Skip to main content
SpringerLink
Log in

Cell models in the study of mechanisms of toxicity

  • Regulation of Respiration
  • Models in Toxicology
  • Published:
Agents and Actions Aims and scope Submit manuscript

Abstract

Cell models, particularly in vitro systems, allow studies of toxicological mechanisms to be made under controlled conditions. One way that such mechanisms can be studied is by determining the reproducible changes that toxins induce, at the electron microscopic level, in the structure of cultured cells. A detailed description of such a study is given and includes preparation of the cell model, treatment of the cells, assessment of toxin-induced changes, and some general conclusions derived from experiments with this cell model.

Other models which have been used for toxicological studies are also discussed with reference to advantages, limitations and potential applications.

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

Similar content being viewed by others

References

  1. J.M. Angevine, A. Kappas, R.L. DeGowin andB.H. Spargo,Renal Tubular Nuclear Inclusion of Lead Poisoning, Arch. Pathol.73, 486–494 (1972).

    Google Scholar 

  2. D.L. Beaver andR.E. Burr,Electron Microscopy of Bismuth Inclusions, Am. J. Pathol.42, 609–617 (1963).

    PubMed  Google Scholar 

  3. S.S. Blackman,Intranuclear Inclusion Bodies in the Kidney and Liver Caused by Lead Poisoning, Bull. Johns Hopkins Hosp.58, 384–404 (1936).

    Google Scholar 

  4. N. Brock andH.-J. Hohorst,Metabolism of Cyclophosphamide, Cancer20, 900–904 (1967).

    PubMed  Google Scholar 

  5. I.K. Buckley,A Simple Technique of Comparative Light and Electron Microscopy of Designated Living Cultured Cells, Lab. Invest.25, 295–301 (1971).

    PubMed  Google Scholar 

  6. I.K. Buckley andJ.R. Walton,A Simple Method for Culturing Chick Embryo Liver and Kidney Parenchymal Cells for Microscopic Studies, Tissue and Cell,6, 641–652 (1974).

    PubMed  Google Scholar 

  7. L.W. Chang andH.A. Hartmann,Electron Microscopic Histochemical Localisation and Distribution of Mercury in the Nervous System after Mercury Intoxication, Exp. Neurol.35, 122–137 (1972).

    PubMed  Google Scholar 

  8. J. Chayen andL. Bitensky,Multiphasic Chemistry, in:The Biological Basis of Medicine (Eds. Bittar and Bittar: Academic Press, London 1968), pp. 337–368.

    Google Scholar 

  9. T.B. Clarkson,Animal Models of Atherosclerosis, Adv. Vet. Sci. and Comp. Med.16, 151–173 (1972).

    Google Scholar 

  10. H. Eagle,Metabolic Controls in Cultured Mammalian Cells, Science148, 42–51 (1965).

    PubMed  Google Scholar 

  11. R.W. Ellis andS.C. Fang,The Metabolism of [ 14 C] Lactate by Rat Kidney Slices after Acute Mercurial Intoxication, Toxic. appl. Pharmac.24, 230–238 (1973).

    Google Scholar 

  12. A.P. Evan,The Effect, of Lithium Carbonate on the Ultrastructural Transformation of Kidney Mitochondria, Toxic. appl. Pharmac.24, 413–422 (1973).

    Google Scholar 

  13. E.A. Evans, G. Eisenlord andC.H. Hine,Studies in Detoxication by Means of the Isolated Perfused Liver, Toxic. appl. Pharmac.5, 129–141 (1963).

    Google Scholar 

  14. E.T. Everett, C.M. Pomerat, F.N. Hu andC.S. Livingood,Tissue Culture Studies on Human Skin. I. A Method of Evaluating the Toxicity of Certain Drugs Employed Locally on the Skin, Tex. Rep. Biol. Med.9, 281–291 (1951).

    PubMed  Google Scholar 

  15. H.B. Fell andE. Mellanby,The Effect of Hypervitaminosis A on Embryonic Limbbones Cultivated in vitro, J. Physiol.116, 320–349 (1952).

    PubMed  Google Scholar 

  16. D.O.E. Gebhardt,The Use of the Chick Embryo in Applied Teratology, Adv. Teratol.5, 97–111 (1972).

    Google Scholar 

  17. D.O.E. Gebhardt andM.J. Van Logten,The Chick Embryo Test as Used in the Study of the Toxicity of Certain Dithiocarbamates, Toxic. appl. Pharmac.13, 316–24 (1968).

    Google Scholar 

  18. R.W. Gillette andD. Goulian,A Study of the Functional Capacities of Spleen Cells after Maintenance in vitro, Proc. Soc. Exp. Biol. Med.123, 64–66 (1966).

    PubMed  Google Scholar 

  19. F.L. Ginn, J.D. Shelburne andB.F. Trump,Disorders of Cell Volume Regulation. I. Effects of Inhibition of Plasma Membrane Adenosine Triphosphate with Ouabain. Am. J. Pathol.53, 1041–1071 (1968).

    PubMed  Google Scholar 

  20. L.S. Goodman andA. Gilman,The Pharmacological Basis of Therapeutics (4th Ed., Macmillan Co., New York 1972).

    Google Scholar 

  21. R.A. Goyer,The Renal Tubule in Lead Poisoning. I. Mitochondrial Swelling and Aminoaciduria, Lab. Invest.19, 71–77 (1968).

    PubMed  Google Scholar 

  22. R.A. Goyer andB.C. Rhyne,Pathological Effects of Lead, Int. Rev. Exp. Pathol.12, 1–77 (1973).

    PubMed  Google Scholar 

  23. S. Granick, A. Kappas andR. Levere,Regulation of Porphyrin and Heme Biosynthesis: a New Control Function of Steroids, Science156, 538 (1967).

    Google Scholar 

  24. A. Hadani andM.N. Egyed,Use of the Chick Embryo for Testing the Toxicity of Cholinesteraseinhibiting Compounds, Toxicol. Appl. Pharmacol.10, 313–321 (1967).

    PubMed  Google Scholar 

  25. U. Heine, A.J. Langlois andJ.W. Beard,Ultrastructural Alterations in Avian Leukemic Myeloblasts Exposed to Actinomycin in vitro, Cancer Res.26, 1847–1858 (1966).

    PubMed  Google Scholar 

  26. R. House,Water Transport in Cells and Tissues (Edward Arnold Ltd., London 1974).

    Google Scholar 

  27. Z. Hruban, H. Swift andA. Slesers,Effect of Triparanol and Diethanolamine on the Fine Structure of Hepatocytes and Pancreatic Acinar Cells, Lab. Invest.14, 1652–1672, (1965).

    PubMed  Google Scholar 

  28. F. Hu, C.S. Livingood, P. Johnson andC.M. Pomerat,Tissue Culture Studies on Human Skin IV. The Comparative Toxic Effects of Antibiotics on Tissue Culture Explants of Human Skin and Embryonic Chick Spleen, J. Invest. Dermatol.20, 357–372 (1953).

    PubMed  Google Scholar 

  29. A.-M. Jézéquel andW. Bernhard,Modifications ultrastructurales du pancréas exocrine de rat sous l'effet de l'actinomycine D, J. Microsc.3, 279–296 (1964).

    Google Scholar 

  30. A.I. Kahri,Effects of Actinomycin D and Puromycin on the ACTH-induced Ultrastructural Transformation of Mitochondria of Cortical Cells of Rat Adrenals in Tissue Culture, J. Cell Biol.36, 181–195 (1968).

    Google Scholar 

  31. H.R. Kinns andJ.R. Walton,Computer Analysis in the Electron Microscopic Assessment of Cellular Injury, Comput. Biol. Med. Submitted for publication, 1974.

  32. G.D. Kudzina andD.I. Golovan,Comparative Sanitarytoxicological and Cell-culture Evaluation of the Chlorobenzoic Acid Herbicides, Vrach. Delo1, 125–128 (1972).

    PubMed  Google Scholar 

  33. M.L. Maayan andS.H. Ingbar,Effects of Epinephrine on Iodine and Intermediary Metabolism in Isolated Thyroid Cells, Endocrinol.87, 588–595 (1970).

    Google Scholar 

  34. R.L. McCarl, B.F. Szuhaj andR.T. Houlihan,Steroid Stimulation of Beating of Cultured Rat-Heart Cells, Science150, 1611–1613 (1965).

    PubMed  Google Scholar 

  35. E.M. McDowell,Light and Electron Microscopic Studies of the Rat Kidney after Administration of Inhibitors of the Citric Acid Cycle in vivo. I. Effects of Sodium Fluoroacetate on the Proximal Convoluted Tubule, Am. J. Pathol.66, 513–542 (1972).

    PubMed  Google Scholar 

  36. J. McLaughlin, J.P. Marliac, M.J. Verrett, M. Mutchler andO.G. Fitzhugh,The Injection of Chemicals into the Yolk Sac of Fertile Eggs Prior to Incubation as a Toxicity Test, Toxic. appl. Pharmac.5, 760–771 (1963).

    Google Scholar 

  37. T.H. Massey andS.C. Fang,A Comparative Study of the Subcellular Binding of Phenylmercuric Acetate and Mercuric Acetate in Rat Liver and Kidney Slices, Toxic. appl. Pharmac.12, 7–14 (1968).

    Google Scholar 

  38. S.M. Metcalfe,Cell Culture as a Test System for Toxicity, J. Pharm. Pharmac.23, 817–823 (1971).

    Google Scholar 

  39. M.C. Michaelides andA.H. Coons,Studies on Antibody Production. V. The Secondary Response in vitro, J. Exp. Med.117, 1035–1051 (1963).

    PubMed  Google Scholar 

  40. A.J. Milner andD.B. Villee,Steroidogenic and Morphologic Effects of ACTH on Human Fetal Adrenal Cells Grown in Tissue Culture, Endocrinol.87, 596–601 (1970).

    Google Scholar 

  41. J. Muriel,Amoeba Proteus as a Cell Model in Toxicology, in:Symposium on Mechanisms of Toxicity (Ed., W.H. Aldridge, St. Martin's Press, New York 1971).

    Google Scholar 

  42. M.R. Murray andG. Kopeck,A Bibliography of the Research in Tissue Culture. 1884–1950: An Index to the Living Cell Cultivated in vitro I, II (Academic Press, New York 1953).

    Google Scholar 

  43. J. Nagler,Effect of Hyperbaric Oxygen on Cultured Foetal Hearts, Nature242, 197–198 (1973).

    PubMed  Google Scholar 

  44. T. Narahashi,Effect of the Insecticide Allethrin on Membrane Potentials of Cockroach Giant Axons, J. cell. comp. Physiol.59, 61–65 (1962).

    PubMed  Google Scholar 

  45. T. Narahashi andN.C. Anderson,Mechanism of Excitation Block by the Insecticide Allethrin Applied Externally and Internally to Squid Giant Axons, Toxic. appl. Pharmac.10, 529–547 (1967).

    Google Scholar 

  46. K.A. Palmer, S. Green andM.S. Legator,Cytogenic Effects of DDT and Derivatives of DDT in a Cultured Mammalian Cell Line, Toxic. appl. Pharmac.22, 355–364 (1972).

    Google Scholar 

  47. J. Paul,Cell and Tissue Culture (4th Ed., Williams and Wilkins Co., Baltimore 1972).

    Google Scholar 

  48. C.M. Pomerat andC.D. Leake,Short Term Cultures for Drug Assays: General Considerations, Ann. N.Y. Acad. Sci.58, 1110–1128 (1954).

    PubMed  Google Scholar 

  49. K.T. Rajan, J.C. Wagner andP.H. Evans,The Response of Human Pleura in Organ Culture to Asbestos, Nature238, 346–347 (1972).

    PubMed  Google Scholar 

  50. L. Recher, N.T. Parry, L.G. Briggs andJ. Whitescarver,Differences in Effects of Proflavine and Actinomycin D on Mammalian Cell Nucleoli, Cancer Res.31, 1915–1922 (1971).

    PubMed  Google Scholar 

  51. I.M. Reid, D.S. Sarma andH. Sidransky,Actinomycin D and Hepatic Polyribosomal Disaggregation. Evidence for Different Half-lives of mRNA of Free and Membrane-bound Polyribosomes, Lab. Invest.25, 141–148 (1971).

    PubMed  Google Scholar 

  52. G. Rose,A Separable and Multipurpose Tissue Culture Chamber, Texas Repts. Biol. Med.12, 1074–1083 (1954).

    Google Scholar 

  53. S. Sahaphong andB.F. Trump,Studies of Cellular Injury in Isolated Kidney Tubules of the Flounder. V. Effects of Inhibiting Sulfhydryl Groups of Plasma Membrane with Organic Mercurials PCMB (Parachloromercuribenzoate) and PCMBS (Parachloromercuribenzensulfonate), Am. J. Pathol.63, 277–298 (1971).

    PubMed  Google Scholar 

  54. A.J. Saladino, P.J. Bentley andB.F. Trump,Ion Movements in Cell Injury. Effect of Amphotericin B on the Ultrastructure and Function of the Epithelial Cells of the Toad Bladder, Am. J. Pathol.54, 421–466 (1969).

    PubMed  Google Scholar 

  55. A.J. Saladino, H.K. Hawkins andB.F. Trump,Ion Movements in Cell Injury. Effects of the Cationic Detergent Cetyl Pyridinium Chloride on the Ultrastructure and Function of the Toad, Bladder, Am. J. Pathol.64, 271–299 (1971).

    PubMed  Google Scholar 

  56. A.J. Saladino andB.F. Trump,Ion Movements in Cell Injury. Effects of Inhibition of Respiration and Glycolysis on the Ultrastructure and Function of the Epithelial Cells of the Toad Bladder, Am. J. Pathol.52, 737–776 (1968).

    PubMed  Google Scholar 

  57. W.W. Schlaepfer,Sequential Study of Endothelial Changes in Acute Cadmium Intoxication, Lab. Invest.25, 556–564 (1971).

    PubMed  Google Scholar 

  58. J.L. Schmidt, F.C. McIntire, D.L. Martin, M.A. Hawthorne andR.K. Richards,The Relationships Among Different in vivo Properties of Local Anesthetics and Toxicity to Cell Cultures in vitro, Toxic. appl. Pharmac.1, 454–461 (1959).

    Google Scholar 

  59. G. Schoefl,The Effect of Actinomycin D on the Fine Structure of the Nucleolus, J. Ultrastruct. Res.10, 224–243 (1964).

    PubMed  Google Scholar 

  60. C.S. Shipman,Evaluation of 4-(2-Hydroxyethyl)-1-piperazine-ethanesulfonic Acid (HEPES) as a Tissue Culture Buffer, Proc. Soc. Exp. Biol. Med.130, 305–310 (1969).

    PubMed  Google Scholar 

  61. R. Simard,The Nucleus: Action of Chemical and Physical Agents, Int. Rev. Cytol.28, 169–211 (1970).

    PubMed  Google Scholar 

  62. A. Strother,In vitro Metabolism of Methylcarbamate Insecticides by Human and Rat Liver Fraction, Toxic. appl. Pharmac.21, 112–129 (1972).

    Google Scholar 

  63. T. Sugimura,Is Carcinogenesis Related to Somatic Mutation? UICC Bulletin of Cancer 1–3 (June, 1974).

  64. J.D. Thrasher,The Effects of Mercuric Compounds on Dividing Cells in:Drugs and the Cell Cycle (Eds., Zimmermann, Padilla and Cameron, Academic Press, New York 1973), pp. 25–48.

    Google Scholar 

  65. B.F. Trump andR.E. Bulger,Studies of Cellular Injury in Isolated Flounder Tubules. IV. Electron Microscopic Observations of Changes During the Phase of Altered Homeostasis in Tubules Treated with Cyanide, Lab. Invest.18, 731–739 (1968).

    PubMed  Google Scholar 

  66. S.D. Wainwright andL.K. Wainwright,Regulation of the Initiation of Hemoglobin Synthesis in the Blood Island Cells of Chick Embryos. V. Qualitative Studies of the Effects of Proflavine, Can. J. Biochem.45, 1483–1493 (1967).

    PubMed  Google Scholar 

  67. S.D. Wainwright andL.K. Wainwright,Regulation of Onset of Rapid Hemoglobin Formation in Chick Blastodisc Blood Islands at the Transcription and Translation Levels. A Quantitative Analysis of Effects of Actinomycin, Ethanol and Heme Precursors, Can. J. Biochem.50, 1165–1173 (1972).

    PubMed  Google Scholar 

  68. S.D. Wainwright, L.K. Wainwright andI.H. Fraser,Hemoglobin Formation in the Explanted Chick Blastodisc: A Model System for Evaluation of Embryo-toxic Agents as Illustrated by Effects of Vinblastine, 1,1,1-Trichloro-2,2-bis-(p-chlorophenyl) ethane (DDT) and Sodium Diethylbarbiturate, Toxic. appl. Pharmac.21, 112–129 (1972).

    Google Scholar 

  69. N.E. Walker,Distribution of Chemicals Injected into Fertile Eggs and Its Effect Upon Apparent Toxicity, Toxic. appl. Pharmac.10, 290–299 (1967).

    Google Scholar 

  70. J.R. Walton,Granules Containing Lead in Isolated Mitochondria, Nature243, 100–101 (1973).

    PubMed  Google Scholar 

  71. J.R. Walton,Intranuclear Inclusions in the Lead-poisoned Cultured Kidney Cell, J. Path.112, 213–215 (1974).

    PubMed  Google Scholar 

  72. J.R. Walton,Thesis. Subcellular Injury. Ultrastructural Changes Induced in Cultured Cells by Metabolic Inhibitors and Other Agents, The Australian National University, Canberra, ACT, Australia (1974).

    Google Scholar 

  73. J.R. Walton,Unpublished Observations (1974).

  74. J.R. Walton,The Systematic Appraisal of Cellular Injury, submitted for publication (1975).

  75. J.R. Walton,Can Microbodies Arise from Mitochondria? In preparation (1975).

  76. W.M. Watrous andG.L. Plaa,Effect of Halogenated Hydrocarbons on Organic Ion Accumulation by Renal Cortical Slices of Rats and Mice, Toxicol. Appl. Pharmac.22, 528–543 (1972).

    Google Scholar 

  77. D.G. Wenzel, J.W. Wheatley andG.D. Byrd,Effects of Nicotine on Cultured Rat Heart Cells, Toxic. appl. Pharmac.17, 774–785 (1970).

    Google Scholar 

  78. E.N. Willmer,Cells and Tissues in Culture: Methods, Biology and Physiology, I–III (Academic Press, London 1966).

    Google Scholar 

  79. R.D. Yates, I.-L. Chen andJ.A. Mascorro,Some Morphological Effects of 20,25-Diazacholesterol (SC-12937) on Adrenocortical Cells of the Syrian Hamster, Texas Repts. Biol. Med.26, 241–248 (1968).

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Experimental Pathology, John Curtin School of Medical Research, Australian National University, 2601, Canberra, Australia

    J. R. Walton & I. K. Buckley

Authors
  1. J. R. Walton
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. I. K. Buckley
    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

Walton, J.R., Buckley, I.K. Cell models in the study of mechanisms of toxicity. Agents and Actions 5, 69–88 (1975). https://doi.org/10.1007/BF02027163

Download citation

  • Received:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF02027163

Keywords

Search

Navigation