Skip to main content
SpringerLink
Log in

Postnatal Methylmercury Exposure Induces Hyperlocomotor Activity and Cerebellar Oxidative Stress in Mice: Dependence on the Neurodevelopmental Period

  • Published:
Neurochemical Research Aims and scope Submit manuscript

During the early postnatal period the central nervous system (CNS) is extremely sensitive to external agents. The present study aims at the investigation of critical phases where methylmercury (MeHg) induces cerebellar toxicity during the suckling period in mice. Animals were treated with daily subcutaneous injections of MeHg (7 mg/kg of body weight) during four different periods (5 days each) at the early postnatal period: postnatal day (PND) 1–5, PND 6–10, PND 11–15, or PND 16–20. A control group was treated with daily subcutaneous injections of a 150 mM NaCl solution (10 ml/kg of body weight). Subjects exposed to MeHg at different postnatal periods were littermate. At PND 35, behavioral tests were performed to evaluate spontaneous locomotor activity in the open field and motor performance in the rotarod task. Biochemical parameters related to oxidative stress (levels of glutathione and thiobarbituric acid reactive substances, as well as glutathione peroxidase and glutathione reductase activity) were evaluated in cerebellum. Hyperlocomotor activity and high levels of cerebellar thiobarbituric acid reactive substances were observed in animals exposed to MeHg during the PND 11–15 or PND 16–20 periods. Cerebellar glutathione reductase activity decreased in MeHg-exposed animals. Cerebellar glutathione peroxidase activity was also decreased after MeHg exposure and the lowest enzymatic activity was found in animals exposed to MeHg during the later days of the suckling period. In addition, low levels of cerebellar glutathione were found in animals exposed to MeHg during the PND 16–20 period. The present results show that the postnatal exposure to MeHg during the second half of the suckling period causes hyperlocomotor activity in mice and point to this phase as a critical developmental stage where mouse cerebellum is a vulnerable target for the neurotoxic and pro-oxidative effects of MeHg.

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

Access this article

Log in via an institution

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

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1.
Fig. 2.

Similar content being viewed by others

References

  1. Clarkson TW, Magos L, Myers GJ (2003) The toxicology of mercury–current exposures and clinical manifestations. N Engl J Med 349:1731–1737

    Article  PubMed  CAS  Google Scholar 

  2. Sirois JE, Atchison WD (2000) Methylmercury affects multiple subtypes of calcium channels in rat cerebellar granule cells. Toxicol Appl Pharmacol 167:1–11

    Article  PubMed  CAS  Google Scholar 

  3. Ou YC, White CC, Krejsa CM, Ponce RA, Kavanagh TJ, Faustman EM (1999) The role of intracellular glutathione in methylmercury-induced toxicity in embryonic neuronal cells. Neurotoxicology 20:793–804

    PubMed  CAS  Google Scholar 

  4. Aschner M, Yao CP, Allen JW, Tan KH (2000) Methylmercury alters glutamate transport in astrocytes. Neurochem Int 37:199–206

    Article  PubMed  CAS  Google Scholar 

  5. Farina M, Dahm KC, Schwalm FD, Brusque AM, Frizzo ME, Zeni G, Souza DO, Rocha JB (2003a) Methylmercury increases glutamate release from brain synaptosomes and glutamate uptake by cortical slices from suckling rat pups: modulatory effect of ebselen. Toxicol Sci 73:135–140

    Article  CAS  Google Scholar 

  6. Manfroi CB, Schwalm FD, Cereser V, Abreu F, Oliveira A, Bizarro L, Rocha JB, Frizzo ME, Souza DO, Farina M (2004) Maternal milk as methylmercury source for suckling mice: neurotoxic effects involved with the cerebellar glutamatergic system. Toxicol Sci 81:172–178

    Article  PubMed  CAS  Google Scholar 

  7. Costa LG, Aschner M, Vitalone A, Syversen T, Soldin OP (2004) Developmental neuropathology of environmental agents. Annu Rev Pharmacol Toxicol 44:87–110

    Article  PubMed  CAS  Google Scholar 

  8. Rasmussen EB, Newland MC (2001) Developmental exposure to methylmercury alters behavioral sensitivity to d-amphetamine and pentobarbital in adult rats. Neurotoxicol Teratol 23:45–55

    Article  PubMed  CAS  Google Scholar 

  9. Newland MC, Reile PA, Langston JL (2004) Gestational exposure to methylmercury retards choice in transition in aging rats. Neurotoxicol Teratol 26:179–194

    Article  PubMed  CAS  Google Scholar 

  10. Weiss B, Stern S, Cox C, Balys M (2005) Perinatal and lifetime exposure to methylmercury in the mouse: behavioral effects. Neurotoxicology 26:675–690

    Article  PubMed  CAS  Google Scholar 

  11. Stern S, Cox C, Cernichiari E, Balys M, Weiss B (2001) Perinatal and lifetime exposure to methylmercury in the mouse: blood and brain concentrations of mercury to 26 months of age. Neurotoxicology 22:467–477

    Article  PubMed  CAS  Google Scholar 

  12. Gottlieb A, Keydar I, Epstein HT (1977) Rodent brain growth stages: an analytical review Biol Neonate 32:166–176

    Article  PubMed  CAS  Google Scholar 

  13. Aschner M (1996) Methylmercury in astrocytes – what possible significance? Neurotoxicology 17:93–106

    PubMed  CAS  Google Scholar 

  14. Choi BH, Yee S, Robles M (1996) The effects of glutathione glycoside in methyl mercury poisoning. Toxicol Appl Pharmacol 141:357–364

    Article  PubMed  CAS  Google Scholar 

  15. Danbolt NC (2001) Glutamate uptake. Prog Neurobiol 65:1–105

    Article  PubMed  CAS  Google Scholar 

  16. Khan JY, Black SM (2003) Developmental changes in murine brain antioxidant enzymes. Pediatr Res 54:77–82

    Article  PubMed  CAS  Google Scholar 

  17. Farina M, Frizzo ME, Soares FA, Schwalm FD, Dietrich MO, Zeni G, Rocha JB, Souza DO (2003b) Ebselen protects against methylmercury-induced inhibition of glutamate uptake by cortical slices from adult mice. Toxicol Lett 144:351–357

    Article  CAS  Google Scholar 

  18. Goulet S, Dore FY, Mirault ME (2003) Neurobehavioral changes in mice chronically exposed to methylmercury during fetal and early postnatal development. Neurotoxicol Teratol 25:335–347

    Article  PubMed  CAS  Google Scholar 

  19. Farina M, Franco JL, Ribas CM, Meotti FC, Pizzolatti MG, Dafre AL, Santos ARS (2005) Protective effects of Polygala paniculata extract against methylmercury-induced neurotoxicity in mice. J Pharm Pharmacol 57:1503–1508

    Article  PubMed  CAS  Google Scholar 

  20. Duhan NW, Miya TS (1957) A note on a simple apparatus for detecting neurological deficit in rats and mice. J Am Pharm Assoc 46:208–209

    Google Scholar 

  21. Klein R, Herman SP, Brubaker PE, Lucier GW, Krigman MR (1972) A model of acute methyl mercury intoxication in rats. Arch Pathol 93:408–418

    PubMed  CAS  Google Scholar 

  22. Sanfeliu C, Sebastia J, Cristofol R, Rodriguez-Farre E (2003) Neurotoxicity of organomercurial compounds. Neurotox Res 5:283–305

    Article  PubMed  Google Scholar 

  23. Grandjean P, Weihe P, White RF, Debes F, Araki S, Yokoyama K, Murata K, Sorensen N, Dahl R, Jorgensen PJ (1997) Cognitive deficit in 7-year-old children with prenatal exposure to methylmercury. Neurotoxicol Teratol 19:417–428

    Article  PubMed  CAS  Google Scholar 

  24. Carlberg I, Mannervik B (1985) Glutathione reductase. Methods Enzymol 113:484–490

    Article  PubMed  CAS  Google Scholar 

  25. Wendel A (1981) Glutathione peroxidase. Methods Enzymol 77:325–333

    PubMed  CAS  Google Scholar 

  26. Ellman GL (1959) Tissue sulfhydryl groups. Arch Biochem Biophys 82:70–77

    Article  PubMed  CAS  Google Scholar 

  27. Farina M, Brandão R, de Lara FS, Pagliosa LB, Soares FA, Souza DO, Rocha JB (2003c) Profile of nonprotein thiols, lipid peroxidation and delta-aminolevulinate dehydratase activity in mouse kidney and liver in response to acute exposure to mercuric chloride and sodium selenite. Toxicology 184:179–187

    Article  CAS  Google Scholar 

  28. Ohkawa H, Ohishi N, Yagi K (1979) Assay for lipid peroxides in animal tissues by thiobarbituric acid reaction. Anal Biochem 95:351–358

    Article  PubMed  CAS  Google Scholar 

  29. Bradford MM (1976) A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem 72:248–254

    Article  PubMed  CAS  Google Scholar 

  30. Flohe L (1971) Glutathione peroxidase: enzymology and biological aspects. Klin Wochenschr 49:669–683

    Article  PubMed  CAS  Google Scholar 

  31. Gul M, Kutay FZ, Temocin S, Hanninen O (2000) Cellular and clinical implications of glutathione. Indian J Exp Biol 38:625–634

    PubMed  CAS  Google Scholar 

  32. Peuchen S, Bolanos JP, Heales SJ, Almeida A, Duchen MR, Clark JB (1997) Interrelationships between astrocyte function, oxidative stress and antioxidant status within the central nervous system. Prog Neurobiol 52:261–281

    Article  PubMed  CAS  Google Scholar 

  33. Tiffany-Castiglioni E, Guerri C, Aschner M, Matsushima GK, O’Callaghan JP, Streit WJ (2001) Roles of glia in developmental neurotoxicity: session VI summary and research needs. Neurotoxicology 22:567–573

    Article  PubMed  CAS  Google Scholar 

  34. Raps SP, Lai JC, Hertz L, Cooper AJ (1989) Glutathione is present in high concentrations in cultured astrocytes but not in cultured neurons. Brain Res 493:398–401

    Article  PubMed  CAS  Google Scholar 

  35. Makar TK, Nedergaard M, Preuss A, Gelbard AS, Perumal AS, Cooper AJ (1994) Vitamin E, ascorbate, glutathione, glutathione disulfide, and enzymes of glutathione metabolism in cultures of chick astrocytes and neurons: evidence that astrocytes play an important role in antioxidative processes in the brain. J Neurochem 62:45–53

    Article  PubMed  CAS  Google Scholar 

  36. Booth RF, Patel TB, Clark JB (1980) The development of enzymes of energy metabolism in the brain of a precocial (guinea pig) and non-precocial (rat) species. J Neurochem 34:17–25

    Article  PubMed  CAS  Google Scholar 

  37. Sakamoto M, Nakano A, Kajiwara Y, Naruse I, Fujisaki T (1993) Effects of methyl mercury in postnatal developing rats. Environ Res 61:43–50

    Article  PubMed  CAS  Google Scholar 

  38. Dietrich MO, Mantese CE, Anjos GD, Souza DO, Farina M (2005) Motor impairment induced by oral exposure to methylmercury in adult mice. Environ Toxicol Pharmacol 19:169–175

    Article  CAS  Google Scholar 

  39. Farina M, Cereser V, Portela LV, Mendez A, Porciúncula LO, Fornaguera J, Gonçalves CA, Wofchuk ST, Rocha JBT, Souza DO (2005c) Methylmercury increases S100B content in rat cerebrospinal fluid. Environ Toxicol Pharmacol 19:249–253

    Article  CAS  Google Scholar 

  40. Fredriksson A, Dencker L, Archer T, Danielsson BR (1977) Prenatal coexposure to metallic mercury vapour and methylmercury produce interactive behavioural changes in adult rats. Neurotoxicol Teratol 18:129–134

    Article  Google Scholar 

  41. Dare E, Fetissov S, Hokfelt T, Hall H, Ogren SO, Ceccatelli S (2003) Effects of prenatal exposure to methylmercury on dopamine-mediated locomotor activity and dopamine D2 receptor binding. Naunyn Schmiedebergs Arch Pharmacol 367:500–508

    Article  PubMed  CAS  Google Scholar 

  42. Myers GJ, Davidson PW, Cox C, Shamlaye CF, Palumbo D, Cernichiari E, Sloane-Reeves J, Wilding GE, Kost J, Huang LS, Clarkson TW (2003) Prenatal methylmercury exposure from ocean fish consumption in the Seychelles child development study. Lancet 361:1686–1692

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgements

This study was supported by grants from CNPq to M. Farina (475329/2004–0). J. Strigari was a recipient of a CNPq/PIBIC fellowship.

Author information

Authors and Affiliations

  1. Departamento de Bioquímica, Centro de Ciências Biológicas, Universidade Federal de Santa Catarina, 88040-900, Florianópolis, SC, Brazil

    James Stringari & Marcelo Farina

  2. Departamento de Ciências Fisiológicas, Centro de Ciências Biológicas, Universidade Federal de Santa Catarina, 88040-900, Florianópolis, SC, Brazil.

    Flávia C. Meotti & Adair R. S. Santos

  3. Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil.

    Diogo O. Souza

Authors
  1. James Stringari
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Flávia C. Meotti
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Diogo O. Souza
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Adair R. S. Santos
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Marcelo Farina
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Stringari, J., Meotti, F.C., Souza, D.O. et al. Postnatal Methylmercury Exposure Induces Hyperlocomotor Activity and Cerebellar Oxidative Stress in Mice: Dependence on the Neurodevelopmental Period. Neurochem Res 31, 563–569 (2006). https://doi.org/10.1007/s11064-006-9051-9

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11064-006-9051-9

Keywords

Search

Navigation