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The Welfare Problems Associated with Using Transgenic Mice to Bioassay for Bovine Spongiform Encephalopathy

Published online by Cambridge University Press:  11 January 2023

E S Jenkins  and
R D Combes
E S Jenkins*
Affiliation:
FRAME, Russell & Burch House, 96-98 North Sherwood Street, Nottingham NG1 4EE, UK
R D Combes
Affiliation:
FRAME, Russell & Burch House, 96-98 North Sherwood Street, Nottingham NG1 4EE, UK
*
† Contact for correspondence and requests for reprints
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Abstract

Prion diseases are fatal neurodegenerative disorders, epitomized by the recent bovine spongiform encephalopathy (BSE) epidemic in cattle and the emergence of a novel variant of Creutzfeldt-Jacob disease (vCJD) in humans. In prion disease, the agent of infection is believed to be composed of proteinaceous particles, termed prions, which are converted from a normal isoform into a pathogenic isoform during pathogenesis. A bioassay to detect pathogenic prions of BSE in bovine products consumed by humans was unattainable until the development of transgenic mice, due to the significantly lower susceptibility of wild-type mice to BSE. Transgenic mice have now been generated which express the bovine prion protein and are susceptible to BSE. Following an intracerebral injection with brain homogenate of BSE-infected cattle, transgenic mice develop numerous clinical signs of prion disease, including truncal ataxia (inability to coordinate the torso's muscular activity), increased tone of the tail, generalized tremor, and lack of a forelimb extensor response.

In this study, the ethical score system devised by Porter (1992) was applied to the BSE bioassay as a tool for identifying welfare issues affecting animals used in the bioassay. We acknowledge that there are limitations to the use of the information arising from the application of the Porter scoring scheme for assessing the justification to proceed with any animal experiment; notwithstanding these problems, however, our application of the Porter model to the BSE bioassay enabled us to identify potential targets for refinement: pain involved, duration of distress and the duration of the experiment. This was despite lenient scoring for the duration of distress and pain experienced by the mice, and optimal scoring for the quality of animal care. The targets identified for refinement are discussed in relation to the method of inoculation, the duration of the bioassay, and the duration of the clinical phase, with the objective of exploring ways of reducing the severity of the bioassay.

Keywords

animal welfareBSE bioassayprion diseasetransgenic mice
Type
Research Article
Information
Animal Welfare , Volume 8 , Issue 4: Special Issue: Genetics and Animal Welfare , November 1999 , pp. 421 - 431
Copyright
© 1999 Universities Federation for Animal Welfare

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References

Anonymous CJD Statistics, http://www.cjd.ed.ac.uk/figures.htmGoogle Scholar
Baldauf, E, Beekes, M and Diringer, H 1997 Evidence for an alternative direct route of access for the scrapie agent to the brain bypassing the spinal cord. Journal of General Virology 78: 1187–1197CrossRefGoogle Scholar
Baumans, V, Brain, P F, Brugére, H, Clausing, P, Jeneskog, T and Perretta, G 1994 Pain and distress in laboratory rodents and lagomorphs. (FELASA Working Party report). Laboratory Animals 28: 97–112CrossRefGoogle Scholar
Bruce, M E, Will, R G, Ironside, J W, McConnell, I, Drummond, D, Suttie, A, McCardle, L, Chree, A, Hope, J, Birkert, C, Cousens, S, Fraser, H and Bostock, C J 1997 Transmissions to mice indicate that ‘new variant’ CJD is caused by the BSE agent. Nature 389: 498–501CrossRefGoogle ScholarPubMed
Collinge, J, Sidle, KCL, Meads, J, Ironside, J and Hill, A F 1996 Molecular analysis of prion strain variation and the aetiology of ‘new variant’ CJD. Nature 383: 685–690CrossRefGoogle ScholarPubMed
De Cock Buning, T and Theune, E 1994 A comparison of three models for ethical evaluation of proposed animal experiments. Animal Welfare 3: 107–128CrossRefGoogle ScholarPubMed
Farquhar, C F, Dornan, J, Moore, R C, Somerville, R A, Tunstall, A M and Hope, J 1996 Protease-resistant PrP deposition in brain and non-central nervous system tissues of a murine model of bovine spongiform encephalopathy. Journal of General Virology 77: 1941–1946CrossRefGoogle ScholarPubMed
Fraser, H, Bruce, M E, Chree, A, McConnell, I and Wells, GAH 1992 Transmission of bovine spongiform encephalopathy and scrapie to mice. Journal of General Virology 73: 1891–1897CrossRefGoogle ScholarPubMed
Hill, A F, Desbrulais, M, Joiner, S, Sidle, K C, Gowland, I, Collinge, J, Doey, L J and Lantos, P 1997 The same strain causes vCJD and BSE. Nature 389: 448–450CrossRefGoogle ScholarPubMed
Home Office 1986 Animals (Scientific Procedures) Act 1986. HMSO: London, UKGoogle Scholar
Kimberlin, R H and Walker, C A 1979 Pathogenesis of mouse scrapie: dynamics of agent replication in spleen, spinal cord and brain after infection by different routes. Journal of Comparative Pathology 89: 551–562CrossRefGoogle ScholarPubMed
Kimberlin, R H and Walker, C A 1986 Pathogenesis of scrapie (strain 263K) in hamsters infected intracerebrally, intraperitoneally or intraocularly. Journal of General Virology 67: 255–263CrossRefGoogle ScholarPubMed
Lasmézas, C I, Deslys, J-P, Demaimay, R, Adjou, K T, Hauw, J-J and Dormont, D 1996 Strain specific and common pathogenic events in murine models of scrapie and bovine spongiform encephalopathy. Journal of General Virology 77: 1601–1609CrossRefGoogle ScholarPubMed
Lasmézas, C I, Deslys, J P, Robain, O, Jaegly, A, Beringue, V, Peyrin, J M, Fournier, J G, Hauw, J-J, Rossier, J and Dormont, D 1997 Transmission of the BSE agent to mice in the absence of detectable abnormal prion protein. Science 275: 402–405CrossRefGoogle ScholarPubMed
MacKenzie, D 1998a In the nick of time: Switzerland’s latest mad cow may have nasty lessons for Europe. New Scientist 2156: 16Google Scholar
MacKenzie, D 1998b Hard to swallow. New Scientist 2160: 22–23Google Scholar
Mepham, T B, Combes, R D, Balls, M, Barbieri, O, Blockhuis, H J, Costa, P, Crilly, R E, de Cock Buning, T, Delpire, V C, O’Hare, M J, Houdebine, L-M, Van Kreijl, C F, Van der Meer, M, Reinhardt, C A, Wolf, E, Van, Zeller A-M 1998 The use of transgenic animals in the European Union. The report and recommendations of ECVAM Workshop 28. ATLA 26: 33–34Google ScholarPubMed
Moore, R C and Melton, D W 1997 Transgenic analysis of prion diseases. Molecular Human Reproduction 3: 529–544CrossRefGoogle ScholarPubMed
OECD 1998 Recognition, Assessment and Use of Clinical Signs as Humane endpoints for Experimental Animals Used in Safety Evaluation Studies. (Draft guidance document compiled by Bos-Kuijpers M, Morton D, Schiede E and Stokes W S available at: http://www.0ecd.0rg//ehs/ehsm0n0/gdhumane.d0c)Google Scholar
Pan, K M, Baldwin, M, Nguyen, J, Gasset, M, Serban, A, Groth, D, Mehlhorn, I, Huang, Z, Fletterick, R J, Cohen, F E et al 1993 Conversion of alpha-helices into beta-sheets features in the formation of the scrapie prion proteins. Proceedings of the National Academy of Science USA 90·. 10962–10966CrossRefGoogle Scholar
Porter, D G 1992 Ethical scores for animal experiments. Nature 356:101-102CrossRefGoogle Scholar
Prusiner, S B 1982 Novel proteinaceous infectious particles cause scrapie. Science 216: 136–144CrossRefGoogle ScholarPubMed
Prusiner, S B, Groth, D F, Bolton, D C, Kent, S B and Hood, L E 1984 Purification and structural studies of a major scrapie prion protein. Cell 38: 127–134CrossRefGoogle ScholarPubMed
Prusiner, S B, McKinley, M P, Groth, D F, Bowman, K A, Mock, N I, Cochran, S P and Masiarz, F R 1981 Scrapie agent contains a hydrophobic protein. Proceedings of the National Academy of Science USA 78: 6675–6679CrossRefGoogle ScholarPubMed
Prusiner, S B, Scott, M, Foster, D, Pan, K-M, Groth, D, Mirenda, C, Torchia, M, Yang, S-L, Serban, D, Carlson, G A, Hoppe, P C, Westaway, D and DeArmond, S J 1990 Transgenic studies implicate interactions between homologous PrP isoforms in scrapie prion replication. Cell 63: 673–686CrossRefGoogle ScholarPubMed
Russell, W M S and Burch, R L 1959 The Principles of Humane Experimental Technique: Methuen and Co Ltd: London, UKGoogle Scholar
Safar, J, Wille, H, Itri, V, Groth, D, Serban, H, Torchia, M, Cohen, F E, and Prusiner, S B 1998 Eight prion strains have PrPSc molecules with different conformations. Nature Medicine 4: 1157–1165CrossRefGoogle ScholarPubMed
Schweitzer, A 1989 The ethic of reverence for life. In: Regan, T and Singer, P (eds) Animal Rights and Human Obligations pp 32–37. Prentice-Hall International: London, UKGoogle Scholar
Scott, M, Foster, D, Mirenda, C, Serban, D, Coufal, F, Walchli, M, Torchia, M, Groth, D, Carlson, G, DeArmond, S J, Westaway, D and Prusiner, S B 1989 Transgenic mice expressing hamster prion protein produce species-specific scrapie infectivity and amyloid plaques. Cell 59: 847–857CrossRefGoogle ScholarPubMed
Scott, M R, Safar, J, Telling, G, Nguyen, O, Groth, D, Torchia, M, Koehler, K, Tremblay, P, Walther, D, Cohen, F E, DeArmond, S J and Prusiner, S B 1997 Identification of a prion protein epitope modulating transmission of bovine spongiform encephalopathy prions to transgenic mice. Proceedings of the National Academy of Science USA 94: 14279–14284CrossRefGoogle ScholarPubMed
Smaje, L H, Smith, J A, Combes, R D, Ewbank, R, Gregory, J A, Jennings, M, Moore, G and Morton, D B 1998 Advancing refinement of laboratory animal use. (Boyd Working Party report). Laboratory Animals 32: 137–142CrossRefGoogle Scholar
Smith, J A and Boyd, KM 1991 The assessment and ‘weighing’ of costs and benefits. In: Lives in the Balance: The Ethics of Using Animals in Biomedical Research pp 138–147. Oxford University Press: Oxford, UKGoogle ScholarPubMed
Telling, G C, Scott, M, Hsiao, K K, Foster, D, Yang, S L, Torchia, M, Sidle, KCL, Collinge, J, DeArmond, S J and Prusiner, S B 1994 Transmission of Creutzfeldt-Jacob disease from humans to transgenic mice expressing chimeric human-mouse prion protein. Proceedings of the National Academy of Science USA 91: 9936–9940CrossRefGoogle ScholarPubMed
Theune E P and de Cock Buning Tj 1991 Grenzen aan dierexperimenteel onderzoek Toetsingsprocedure. Dierproefvraagstukken RUL: Leiden, The NetherlandsGoogle Scholar
Theune E P and de Cock Buning Tj 1993 Assessing interests. An operational approach. In: Hicks, E K (ed) Science and the Human-Animal Relationship pp 143–160. SISWO (Inter-university Social Science Research Foundation): Amsterdam, The NetherlandsGoogle Scholar
Wallace, J, Sanford, J, Smith, M W and Spencer, K V 1990 The assessment and control of the severity of scientific procedures on laboratory animals. (LASA Working Party report). Laboratory Animals 24: 97–130Google Scholar
Wells, GAH, Scott, A C, Johnson, C T, Gunning, R F, Hancock, R D, Jeffrey, M, Dawson, M and Bradley, R 1987 A novel progressive spongiform encephalopathy in cattle. Veterinary Record 121: 419–420CrossRefGoogle ScholarPubMed
Williams, N 1997 New studies affirm BSE-human link. Science 278:31CrossRefGoogle Scholar