Skip to main content

Advertisement

Log in

Lead and Cadmium Synergistically Enhance the Expression of Divalent Metal Transporter 1 Protein in Central Nervous System of Developing Rats

  • ORIGINAL PAPER
  • Published:
Neurochemical Research Aims and scope Submit manuscript

Abstract

Divalent metal transporter 1 (DMT1) can transport a large range of ions, including toxic lead (Pb) and cadmium (Cd), across membranes. In this study, a total of 24 rats were divided into four groups for intragastrical perfusion treatment: control, Pb alone, Cd alone, and Pb + Cd. Pb and Cd contents in blood were detected, and the mRNA and protein levels of DMT1 were analyzed in the cerebellum, cortex, and hippocampus. Both Pb and Cd levels were elevated in all groups perfused with Pb and/or Cd, except for Pb level in the Cd-alone group (P < 0.05). The mRNA level of DMT1 did not differ among the four groups (P > 0.05). However, the DMT1 protein expression was significantly increased by 0.9-, 1.0-, and 1.1-fold in cerebellum, cortex, and hippocampus of the Pb + Cd group than in controls, respectively. Pb and Cd exposure can synergistically induce DMT1 protein synthesis and has implications for transportation of toxic ions in the developing rat’s brain.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. Romero-Gonzalez ME, Williams CJ, Gardiner PH (2001) Study of the mechanisms of cadmium biosorption by dealginated seaweed waste. Environ Sci Technol 35:3025–3030. doi:10.1021/es991133r

    Article  PubMed  CAS  Google Scholar 

  2. Chetty CS, Vemuri MC, Reddy GR et al (2007) Protective effect of 17-[beta]-estradiol in human neurocellular models of lead exposure. Neurotoxicology 28:396–401. doi:10.1016/j.neuro.2006.03.012

    Article  PubMed  CAS  Google Scholar 

  3. Massanyi P, Lukac N, Makarevich AV et al (2007) Lead-induced alterations in rat kidneys and testes in vivo. J Environ Sci Health A Toxic Hazard Subst Environ Eng 42:671–676

    CAS  Google Scholar 

  4. Ahamed M, Singh S, Behari JR et al (2007) Interaction of lead with some essential trace metals in the blood of anemic children from Lucknow, India. Clin Chim Acta 377:92–97. doi:10.1016/j.cca.2006.08.032

    Article  PubMed  CAS  Google Scholar 

  5. Jamieson JA, Taylor CG, Weiler HA (2006) Marginal zinc deficiency exacerbates bone lead accumulation and high dietary zinc attenuates lead accumulation at the expense of bone density in growing rats. Toxicol Sci 92:286–294. doi:10.1093/toxsci/kfj201

    Article  PubMed  CAS  Google Scholar 

  6. Dietert RR, Piepenbrink MS (2006) Lead and immune function. Crit Rev Toxicol 36:359–385. doi:10.1080/10408440500534297

    Article  PubMed  CAS  Google Scholar 

  7. Krieg EF Jr (2007) The relationships between blood lead levels and serum follicle stimulating hormone and luteinizing hormone in the third national health and nutrition examination survey. Environ Res 104:374–382. doi:10.1016/j.envres.2006.09.009

    Article  PubMed  CAS  Google Scholar 

  8. Tong S, Baghurst PA, Sawyer MG et al (1998) Declining blood lead levels and changes in cognitive function during childhood: the Port Pirie Cohort Study. JAMA 280:1915–1919. doi:10.1001/jama.280.22.1915

    Article  PubMed  CAS  Google Scholar 

  9. Reddy GR, Devi BC, Chetty CS (2007) Developmental lead neurotoxicity: alterations in brain cholinergic system. Neurotoxicology 28:402–407. doi:10.1016/j.neuro.2006.03.018

    Article  PubMed  CAS  Google Scholar 

  10. Lindahl LS, Bird L, Legare ME et al (1999) Differential ability of astroglia and neuronal cells to accumulate lead: dependence on cell type and on degree of differentiation. Toxicol Sci 50:236–243. doi:10.1093/toxsci/50.2.236

    Article  PubMed  CAS  Google Scholar 

  11. Henson MC, Chedrese PJ (2004) Endocrine disruption by cadmium, a common environmental toxicant with paradoxical effects on reproduction. Exp Biol Med (Maywood) 229(5):383–392

    CAS  Google Scholar 

  12. Darbre PD (2006) Metalloestrogens: an emerging class of inorganic xenoestrogens with potential to add to the oestrogenic burden of the human breast. J Appl Toxicol 26(3):191–197. doi:10.1002/jat.1135

    Article  PubMed  CAS  Google Scholar 

  13. Stoica A, Katzenellenbogen BS, Martin MB et al (2000) Activation of estrogen receptor-alpha by the heavy metal cadmium. Mol Endocrinol 14(4):545–553. doi:10.1210/me.14.4.545

    Article  PubMed  CAS  Google Scholar 

  14. Médez-Armenta M, Ríos C (2007) Cadmium neurotoxicity. Environ Toxicol Pharmacol 23(3):350–358. doi:10.1016/j.etap.2006.11.009

    Article  CAS  Google Scholar 

  15. Valverde M, Trejo C, Rojas E et al (2001) Is the capacity of lead acetate and cadmium chloride to induce genotoxic damage due to direct DNA-metal interaction? Mutagenesis 16(3):265–270. doi:10.1093/mutage/16.3.265

    Article  PubMed  CAS  Google Scholar 

  16. Gruenheid S, Cellier M, Vidal S et al (1995) Identification and characterization of a second mouse Nramp gene. Genomics 25:514–525. doi:10.1016/0888-7543(95)80053-O

    Article  PubMed  CAS  Google Scholar 

  17. Lee PL, Gelbart T, West C et al (1998) The human Nramp2 gene: characterization of the gene structure, alternative splicing, promoter region and polymorphisms. Blood Cells Mol Dis 24:199–215. doi:10.1006/bcmd.1998.0186

    Article  PubMed  CAS  Google Scholar 

  18. Tandy S, Williams M, Leggett A et al (2000) Nramp2 expression is associated with pH-dependent iron uptake across the apical membrane of human intestinal Caco-2 cells. J Biol Chem 275:1023–1029. doi:10.1074/jbc.275.2.1023

    Article  PubMed  CAS  Google Scholar 

  19. Hubert N, Hentze MW (2002) Previously uncharacterized isoforms of divalent metal transporter (DMT)-1: implications for regulation and cellular function. Proc Natl Acad Sci USA 99:12345–12350. doi:10.1073/pnas.192423399

    Article  PubMed  CAS  Google Scholar 

  20. Kim DW, Kim KY, Choi BS et al (2007) Regulation of metal transporters by dietary iron, and the relationship between body iron levels and cadmium uptake. Arch Toxicol 81:327–334. doi:10.1007/s00204-006-0160-7

    Article  PubMed  CAS  Google Scholar 

  21. Leret ML, Millan JA, Antonio MT (2003) Perinatal exposure to lead and cadmium affects anxiety-like behaviour. Toxicology 186:125–130. doi:10.1016/S0300-483X(02)00728-X

    Article  PubMed  CAS  Google Scholar 

  22. Institoris L, Kovacs D, Kecskemeti-Kovacs I et al (2006) Immunotoxicological investigation of subacute combined exposure with low doses of Pb, Hg and Cd in rats. Acta Biol Hung 57(4):433–439. doi:10.1556/ABiol.57.2006.4.5

    Article  PubMed  CAS  Google Scholar 

  23. Ke Y, Chang YZ, Duan XL et al (2005) Age-dependent and iron-independent expression of two mRNA isoforms of divalent metal transporter 1 in rat brain. Neurobiol Aging 26:739–748. doi:10.1016/j.neurobiolaging.2004.06.002

    Article  PubMed  CAS  Google Scholar 

  24. Shi LZ, Zheng W (2007) Early lead exposure increases the leakage of the blood-cerebrospinal fluid barrier, in vitro. Hum Exp Toxicol 26:159–167. doi:10.1177/0960327107070560

    Article  PubMed  CAS  Google Scholar 

  25. Fleming TP, Papenbrock T, Fesenko I et al (2000) Assembly of tight junctions during early vertebrate development. Semin Cell Dev Biol 11:291–299. doi:10.1006/scdb.2000.0179

    Article  PubMed  CAS  Google Scholar 

  26. Virgintino D, Errede M, Robertson D et al (2004) Immunolocalization of tight junction proteins in the adult and developing human brain. Histochem Cell Biol 122:51–59. doi:10.1007/s00418-004-0665-1

    Article  PubMed  CAS  Google Scholar 

  27. Duval G, Grubb B (1986) Tissue accumulation of cadmium as a function of blood concentration. Biol Trace Elem Res 9(2):101–112. doi:10.1007/BF02916519

    Article  CAS  Google Scholar 

  28. Rader JI, Peeler JT, Mahaffey KR (1981) Comparative toxicity and tissue distribution of lead acetate in weanling and adult rats. Environ Health Perspect 42:187–195. doi:10.2307/3429208

    Article  PubMed  CAS  Google Scholar 

  29. Lidsky TI, Schneider JS (2003) Lead neurotoxicity in children: basic mechanisms and clinical correlates. Brain 126:5–19. doi:10.1093/brain/awg014

    Article  PubMed  Google Scholar 

  30. Nordberg M (2004) Environmental exposure and preventive measures in Sweden and EU. Biometals 17(5):589–592. doi:10.1023/B:BIOM.0000045743.55410.45

    Article  PubMed  CAS  Google Scholar 

  31. Chen HH, Ma T, Hume AS et al (1998) Developmental lead exposure alters the distribution of protein kinase C activity in the rat hippocampus. Biomed Environ Sci 11:61–69. doi:10.1159/000029810

    PubMed  CAS  Google Scholar 

  32. Bradbury MW, Deane R (1993) Permeability of the blood-brain barrier to lead. Neurotoxicology 14:131–136

    PubMed  CAS  Google Scholar 

  33. Jones LG, Prins J, Park S et al (2008) Lead exposure during development results in increased neurofilament phosphorylation, neuritic beading, and temporal processing deficits within the murine auditory brainstem. J Comp Neurol 506:1003–1017. doi:10.1002/cne.21563

    Article  PubMed  CAS  Google Scholar 

  34. Cohn J, Cory-Slechta DA (1994) Lead exposure potentiates the effects of NMDA on repeated learning. Neurotoxicol Teratol 16:455–465. doi:10.1016/0892-0362(94)90123-6

    Article  PubMed  CAS  Google Scholar 

  35. Laterra J, Bressler JP, Indurti RR et al (1992) Inhibition of astroglia-induced endothelial differentiation by inorganic lead: a role for protein kinase C. Proc Natl Acad Sci USA 89:10748–10752. doi:10.1073/pnas.89.22.10748

    Article  PubMed  CAS  Google Scholar 

  36. Yoshida S (2001) Re-evaluation of acute neurotoxic effects of Cd2+ on mesencephalic trigeminal neurons of the adult rat. Brain Res 892(1):102–110. doi:10.1016/S0006-8993(00)03240-6

    Article  PubMed  CAS  Google Scholar 

  37. Lopez E, Figueroa S, Oset-Gasque MJ et al (2003) Apoptosis and necrosis: two distinct events induced by cadmium in cortical neurons in culture. Br J Pharmacol 138(5):901–911. doi:10.1038/sj.bjp.0705111

    Article  PubMed  CAS  Google Scholar 

  38. Rising L, Vitarella D, Kimelberg HK et al (1995) Cadmium chloride (CdCl2)-induced metallothionein (MT) expression in neonatal rat primary astrocyte cultures. Brain Res 678(1–2):91–98. doi:10.1016/0006-8993(95)00170-U

    Article  PubMed  CAS  Google Scholar 

  39. Huo X, Peng L, Xu X et al (2007) Elevated blood lead levels of children in Guiyu, an electronic waste recycling town in China. Environ Health Perspect 115(7):1113–1117

    Article  PubMed  CAS  Google Scholar 

  40. Zheng L, Wu K, Li Y et al (2008) Blood lead and cadmium levels and relevant factors among children from an e-waste recycling town in China. Environ Res 108(1):15–20. doi:10.1016/j.envres.2008.04.002

    Article  PubMed  CAS  Google Scholar 

  41. Han D, Huo X, Zheng L et al (2007) Investigation on blood lead and intelligence levels of children in electronic waste recycling area. J Shantou Univ Med Coll 20(3):170–172

    Google Scholar 

  42. Li Y, Xu X, Wu K et al (2008) Monitoring of lead load and its effect on neonatal behavioral neurological assessment scores in Guiyu, an electronic waste recycling town in China. J Environ Monit 10:1233–1238. doi:10.1039/b804959a

    Article  PubMed  CAS  Google Scholar 

  43. Kato J, Kobune M, Ohkubo S et al (2007) Iron/IRP-1-dependent regulation of mRNA expression for transferrin receptor, DMT1 and ferritin during human erythroid differentiation. Exp Hematol 35:879–887. doi:10.1016/j.exphem.2007.03.005

    Article  PubMed  CAS  Google Scholar 

  44. Hentze MW, Muckenthaler MU, Andrews NC et al (2004) Balancing acts: molecular control of mammalian iron metabolism. Cell 17:285–297. doi:10.1016/S0092-8674(04)00343-5

    Article  Google Scholar 

  45. Trinder D, Oates PS, Thomas C et al (2000) Localisation of divalent metal transporter 1 (DMT1) to the microvillus membrane of rat duodenal enterocytes in iron deficiency, but to hepatocytes in iron overload. Gut 46:270–276. doi:10.1136/gut.46.2.270

    Article  PubMed  CAS  Google Scholar 

  46. Wardrop SL, Richardson DR (1999) The effect of intracellular iron concentration and nitrogen monoxide on Nramp2 expression and non-transferrin-bound iron uptake. Eur J Biochem 263(1):41–49. doi:10.1046/j.1432-1327.1999.00447.x

    Article  PubMed  CAS  Google Scholar 

  47. Gunshin H, Mackenzie B, Berger UV et al (1997) Cloning and characterization of a mammalian proton-coupled metal-ion transporter. Nature 388:482–488. doi:10.1038/41343

    Article  PubMed  CAS  Google Scholar 

  48. Gunshin H, Allerson CR, Polycarpou-Schwarz M et al (2001) Iron-dependent regulation of the divalent metal ion transporter. FEBS Lett 509:309–316. doi:10.1016/S0014-5793(01)03189-1

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

This research was funded by the Scientific Research Foundation for the ROCS of State Education Ministry, China, and Natural Science Foundation of Guangdong Province (No. 5008352). We also thank members of the Central Laboratory and Animal Centre for technical assistance and Laura Heraty for editing this manuscript.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Xia Huo.

Additional information

Chengwu Gu and Songjian Chen contributed equally to this work, they are joint first authors.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Gu, C., Chen, S., Xu, X. et al. Lead and Cadmium Synergistically Enhance the Expression of Divalent Metal Transporter 1 Protein in Central Nervous System of Developing Rats. Neurochem Res 34, 1150–1156 (2009). https://doi.org/10.1007/s11064-008-9891-6

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11064-008-9891-6

Keywords

Navigation