Skip to main content
SpringerLink
Log in

In Vitro Developmental Neurotoxicity Testing: Relevant Models and Endpoints

  • Protocol
  • First Online:
In Vitro Toxicology Systems

Part of the book series: Methods in Pharmacology and Toxicology ((MIPT))

Abstract

Neurotoxicity detection induced by chemicals represents a major challenge due to the physiological and morphological complexity of the central nervous system (CNS) and peripheral nervous system (PNS). Currently in vitro test methods are mainly used to study the mechanisms of neurotoxicity rather than to predict hazards to human health, and so far they play only a complementary role to in vivo testing. The brain consists of numerous different cell types such as neurons, astrocytes, oligodendrocytes, and microglia, and the cell–cell interactions are of key importance for brain development and function. Several promising in vitro models for adult and developmental neurotoxicity testing have been developed. These models have shown to be useful and provide an important tool for functional studies at both cellular and molecular levels. A number of biological processes that are functional target sites for neurotoxicants in vivo can be studied at the level of cell morphology and function using an in vitro system. The range of various in vitro models can be applied starting from simple neuronal or glial cell lines where usually only one cell type is present, to more complex models such as monolayer of primary mixed neuronal and glial cultures or three-dimensional models, e.g., brain slices or re-aggregating primary cultures. These in vitro models and relevant endpoints are characterized, and their applications for NT and DNT are discussed in this chapter.

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

Access this chapter

Log in via an institution
Protocol
USD 49.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 119.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 159.00
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 249.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

We’re sorry, something doesn't seem to be working properly.

Please try refreshing the page. If that doesn't work, please contact support so we can address the problem.

References

  1. Grandjean P, Landrigan PJ (2006) Developmental neurotoxicity of industrial chemicals. Lancet 368:2167–2178

    CAS  PubMed  Google Scholar 

  2. Landrigan PJ (2010) What causes autism? Exploring the environmental contribution. Curr Opin Pediatr 22:219–225

    PubMed  Google Scholar 

  3. Rauh VA, Garfinkel R, Perera FP, Andrews HF, Hoepner L, Barr DB, Whitehead R, Tang D, Whyatt RW (2006) Impact of prenatal chlorpyrifos exposure on neurodevelopment in the first 3 years of life among inner-city children. Pediatrics 118:e1845–e1859

    PubMed Central  PubMed  Google Scholar 

  4. OECD (2007) Test no. 426: developmental neurotoxicity study. http://dx.doi.org/10.1787/9789264067394-en. Accessed 18 Sept 2013

  5. OECD (1997) Test no. 424: neurotoxicity study in rodents. http://www.oecd-ilibrary.org/environment/test-no-424-neurotoxicity-study-in-rodents_9789264071025-en. Accessed 18 Sept 2013

  6. Crofton KM, Mundy WR, Shafer TJ (2012) Developmental neurotoxicity testing: a path forward. Congenit Anom (Kyoto) 52:140–146

    Google Scholar 

  7. Bal-Price AK, Hogberg HT, Buzanska L, Coecke S (2010) Relevance of in vitro neurotoxicity testing for regulatory requirements: challenges to be considered. Neurotoxicol Teratol 32:36–41

    CAS  PubMed  Google Scholar 

  8. Coecke S, Goldberg AM, Allen S, Buzanska L, Calamandrei G, Crofton K, Hareng L, Hartung T, Knaut H, Honegger P, Jacobs M, Lein P, Li A, Mundy W, Owen D, Schneider S, Silbergeld E, Reum T, Trnovec T, Monnet-Tschudi F, Bal-Price A (2007) Workgroup report: incorporating in vitro alternative methods for developmental neurotoxicity into international hazard and risk assessment strategies. Environ Health Perspect 115: 924–931

    PubMed Central  PubMed  Google Scholar 

  9. Bal-Price AK, Hogberg HT, Buzanska L, Lenas P, van Vliet E, Hartung T (2010) In vitro developmental neurotoxicity (DNT) testing: relevant models and endpoints. Neurotoxicology 31:545–554

    CAS  PubMed  Google Scholar 

  10. Rice D, Barone S Jr (2000) Critical periods of vulnerability for the developing nervous system: evidence from humans and animal models. Environ Health Perspect 108(Suppl 3): 511–533

    PubMed Central  PubMed  Google Scholar 

  11. Rodier PM (1994) Vulnerable periods and processes during central nervous system development. Environ Health Perspect 102(Suppl 2):121–124

    PubMed Central  PubMed  Google Scholar 

  12. Bal-Price AK, Sunol C, Weiss DG, van Vliet E, Westerink RH, Costa LG (2008) Application of in vitro neurotoxicity testing for regulatory purposes: symposium III summary and research needs. Neurotoxicology 29:520–531

    PubMed  Google Scholar 

  13. Greene LA, Tischler AS (1976) Establishment of a noradrenergic clonal line of rat adrenal pheochromocytoma cells which respond to nerve growth factor. Proc Natl Acad Sci U S A 73:2424–2428

    CAS  PubMed Central  PubMed  Google Scholar 

  14. Augusti-Tocco G, Sato G (1969) Establishment of functional clonal lines of neurons from mouse neuroblastoma. Proc Natl Acad Sci U S A 64:311–315

    CAS  PubMed Central  PubMed  Google Scholar 

  15. Bartlett PF, Reid HH, Bailey KA, Bernard O (1988) Immortalization of mouse neural precursor cells by the c-myc oncogene. Proc Natl Acad Sci U S A 85:3255–3259

    CAS  PubMed Central  PubMed  Google Scholar 

  16. De Vries GH, Boullerne AI (2010) Glial cell lines: an overview. Neurochem Res 35: 1978–2000

    PubMed  Google Scholar 

  17. Radio NM, Freudenrich TM, Robinette BL, Crofton KM, Mundy WR (2010) Comparison of PC12 and cerebellar granule cell cultures for evaluating neurite outgrowth using high content analysis. Neurotoxicol Teratol 32:25–35

    CAS  PubMed  Google Scholar 

  18. Pellacani C, Tagliaferri S, Caglieri A, Goldoni M, Giordano G, Mutti A, Costa LG (2012) Synergistic interactions between PBDEs and PCBs in human neuroblastoma cells. Environ Toxicol. doi: 10.1002/tox.21768. [Epub ahead of print]

  19. Krug AK, Balmer NV, Matt F, Schonenberger F, Merhof D, Leist M (2013) Evaluation of a human neurite growth assay as specific screen for developmental neurotoxicants. Arch Toxicol 87(12):2215–2231

    CAS  PubMed  Google Scholar 

  20. Zhang SC, Wernig M, Duncan ID, Brustle O, Thomson JA (2001) In vitro differentiation of transplantable neural precursors from human embryonic stem cells. Nat Biotechnol 19:1129–1133

    CAS  PubMed  Google Scholar 

  21. Wang S, Bates J, Li X, Schanz S, Chandler-Militello D, Levine C, Maherali N, Studer L, Hochedlinger K, Windrem M, Goldman SA (2013) Human iPSC-derived oligodendrocyte progenitor cells can myelinate and rescue a mouse model of congenital hypomyelination. Cell Stem Cell 12:252–264

    CAS  PubMed Central  PubMed  Google Scholar 

  22. Caldwell MA, He X, Wilkie N, Pollack S, Marshall G, Wafford KA, Svendsen CN (2001) Growth factors regulate the survival and fate of cells derived from human neurospheres. Nat Biotechnol 19:475–479

    CAS  PubMed  Google Scholar 

  23. Seaberg RM, van der Kooy D (2003) Stem and progenitor cells: the premature desertion of rigorous definitions. Trends Neurosci 26:125–131

    CAS  PubMed  Google Scholar 

  24. Przyborski SA, Christie VB, Hayman MW, Stewart R, Horrocks GM (2004) Human embryonal carcinoma stem cells: models of embryonic development in humans. Stem Cells Dev 13:400–408

    CAS  PubMed  Google Scholar 

  25. Moors M, Rockel TD, Abel J, Cline JE, Gassmann K, Schreiber T, Schuwald J, Weinmann N, Fritsche E (2009) Human neurospheres as three-dimensional cellular systems for developmental neurotoxicity testing. Environ Health Perspect 117:1131–1138

    CAS  PubMed Central  PubMed  Google Scholar 

  26. Stummann TC, Hareng L, Bremer S (2009) Hazard assessment of methylmercury toxicity to neuronal induction in embryogenesis using human embryonic stem cells. Toxicology 257:117–126

    CAS  PubMed  Google Scholar 

  27. Yla-Outinen L, Heikkila J, Skottman H, Suuronen R, Aanismaa R, Narkilahti S (2010) Human cell-based micro electrode array platform for studying neurotoxicity. Front Neuroeng 3

    Google Scholar 

  28. Buzanska L, Sypecka J, Nerini-Molteni S, Compagnoni A, Hogberg HT, del Torchio R, Domanska-Janik K, Zimmer J, Coecke S (2009) A human stem cell-based model for identifying adverse effects of organic and inorganic chemicals on the developing nervous system. Stem Cells 27:2591–2601

    CAS  PubMed  Google Scholar 

  29. Laurenza I, Pallocca G, Mennecozzi M, Scelfo B, Pamies D, Bal-Price A (2013) A human pluripotent carcinoma stem cell-based model for in vitro developmental neurotoxicity testing: effects of methylmercury, lead and aluminum evaluated by gene expression studies. Int J Dev Neurosci 31(7):679–691

    CAS  PubMed  Google Scholar 

  30. Aschner M, Syversen T (2004) Neurotoxicology: principles and considerations of in vitro assessment. Altern Lab Anim 32:323–327

    CAS  PubMed  Google Scholar 

  31. Hogberg HT, Kinsner-Ovaskainen A, Coecke S, Hartung T, Bal-Price AK (2010) mRNA expression is a relevant tool to identify developmental neurotoxicants using an in vitro approach. Toxicol Sci 113:95–115

    CAS  PubMed  Google Scholar 

  32. Hogberg HT, Kinsner-Ovaskainen A, Hartung T, Coecke S, Bal-Price AK (2009) Gene expression as a sensitive endpoint to evaluate cell differentiation and maturation of the developing central nervous system in primary cultures of rat cerebellar granule cells (CGCs) exposed to pesticides. Toxicol Appl Pharmacol 235:268–286

    CAS  PubMed  Google Scholar 

  33. Belanger M, Yang J, Petit JM, Laroche T, Magistretti PJ, Allaman I (2011) Role of the glyoxalase system in astrocyte-mediated neuroprotection. J Neurosci 31:18338–18352

    CAS  PubMed  Google Scholar 

  34. Costa LG (1998) Neurotoxicity testing: a discussion of in vitro alternatives. Environ Health Perspect 106(Suppl 2):505–510

    PubMed Central  PubMed  Google Scholar 

  35. Limongi T, Cesca F, Gentile F, Marotta R, Ruffilli R, Barberis A, Dal Maschio M, Petrini EM, Santoriello S, Benfenati F, Di Fabrizio E (2013) Nanostructured superhydrophobic substrates trigger the development of 3D neuronal networks. Small 9(3):402–412

    CAS  PubMed  Google Scholar 

  36. Peretz H, Talpalar AE, Vago R, Baranes D (2007) Superior survival and durability of neurons and astrocytes on 3-dimensional aragonite biomatrices. Tissue Eng 13:461–472

    CAS  PubMed  Google Scholar 

  37. Brannvall K, Bergman K, Wallenquist U, Svahn S, Bowden T, Hilborn J, Forsberg-Nilsson K (2007) Enhanced neuronal differentiation in a three-dimensional collagen-hyaluronan matrix. J Neurosci Res 85:2138–2146

    CAS  PubMed  Google Scholar 

  38. Labour MN, Banc A, Tourrette A, Cunin F, Verdier JM, Devoisselle JM, Marcilhac A, Belamie E (2012) Thick collagen-based 3D matrices including growth factors to induce neurite outgrowth. Acta Biomater 8: 3302–3312

    CAS  PubMed  Google Scholar 

  39. van Vliet E, Morath S, Eskes C, Linge J, Rappsilber J, Honegger P, Hartung T, Coecke S (2008) A novel in vitro metabolomics approach for neurotoxicity testing, proof of principle for methyl mercury chloride and caffeine. Neurotoxicology 29:1–12

    PubMed  Google Scholar 

  40. Giobbe GG, Zagallo M, Riello M, Serena E, Masi G, Barzon L, Di Camillo B, Elvassore N (2012) Confined 3D microenvironment regulates early differentiation in human pluripotent stem cells. Biotechnol Bioeng 109(12): 3119–3132

    CAS  PubMed  Google Scholar 

  41. Abbott A (2003) Cell culture: biology’s new dimension. Nature 424:870–872

    CAS  PubMed  Google Scholar 

  42. Gassmann K, Baumann J, Giersiefer S, Schuwald J, Schreiber T, Merk HF, Fritsche E (2012) Automated neurosphere sorting and plating by the COPAS large particle sorter is a suitable method for high-throughput 3D in vitro applications. Toxicol In Vitro 26:993–1000

    CAS  PubMed  Google Scholar 

  43. NIH (2012) 2012 Tissue chip project awards. http://www.ncats.nih.gov/research/reengineering/tissue-chip/projects/awards-2012.html. Accessed 18 Sept 2013

  44. Rodier PM (1980) Chronology of neuron development: animal studies and their clinical implications. Dev Med Child Neurol 22: 525–545

    CAS  PubMed  Google Scholar 

  45. Caviness VS Jr, Takahashi T (1995) Proliferative events in the cerebral ventricular zone. Brain Dev 17:159–163

    PubMed  Google Scholar 

  46. Yamanaka H, Obata K (2004) Displaced granule cells in the molecular layer of the cerebellar cortex in mice treated with methylazoxymethanol. Neurosci Lett 358:132–136

    CAS  PubMed  Google Scholar 

  47. Guizzetti M, Pathak S, Giordano G, Costa LG (2005) Effect of organophosphorus insecticides and their metabolites on astroglial cell proliferation. Toxicology 215:182–190

    CAS  PubMed  Google Scholar 

  48. Bose R, Onishchenko N, Edoff K, Janson Lang AM, Ceccatelli S (2012) Inherited effects of low-dose exposure to methylmercury in neural stem cells. Toxicol Sci 130: 383–390

    CAS  PubMed  Google Scholar 

  49. Go HS, Shin CY, Lee SH, Jeon SJ, Kim KC, Choi CS, Ko KH (2009) Increased proliferation and gliogenesis of cultured rat neural progenitor cells by lipopolysaccharide-stimulated astrocytes. Neuroimmunomodulation 16: 365–376

    CAS  PubMed  Google Scholar 

  50. Spitzer NC (2006) Electrical activity in early neuronal development. Nature 444:707–712

    CAS  PubMed  Google Scholar 

  51. Ayala R, Shu T, Tsai LH (2007) Trekking across the brain: the journey of neuronal migration. Cell 128:29–43

    CAS  PubMed  Google Scholar 

  52. Hatten ME (2002) New directions in neuronal migration. Science 297:1660–1663

    CAS  PubMed  Google Scholar 

  53. Tiffany-Castiglioni E, Sierra EM, Wu JN, Rowles TK (1989) Lead toxicity in neuroglia. Neurotoxicology 10:417–443

    CAS  PubMed  Google Scholar 

  54. Miller MW (1993) Migration of cortical neurons is altered by gestational exposure to ethanol. Alcohol Clin Exp Res 17:304–314

    CAS  PubMed  Google Scholar 

  55. Choi BH, Lapham LW, Amin-Zaki L, Saleem T (1978) Abnormal neuronal migration, deranged cerebral cortical organization, and diffuse white matter astrocytosis of human fetal brain: a major effect of methylmercury poisoning in utero. J Neuropathol Exp Neurol 37:719–733

    CAS  PubMed  Google Scholar 

  56. de la Monte SM, Tong M, Carlson RI, Carter JJ, Longato L, Silbermann E, Wands JR (2009) Ethanol inhibition of aspartyl-asparaginyl-beta-hydroxylase in fetal alcohol spectrum disorder: potential link to the impairments in central nervous system neuronal migration. Alcohol 43:225–240

    PubMed Central  PubMed  Google Scholar 

  57. Sass JB, Haselow DT, Silbergeld EK (2001) Methylmercury-induced decrement in neuronal migration may involve cytokine-dependent mechanisms: a novel method to assess neuronal movement in vitro. Toxicol Sci 63:74–81

    CAS  PubMed  Google Scholar 

  58. Ruiz A, Buzanska L, Gilliland D, Rauscher H, Sirghi L, Sobanski T, Zychowicz M, Ceriotti L, Bretagnol F, Coecke S, Colpo P, Rossi F (2008) Micro-stamped surfaces for the patterned growth of neural stem cells. Biomaterials 29:4766–4774

    CAS  PubMed  Google Scholar 

  59. Raff MC, Barres BA, Burne JF, Coles HS, Ishizaki Y, Jacobson MD (1993) Programmed cell death and the control of cell survival: lessons from the nervous system. Science 262:695–700

    CAS  PubMed  Google Scholar 

  60. Gorman AM, Orrenius S, Ceccatelli S (1998) Apoptosis in neuronal cells: role of caspases. Neuroreport 9:R49–R55

    CAS  PubMed  Google Scholar 

  61. Madden SD, Cotter TG (2008) Cell death in brain development and degeneration: control of caspase expression may be key! Mol Neurobiol 37:1–6

    CAS  PubMed  Google Scholar 

  62. Shield MA, Mirkes PE (1998) In: Slikker W, Chang LW (eds) Handbook of developmental neurotoxicity. Academic, San Diego, CA, pp 159–188

    Google Scholar 

  63. Corbett BA, Kantor AB, Schulman H, Walker WL, Lit L, Ashwood P, Rocke DM, Sharp FR (2007) A proteomic study of serum from children with autism showing differential expression of apolipoproteins and complement proteins. Mol Psychiatry 12:292–306

    CAS  PubMed  Google Scholar 

  64. Sacco R, Militerni R, Frolli A, Bravaccio C, Gritti A, Elia M, Curatolo P, Manzi B, Trillo S, Lenti C, Saccani M, Schneider C, Melmed R, Reichelt KL, Pascucci T, Puglisi-Allegra S, Persico AM (2007) Clinical, morphological, and biochemical correlates of head circumference in autism. Biol Psychiatry 62:1038–1047

    CAS  PubMed  Google Scholar 

  65. Bal-Price A, Brown GC (2000) Nitric-oxide-induced necrosis and apoptosis in PC12 cells mediated by mitochondria. J Neurochem 75:1455–1464

    CAS  PubMed  Google Scholar 

  66. Gavrieli Y, Sherman Y, Ben-Sasson SA (1992) Identification of programmed cell death in situ via specific labeling of nuclear DNA fragmentation. J Cell Biol 119:493–501

    CAS  PubMed  Google Scholar 

  67. Nat R, Radu E, Regalia T, Popescu LM (2001) Apoptosis in human embryo development: 3. Fas-induced apoptosis in brain primary cultures. J Cell Mol Med 5:417–428

    CAS  PubMed  Google Scholar 

  68. Bradbury DA, Simmons TD, Slater KJ, Crouch SP (2000) Measurement of the ADP:ATP ratio in human leukaemic cell lines can be used as an indicator of cell viability, necrosis and apoptosis. J Immunol Methods 240:79–92

    CAS  PubMed  Google Scholar 

  69. Tamamaki N, Nakamura K, Okamoto K, Kaneko T (2001) Radial glia is a progenitor of neocortical neurons in the developing cerebral cortex. Neurosci Res 41:51–60

    CAS  PubMed  Google Scholar 

  70. Lawson LJ, Perry VH, Gordon S (1992) Turnover of resident microglia in the normal adult mouse brain. Neuroscience 48:405–415

    CAS  PubMed  Google Scholar 

  71. Cuadros MA, Navascues J (1998) The origin and differentiation of microglial cells during development. Prog Neurobiol 56:173–189

    CAS  PubMed  Google Scholar 

  72. Bhat NR (1995) Signal transduction mechanisms in glial cells. Dev Neurosci 17:267–284

    CAS  PubMed  Google Scholar 

  73. Fiacco TA, Agulhon C, McCarthy KD (2009) Sorting out astrocyte physiology from pharmacology. Annu Rev Pharmacol Toxicol 49: 151–174

    CAS  PubMed  Google Scholar 

  74. Aschner M, Allen JW, Kimelberg HK, LoPachin RM, Streit WJ (1999) Glial cells in neurotoxicity development. Annu Rev Pharmacol Toxicol 39:151–173

    CAS  PubMed  Google Scholar 

  75. Jebbett NJ, Hamilton JW, Rand MD, Eckenstein F (2013) Low level methylmercury enhances CNTF-evoked STAT3 signaling and glial differentiation in cultured cortical progenitor cells. Neurotoxicology 38:91–100

    CAS  PubMed  Google Scholar 

  76. Eskes C, Juillerat-Jeanneret L, Leuba G, Honegger P, Monnet-Tschudi F (2003) Involvement of microglia-neuron interactions in the tumor necrosis factor-alpha release, microglial activation, and neurodegeneration induced by trimethyltin. J Neurosci Res 71:583–590

    CAS  PubMed  Google Scholar 

  77. Bal-Price A, Brown GC (2001) Inflammatory neurodegeneration mediated by nitric oxide from activated glia-inhibiting neuronal respiration, causing glutamate release and excitotoxicity. J Neurosci 21:6480–6491

    CAS  PubMed  Google Scholar 

  78. Bal-Price A, Moneer Z, Brown GC (2002) Nitric oxide induces rapid, calcium-dependent release of vesicular glutamate and ATP from cultured rat astrocytes. Glia 40:312–323

    PubMed  Google Scholar 

  79. Eagleson KL, Lillien L, Chan AV, Levitt P (1997) Mechanisms specifying area fate in cortex include cell-cycle-dependent decisions and the capacity of progenitors to express phenotype memory. Development 124:1623–1630

    CAS  PubMed  Google Scholar 

  80. McConnell SK (1990) The specification of neuronal identity in the mammalian cerebral cortex. Experientia 46:922–929

    CAS  PubMed  Google Scholar 

  81. Slotkin TA, Lappi SE, Seidler FJ (1993) Impact of fetal nicotine exposure on development of rat brain regions: critical sensitive periods or effects of withdrawal? Brain Res Bull 31:319–328

    CAS  PubMed  Google Scholar 

  82. Rodier PM, Aschner M, Sager PR (1984) Mitotic arrest in the developing CNS after prenatal exposure to methylmercury. Neurobehav Toxicol Teratol 6:379–385

    CAS  PubMed  Google Scholar 

  83. Goldberg JL (2004) Intrinsic neuronal regulation of axon and dendrite growth. Curr Opin Neurobiol 14:551–557

    CAS  PubMed  Google Scholar 

  84. Dotti CG, Banker GA, Binder LI (1987) The expression and distribution of the microtubule-associated proteins tau and microtubule-associated protein 2 in hippocampal neurons in the rat in situ and in cell culture. Neuroscience 23:121–130

    CAS  PubMed  Google Scholar 

  85. van Eden CG, Kros JM, Uylings HB (1990) The development of the rat prefrontal cortex. Its size and development of connections with thalamus, spinal cord and other cortical areas. Prog Brain Res 85:169–183

    PubMed  Google Scholar 

  86. Mrzljak L, Uylings HB, Van Eden CG, Judas M (1990) Neuronal development in human prefrontal cortex in prenatal and postnatal stages. Prog Brain Res 85:185–222

    CAS  PubMed  Google Scholar 

  87. Shingo AS, Kito S (2005) Effects of nicotine on neurogenesis and plasticity of hippocampal neurons. J Neural Transm 112:1475–1478

    CAS  PubMed  Google Scholar 

  88. Sanderson JL, Donald Partridge L, Valenzuela CF (2009) Modulation of GABAergic and glutamatergic transmission by ethanol in the developing neocortex: an in vitro test of the excessive inhibition hypothesis of fetal alcohol spectrum disorder. Neuropharmacology 56:541–555

    CAS  PubMed Central  PubMed  Google Scholar 

  89. Lin HM, Liu CY, Jow GM, Tang CY (2009) Toluene disrupts synaptogenesis in cultured hippocampal neurons. Toxicol Lett 184:90–96

    CAS  PubMed  Google Scholar 

  90. Soares FA, Farina M, Santos FW, Souza D, Rocha JB, Nogueira CW (2003) Interaction between metals and chelating agents affects glutamate binding on brain synaptic membranes. Neurochem Res 28:1859–1865

    CAS  PubMed  Google Scholar 

  91. Veronesi B, Pope C (1990) The neurotoxicity of parathion-induced acetylcholinesterase inhibition in neonatal rats. Neurotoxicology 11:465–482

    CAS  PubMed  Google Scholar 

  92. Kodavanti PR (2005) Neurotoxicity of persistent organic pollutants: possible mode(s) of action and further considerations. Dose Response 3:273–305

    CAS  PubMed Central  Google Scholar 

  93. Harrill JA, Robinette BL, Mundy WR (2011) Use of high content image analysis to detect chemical-induced changes in synaptogenesis in vitro. Toxicol In Vitro 25:368–387

    CAS  PubMed  Google Scholar 

  94. Buckby LE, Mummery R, Crompton MR, Beesley PW, Empson RM (2004) Comparison of neuroplastin and synaptic marker protein expression in acute and cultured organotypic hippocampal slices from rat. Brain Res Dev Brain Res 150:1–7

    CAS  PubMed  Google Scholar 

  95. VijayRaghavan K (1995) Synaptic vesicle recycling intermediates revealed. Bioessays 17:195–198

    CAS  PubMed  Google Scholar 

  96. Hogberg HT, Sobanski T, Novellino A, Whelan M, Weiss DG, Bal-Price AK (2011) Application of micro-electrode arrays (MEAs) as an emerging technology for developmental neurotoxicity: evaluation of domoic acid-induced effects in primary cultures of rat cortical neurons. Neurotoxicology 32:158–168

    CAS  PubMed  Google Scholar 

  97. Baumann N, Pham-Dinh D (2001) Biology of oligodendrocyte and myelin in the mammalian central nervous system. Physiol Rev 81:871–927

    CAS  PubMed  Google Scholar 

  98. Hunter SF, Leavitt JA, Rodriguez M (1997) Direct observation of myelination in vivo in the mature human central nervous system. A model for the behaviour of oligodendrocyte progenitors and their progeny. Brain 120(Pt 11):2071–2082

    PubMed  Google Scholar 

  99. Miller RH (1996) Oligodendrocyte origins. Trends Neurosci 19:92–96

    CAS  PubMed  Google Scholar 

  100. Deng W, Poretz RD (2003) Oligodendroglia in developmental neurotoxicity. Neurotoxicology 24:161–178

    CAS  PubMed  Google Scholar 

  101. Simons M, Trotter J (2007) Wrapping it up: the cell biology of myelination. Curr Opin Neurobiol 17:533–540

    CAS  PubMed  Google Scholar 

  102. Wiggins RC (1986) Myelination: a critical stage in development. Neurotoxicology 7: 103–120

    CAS  PubMed  Google Scholar 

  103. Okamoto H, Miki T, Lee KY, Yokoyama T, Kuma H, Wang ZY, Gu H, Li HP, Matsumoto Y, Irawan S, Bedi KS, Nakamura Y, Takeuchi Y (2006) Oligodendrocyte myelin glycoprotein (OMgp) in rat hippocampus is depleted by chronic ethanol consumption. Neurosci Lett 406:76–80

    CAS  PubMed  Google Scholar 

  104. Bouldin TW, Samsa G, Earnhardt TS, Krigman MR (1988) Schwann cell vulnerability to demyelination is associated with internodal length in tellurium neuropathy. J Neuropathol Exp Neurol 47:41–47

    CAS  PubMed  Google Scholar 

  105. Rogister B, Ben-Hur T, Dubois-Dalcq M (1999) From neural stem cells to myelinating oligodendrocytes. Mol Cell Neurosci 14: 287–300

    CAS  PubMed  Google Scholar 

  106. Monnet-Tschudi F, Zurich MG, Sorg O, Matthieu JM, Honegger P, Schilter B (1999) The naturally occurring food mycotoxin fumonisin B1 impairs myelin formation in aggregating brain cell culture. Neurotoxicology 20:41–48

    CAS  PubMed  Google Scholar 

  107. Felitsyn N, McLeod C, Shroads AL, Stacpoole PW, Notterpek L (2008) The heme precursor delta-aminolevulinate blocks peripheral myelin formation. J Neurochem 106: 2068–2079

    CAS  PubMed Central  PubMed  Google Scholar 

  108. Zurich MG, Honegger P, Schilter B, Costa LG, Monnet-Tschudi F (2000) Use of aggregating brain cell cultures to study developmental effects of organophosphorus insecticides. Neurotoxicology 21:599–605

    CAS  PubMed  Google Scholar 

  109. Gross GW, Williams AN, Lucas JH (1982) Recording of spontaneous activity with photoetched microelectrode surfaces from mouse spinal neurons in culture. J Neurosci Methods 5:13–22

    CAS  PubMed  Google Scholar 

  110. Potter SM, DeMarse TB (2001) A new approach to neural cell culture for long-term studies. J Neurosci Methods 110:17–24

    CAS  PubMed  Google Scholar 

  111. Keefer EW, Gramowski A, Gross GW (2001) NMDA receptor-dependent periodic oscillations in cultured spinal cord networks. J Neurophysiol 86:3030–3042

    CAS  PubMed  Google Scholar 

  112. Streit J (1993) Regular oscillations of synaptic activity in spinal networks in vitro. J Neurophysiol 70:871–878

    CAS  PubMed  Google Scholar 

  113. van Vliet E, Stoppini L, Balestrino M, Eskes C, Griesinger C, Sobanski T, Whelan M, Hartung T, Coecke S (2007) Electrophysiological recording of re-aggregating brain cell cultures on multi-electrode arrays to detect acute neurotoxic effects. Neurotoxicology 28:1136–1146

    PubMed  Google Scholar 

  114. McConnell ER, McClain MA, Ross J, Lefew WR, Shafer TJ (2012) Evaluation of multi-well microelectrode arrays for neurotoxicity screening using a chemical training set. Neurotoxicology 33:1048–1057

    CAS  PubMed Central  PubMed  Google Scholar 

  115. Novellino A, Scelfo B, Palosaari T, Price A, Sobanski T, Shafer TJ, Johnstone AF, Gross GW, Gramowski A, Schroeder O, Jugelt K, Chiappalone M, Benfenati F, Martinoia S, Tedesco MT, Defranchi E, D’Angelo P, Whelan M (2011) Development of micro-electrode array based tests for neurotoxicity: assessment of interlaboratory reproducibility with neuroactive chemicals. Front Neuroeng 4:4

    CAS  PubMed Central  PubMed  Google Scholar 

  116. Defranchi E, Novellino A, Whelan M, Vogel S, Ramirez T, van Ravenzwaay B, Landsiedel R (2011) Feasibility assessment of micro-electrode chip assay as a method of detecting neurotoxicity in vitro. Front Neuroeng 4:6

    CAS  PubMed Central  PubMed  Google Scholar 

  117. Robinette BL, Harrill JA, Mundy WR, Shafer TJ (2011) In vitro assessment of developmental neurotoxicity: use of microelectrode arrays to measure functional changes in neuronal network ontogeny. Front Neuroeng 4:1

    PubMed Central  PubMed  Google Scholar 

  118. Xia Y, Gopal KV, Gross GW (2003) Differential acute effects of fluoxetine on frontal and auditory cortex networks in vitro. Brain Res 973:151–160

    CAS  PubMed  Google Scholar 

  119. Gross GW, Harsch A, Rhoades BK, Gopel W (1997) Odor, drug and toxin analysis with neuronal networks in vitro: extracellular array recording of network responses. Biosens Bioelectron 12:373–393

    CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. European Union Reference Laboratory for Alternatives to Animal Testing (EURL ECVAM), Systems Toxicology Unit, Institute for Health and Consumer Protection, Joint Research Centre, European Commission, Via E. Fermi 2749, 21027, Ispra (VA), Italy

    Anna Bal-Price

  2. Center for Alternative to Animal Testing (CAAT), Department of Environmental Health Science, Bloomberg School of Public Health, The Johns Hopkins University, Baltimore, MD, USA

    Helena T. Hogberg

Authors
  1. Anna Bal-Price
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Helena T. Hogberg
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Anna Bal-Price .

Editor information

Editors and Affiliations

  1. European Commission Joint Research Centre, Ispra, Varese, Italy

    Anna Bal-Price

  2. Innsbruck Medical University, Innsbruck, Austria

    Paul Jennings

Rights and permissions

Reprints and permissions

Copyright information

© 2014 Springer Science+Business Media New York

About this protocol

Cite this protocol

Bal-Price, A., Hogberg, H.T. (2014). In Vitro Developmental Neurotoxicity Testing: Relevant Models and Endpoints. In: Bal-Price, A., Jennings, P. (eds) In Vitro Toxicology Systems. Methods in Pharmacology and Toxicology. Humana Press, New York, NY. https://doi.org/10.1007/978-1-4939-0521-8_6

Download citation

  • DOI: https://doi.org/10.1007/978-1-4939-0521-8_6

  • Published:

  • Publisher Name: Humana Press, New York, NY

  • Print ISBN: 978-1-4939-0520-1

  • Online ISBN: 978-1-4939-0521-8

  • eBook Packages: Springer Protocols

Publish with us

Policies and ethics

Search

Navigation