sub-chronic Aluminum Toxicity Model After Gastrointestinal Administration in Rats

Biological Trace Element Research volume 185, pages 384–394 (2018)Cite this article

Abstract

Although aluminum chronic neurotoxicity is well documented, there are no well-established experimental protocols of Al exposure. In the current study, toxic effects of sub-chronic Al exposure have been evaluated in outbreed male rats (gastrointestinal administration). Forty animals were used: 10 were administered with AlCl3 water solution (2 mg/kg Al per day) for 1 month, 10 received the same concentration of AlCl3 for 3 month, and 20 (10 per observation period) saline as control. After 30 and 90 days, the animals underwent behavioral tests: open field, passive avoidance, extrapolation escape task, and grip strength. At the end of the study, the blood, liver, kidney, and brain were excised for analytical and morphological studies. The Al content was measured by inductively coupled plasma mass-spectrometry. Essential trace elements—Co, Cr, Cu, Fe, Mg, Mn, Mo, Se, and Zn—were measured in whole blood samples. Although no morphological changes were observed in the brain, liver, or kidney for both exposure terms, dose-dependent Al accumulation and behavioral differences (increased locomotor activity after 30 days) between treatment and control groups were indicated. Moreover, for 30 days exposure, strong positive correlation between Al content in the brain and blood for individual animals was established, which surprisingly disappeared by the third month. This may indicate neural barrier adaptation to the Al exposure or the saturation of Al transport into the brain. Notably, we could not see a clear neurodegeneration process after rather prolonged sub-chronic Al exposure, so probably longer exposure periods are required.

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References

  1. Linert W, Kozlowski H (2012) Metal ions in neurological systems. Springer-Verlag Wien, Vienna. https://doi.org/10.1007/978-3-7091-1001-0

    Book  Google Scholar 

  2. Arieff AI, Cooper JD, Armstrong D, Lazarowitz VC (1979) Dementia, renal failure, and brain aluminum. Ann Intern Med 90(5):741–747. https://doi.org/10.7326/0003-4819-90-5-741

    Article  PubMed  CAS  Google Scholar 

  3. Lederman RJ, Henry CE (1978) Progressive dialysis encephalopathy. Ann Neurol 4(3):199–204. https://doi.org/10.1002/ana.410040302

    Article  PubMed  CAS  Google Scholar 

  4. Etteldorf JN, Dobbins WT, Sweeney MJ, Smith JD, Whittington GL, Sheffield JA, Meadows RW (1962) Intermittent peritoneal dialysis in the management of acute renal failure in children. J Pediatr 60(3):327–339. https://doi.org/10.1016/S0022-3476(62)80057-2

    Article  PubMed  CAS  Google Scholar 

  5. Alfrey AC, LeGendre GR, Kaehny D (1976) The dialysis encephalopathy syndrome. Possible aluminium intoxication. New Engl J Med 294(4):184–188. https://doi.org/10.1056/NEJM197601222940402

    Article  PubMed  CAS  Google Scholar 

  6. Exley C (2001) Aluminium and Alzheimer’s disease. The science that describes the link. Elsevier, Amsterdam

    Google Scholar 

  7. Berend K, Van Der Voet G, Boer WH (2001) Acute aluminum encephalopathy in a dialysis center caused by a cement mortar water distribution pipe. Kidney Int 59(2):746–753. https://doi.org/10.1046/j.1523-1755.2001.059002746.x

    Article  PubMed  CAS  Google Scholar 

  8. de la Torre MLR, de la Lopez García SH, Martí del Moral L, Palomares Bayo M, Navarro-Alarcón M (2017) Increased serum Al levels in hemodialysis patients kept enhanced during a 2-year prospective study. Biol Trace Elem Res 178(1):7–13. https://doi.org/10.1007/s12011-016-0902-1

    Article  CAS  Google Scholar 

  9. Fulgenzi A, De Giuseppe R, Bamonti F, Vietti D, Ferrero ME (2015) Efficacy of chelation therapy to remove aluminium intoxication. J Inorg Biochem 152:214–218. https://doi.org/10.1016/j.jinorgbio.2015.09.007

    Article  PubMed  CAS  Google Scholar 

  10. Bhalla P, Garg ML, Dhawan DK (2010) Protective role of lithium during aluminium-induced neurotoxicity. Neurochem Int 56(2):256–262. https://doi.org/10.1016/j.neuint.2009.10.009

    Article  PubMed  CAS  Google Scholar 

  11. Chen C-L, Chang K-Y, Pan T-M (2016) Monascus purpureus NTU 568 fermented product improves memory and learning ability in rats with aluminium-induced Alzheimer’s disease. J Funct Foods 21:167–177. https://doi.org/10.1016/j.jff.2015.12.017

    Article  Google Scholar 

  12. Sideman S, Manor D (1982) The dialysis dementia syndrome and aluminum intoxication. Nephron 31(1):1–10. https://doi.org/10.1159/000182595

    Article  PubMed  CAS  Google Scholar 

  13. Killin LO, Starr JM, Shiue IJ, Russ TC (2016) Environmental risk factors for dementia: a systematic review. BMC Geriatr 16(1):175. https://doi.org/10.1186/s12877-016-0342-y

    Article  PubMed  PubMed Central  Google Scholar 

  14. Mirza A, King A, Troakes C, Exley C (2017) Aluminium in brain tissue in familial Alzheimer’s disease. J Trace Elem Med Biol 40:30–36. https://doi.org/10.1016/j.jtemb.2016.12.001

    Article  PubMed  CAS  Google Scholar 

  15. Walton JR (2012) Cognitive deterioration and associated pathology induced by chronic low-level aluminum ingestion in a translational rat model provides an explanation of Alzheimer's disease, tests for susceptibility and avenues for treatment. Int J Alzheimer’s Dis 2012:914947. https://doi.org/10.1155/2012/914947

    CAS  Article  Google Scholar 

  16. Fernandez-Davila ML, Razo-Estrada AC, Garcia-Medina S, Gomez-Olivan LM, Pinon-Lopez MJ, Ibarra RG, Galar-Martinez M (2012) Aluminum-induced oxidative stress and neurotoxicity in grass carp (Cyprinidae-Ctenopharingodon idella). Ecotoxicol Environ Saf 76(2):87–92. https://doi.org/10.1016/j.ecoenv.2011.09.012

    Article  PubMed  CAS  Google Scholar 

  17. Lecanu L, Papadopoulos V (2013) Modeling Alzheimer’s disease with non-transgenic rat models. Alzheimers Res Ther 5(3):17–17. https://doi.org/10.1186/alzrt171

    PubMed  PubMed Central  Article  Google Scholar 

  18. Thenmozhi AJ, Raja TRW, Janakiraman U, Manivasagam T (2015) Neuroprotective effect of hesperidin on aluminium chloride induced Alzheimer’s disease in Wistar rats. Neurochem Res 40(4):767–776. https://doi.org/10.1007/s11064-015-1525-1

    Article  CAS  Google Scholar 

  19. Korchazhkina OV, Ashcroft AE, Croom J, Exley C (2003) Does either the gastrointestinal peptide PYY or the neuropeptide NPY bind aluminium? J Inorg Biochem 94(4):372–380. https://doi.org/10.1016/s0162-0134(03)00031-x

    Article  PubMed  CAS  Google Scholar 

  20. Shati AA, Elsaid FG, Hafez EE (2011) Biochemical and molecular aspects of aluminium chloride-induced neurotoxicity in mice and the protective role of Crocus sativus L. extraction and honey syrup. Neuroscience 175:66–74. https://doi.org/10.1016/j.neuroscience.2010.11.043

    Article  PubMed  CAS  Google Scholar 

  21. Saiyed SM, Yokel RA (2005) Aluminium content of some foods and food products in the USA, with aluminium food additives. Food Addit Contam 22(3):234–244. https://doi.org/10.1080/02652030500073584

    Article  PubMed  CAS  Google Scholar 

  22. Ivanenko NB, Solovyev ND, Ivanenko AA, Ganeev AA (2012) Application of Zeeman graphite furnace atomic absorption spectrometry with high-frequency modulation polarization for the direct determination of aluminum, beryllium, cadmium, chromium, mercury, manganese, nickel, lead, and thallium in human blood. Arch Environ Contam Toxicol 63(3):299–308. https://doi.org/10.1007/s00244-012-9784-1

    Article  PubMed  CAS  Google Scholar 

  23. Ivanenko NB, Ivanenko AA, Solovyev ND, Zeimal AE, Navolotskii DV, Drobyshev EJ (2013) Biomonitoring of 20 trace elements in blood and urine of occupationally exposed workers by sector field inductively coupled plasma mass spectrometry. Talanta 116:764–769. https://doi.org/10.1016/j.talanta.2013.07.079

    Article  PubMed  CAS  Google Scholar 

  24. Drobyshev EJ, Solovyev ND, Ivanenko NB, Kombarova MY, Ganeev AA (2017) Trace element biomonitoring in hair of school children from a polluted area by sector field inductively coupled plasma mass spectrometry. J Trace Elem Med Biol 39:14–20. https://doi.org/10.1016/j.jtemb.2016.07.004

    Article  PubMed  CAS  Google Scholar 

  25. Valdman AV, Bondarenko NA, Kozlovskaya MM (1986) Psychotropic effect of Tuftsin, a natural phagocytosis-stimulating peptide, and some of its analogs. In: Valdman VA (ed) Drug dependence and emotional behavior: neurophysiological and neurochemical approaches. Springer, New York, pp 175–202. https://doi.org/10.1007/978-1-4684-1656-5_7

    Chapter  Google Scholar 

  26. Grabovska S, Salyha Y (2015) ADHD-like behaviour in the offspring of female rats exposed to low chlorpyrifos doses before pregnancy. Arh Hig Rada Toksikol 66(2):121–127. https://doi.org/10.1515/aiht-2015-66-2624

    Article  PubMed  CAS  Google Scholar 

  27. Gu J (1997) Analytical morphology. Theory, applications and protocols. Birkhäuser Basel, Basel

    Google Scholar 

  28. Michalke B, Willkommen D, Drobyshev E, Solovyev N (2017) The importance of speciation analysis in neurodegeneration research. TrAC Trends Anal Chem:in Press. https://doi.org/10.1016/j.trac.2017.08.008

  29. Solovyev ND, Ivanenko NB, Ivanenko AA (2011) Whole blood thallium determination by GFAAS with high-frequency modulation polarization Zeeman effect background correction. Biol Trace Elem Res 143(1):591–599. https://doi.org/10.1007/s12011-010-8865-0

    Article  PubMed  CAS  Google Scholar 

  30. Ivanenko NB, Solovyev ND, Ivanenko AA, Navolotskii DV (2014) Biological monitoring of arsenic pollution based on whole blood arsenic atomic absorption assessment with in situ hydride trapping. J Anal Atom Spectrom 29(10):1850–1857. https://doi.org/10.1039/c4ja00130c

    Article  CAS  Google Scholar 

  31. Zubakina EA, Solovyev ND, Savinkova ES, Slesar NI (2016) Sample preparation for cadmium quantification in sunflower (Heliánthus ánnuus) seeds using anodic stripping voltammetry. Anal Methods 8(2):326–332. https://doi.org/10.1039/c5ay02275d

    Article  CAS  Google Scholar 

  32. Cochran M, Coates JH, Elliott DC (1990) Aluminium interaction with macromolecules and membranes. In: de Broe ME, Coburn JW (eds) Aluminum and renal failure. Springer Netherlands, Dordrecht, pp 139–153. https://doi.org/10.1007/978-94-009-1868-9_10

    Chapter  Google Scholar 

  33. Solovyev ND (2015) Importance of selenium and selenoprotein for brain function: from antioxidant protection to neuronal signalling. J Inorg Biochem 153:1–12. https://doi.org/10.1016/j.jinorgbio.2015.09.003

    Article  PubMed  CAS  Google Scholar 

  34. González-Domínguez R, García-Barrera T, Gómez-Ariza JL (2014) Characterization of metal profiles in serum during the progression of Alzheimer’s disease. Metallomics 6(2):292–300. https://doi.org/10.1039/c3mt00301a

    Article  PubMed  CAS  Google Scholar 

  35. Haroutunian V, Katsel P, Roussos P, Davis KL, Altshuler LL, Bartzokis G (2014) Myelination, oligodendrocytes, and serious mental illness. Glia 62(11):1856–1877. https://doi.org/10.1002/glia.22716

    Article  PubMed  CAS  Google Scholar 

  36. Exley C, House ER (2011) Aluminium in the human brain. Monatsh Chem 142(4):357–363. https://doi.org/10.1007/s00706-010-0417-y

    Article  CAS  Google Scholar 

  37. Shirabe T, Irie K, Uchida M (2002) Autopsy case of aluminum encephalopathy. Neuropathology 22(3):5–210. https://doi.org/10.1046/j.1440-1789.2002.00432.x

    Article  Google Scholar 

  38. Bhalla P, Singla N, Dhawan DK (2010) Potential of lithium to reduce aluminium-induced cytotoxic effects in rat brain. Biometals 23(2):197–206. https://doi.org/10.1007/s10534-009-9278-4

    Article  PubMed  CAS  Google Scholar 

  39. Somova LI, Missankov A, Khan MS (1997) Chronic aluminum intoxication in rats: dose-dependent morphological changes. Method Find Exp Clin 19(9):599–604

    CAS  Google Scholar 

  40. Yokel RA (2000) The toxicology of aluminum in the brain: a review. Neurotoxicology 21(5):813–828

    PubMed  CAS  Google Scholar 

  41. Mizoroki T, Meshitsuka S, Maeda S, Murayama M, Sahara N, Takashima A (2007) Aluminum induces tau aggregation in vitro but not in vivo. J Alzheimers Dis 11(4):419–427. https://doi.org/10.3233/JAD-2007-11401

    Article  PubMed  CAS  Google Scholar 

  42. Nayak P, Chowdary NVS, Sharma SB (2015) Influence of prooxidant exposure on aluminum-induced alterations in open-field behavioral study in rats. Indian J Physiol Pharmacol 59(3):10

    Google Scholar 

  43. Mirshafa A, Nazari M, Jahani D et al (2017) Size-dependent neurotoxicity of aluminum oxide particles: a comparison between nano- and micrometer size on the basis of mitochondrial oxidative damage. Biol Trace Elem Res. https://doi.org/10.1007/s12011-017-1142-8

  44. Wu X, Li J, Hu JN, Deng ZY (2012) The effects of glutamate and citrate on absorption and distribution of aluminum in rats. Biol Trace Elem Res 148(1):83–90. https://doi.org/10.1007/s12011-012-9345-5

    Article  PubMed  CAS  Google Scholar 

  45. Crepeaux G, Eidi H, David MO, Baba-Amer Y, Tzavara E, Giros B, Authier FJ, Exley C, Shaw CA, Cadusseau J, Gherardi RK (2017) Non-linear dose-response of aluminium hydroxide adjuvant particles: selective low dose neurotoxicity. Toxicology 375:48–57. https://doi.org/10.1016/j.tox.2016.11.018

    Article  PubMed  CAS  Google Scholar 

  46. Banks WA, Kastin AJ (1989) Aluminum-induced neurotoxicity: alterations in membrane function at the blood-brain barrier. Neurosci Biobehav Rev 13(1):47–53. https://doi.org/10.1016/S0149-7634(89)80051-X

    Article  PubMed  CAS  Google Scholar 

  47. Flarend RE, Hem SL, White JL, Elmore D, Suckow MA, Rudy AC, Dandashli EA (1997) In vivo absorption of aluminium-containing vaccine adjuvants using 26Al. Vaccine 15(12-13):1314–1318. https://doi.org/10.1016/S0264-410X(97)00041-8

    Article  PubMed  CAS  Google Scholar 

  48. Ray JG, Ghosh R, Mallick D, Swain N, Gandhi P, Ram SS, Selvaraj S, Rathore A, Mathummal S, Chakraborty A (2011) Correlation of trace elemental profiles in blood samples of Indian patients with leukoplakia and oral submucous fibrosis. Biol Trace Elem Res 144(1–3):295–305. https://doi.org/10.1007/s12011-011-9091-0

    Article  PubMed  CAS  Google Scholar 

  49. Wu Y, Yang X, Ge J, Zhang J (2011) Blood lead level and its relationship to certain essential elements in the children aged 0 to 14years from Beijing, China. Sci Total Environ 409(16):3016–3020. https://doi.org/10.1016/j.scitotenv.2011.04.050

    Article  PubMed  CAS  Google Scholar 

  50. Tokar EJ, Qu W, Person RJ, Ngalame ON, Waalkes MP (2015) Oxidative stress and the inorganic carcinogens. In: Roberts SM, Kehrer JP, Klotz L-O (eds) Studies on experimental toxicology and pharmacology. Humana Press, Cham, pp 323–334. https://doi.org/10.1007/978-3-319-19096-9

    Chapter  Google Scholar 

  51. Frandsen A, Jensen JB, Schousboe A (2000) The role of second messengers in neurodegeneration. In: Reith MEA (ed) Cerebral signal transduction: from first to fourth messengers. Humana Press, Totowa, pp 207–220. https://doi.org/10.1007/978-1-59259-019-3_8

    Chapter  Google Scholar 

  52. Michalke B, Halbach S, Nischwitz V (2009) JEM spotlight: metal speciation related to neurotoxicity in humans. J Environ Monit 11(5):939–954. https://doi.org/10.1039/b817817h

    Article  PubMed  CAS  Google Scholar 

  53. Solovyev N, Vinceti M, Grill P, Mandrioli J, Michalke B (2017) Redox speciation of iron, manganese, and copper in cerebrospinal fluid by strong cation exchange chromatography–sector field inductively coupled plasma mass spectrometry. Anal Chim Acta 973:25–33. https://doi.org/10.1016/j.aca.2017.03.040

    Article  PubMed  CAS  Google Scholar 

  54. Torres-Vega A, Pliego-Rivero BF, Otero-Ojeda GA, Gomez-Olivan LM, Vieyra-Reyes P (2012) Limbic system pathologies associated with deficiencies and excesses of the trace elements iron, zinc, copper, and selenium. Nutr Rev 70(12):679–692. https://doi.org/10.1111/j.1753-4887.2012.00521.x

    Article  PubMed  Google Scholar 

  55. Montgomery SC, Streit SM, Beebe ML, Maxwell PJ (2014) Micronutrient needs of the elderly. Nutr Clin Pract 29(4):435–444. https://doi.org/10.1177/0884533614537684

    Article  PubMed  CAS  Google Scholar 

  56. Nehls M (2016) Unified theory of Alzheimer’s disease (UTAD): implications for prevention and curative therapy. J Mol Psychiatry 4(1):3. https://doi.org/10.1186/s40303-016-0018-8

    Article  PubMed  PubMed Central  Google Scholar 

  57. Roberts NB, Clough A, Bellia JP, Kim JY (1998) Increased absorption of aluminium from a normal dietary intake in dementia. J Inorg Biochem 69(3):171–176. https://doi.org/10.1016/S0162-0134(97)10015-0

    Article  PubMed  CAS  Google Scholar 

  58. Edwardson JA, Candy JM (1990) Aluminium and the pathogenesis of senile plaques: studies in Alzheimer’s disease and chronic renal failure. Environ Geochem Health 12(1):94–96. https://doi.org/10.1007/bf01734057

    Article  PubMed  CAS  Google Scholar 

  59. Gupta VB, Anitha S, Hegde ML, Zecca L, Garruto RM, Ravid R, Shankar SK, Stein R, Shanmugavelu P, Jagannatha Rao KS (2005) Aluminium in Alzheimer’s disease: are we still at a crossroad? Cell Mol Life Sci 62(2):143–158. https://doi.org/10.1007/s00018-004-4317-3

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

The authors are grateful to Maria A. Zaitseva and co-workers for the help with animal handling and Olga N. Gaikova for providing histological images.

Funding

N.D. Solovyev acknowledges the financial support of the Russian Foundation for Basic Research (grant No. 16-33-60004 mol_a_dk).

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Authors and Affiliations

  1. Institut für Ernährungswissenschaft, Universität Potsdam, Arthur-Scheunert-Allee 114-116, Nuthetal, 14558, Potsdam, Germany

    Evgenii J. Drobyshev

  2. St. Petersburg State University, St. Petersburg, Russia

    Evgenii J. Drobyshev & Nikolay D. Solovyev

  3. Institute of Precambrian Geology and Geochronology Russian Academy of Sciences, St. Petersburg, Russia

    Boris M. Gorokhovskiy

  4. Institute of Toxicology of Federal Medico-Biological Agency, St. Petersburg, Russia

    Vadim A. Kashuro

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  1. Evgenii J. Drobyshev
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  2. Nikolay D. Solovyev
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  3. Boris M. Gorokhovskiy
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  4. Vadim A. Kashuro
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Corresponding author

Correspondence to Evgenii J. Drobyshev.

Ethics declarations

The study protocols were approved by Bioethics Committee of the Institute of Toxicology (protocol No. 8/16, dated 16.05.2016) and was conducted in accordance with the European Union law on the care and use of animals for scientific purposes.

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Drobyshev, E.J., Solovyev, N.D., Gorokhovskiy, B.M. et al. Accumulation Patterns of Sub-chronic Aluminum Toxicity Model After Gastrointestinal Administration in Rats. Biol Trace Elem Res 185, 384–394 (2018). https://doi.org/10.1007/s12011-018-1247-8

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Keywords

  • Aluminum
  • Neurotoxicity
  • Rats
  • Per oral administration
  • Sub-chronic exposure
  • Trace elements