Toxicological Research

Korean Society of Toxicology & Korea Environmental Mutagen Society (한국독성학회)
권호 표지
DOI QR코드

DOI QR Code

Studies on the Small Body Size Mouse Developed by Mutagen N-Ethyl-N-nitrosourea

  • Zhang, Qian-Kun (Department of Research & Development, Korea Institute of Toxicology, Korea Research Institute of Chemical Technology) ;
  • Cho, Kyu-Hyuk (Department of Research & Development, Korea Institute of Toxicology, Korea Research Institute of Chemical Technology) ;
  • Cho, Jae-Woo (Department of Research & Development, Korea Institute of Toxicology, Korea Research Institute of Chemical Technology) ;
  • Cha, Dal-Sun (Department of Research & Development, Korea Institute of Toxicology, Korea Research Institute of Chemical Technology) ;
  • Park, Han-Jin (Department of Research & Development, Korea Institute of Toxicology, Korea Research Institute of Chemical Technology) ;
  • Yoon, Seok-Joo (Department of Research & Development, Korea Institute of Toxicology, Korea Research Institute of Chemical Technology) ;
  • Zhang, ShouFa (Department of Veterinary Medicine, YanBian University) ;
  • Song, Chang-Woo (Department of Research & Development, Korea Institute of Toxicology, Korea Research Institute of Chemical Technology)
  • Published : 2008.03.31
Download PDF
⟨ Previous Next ⟩

Abstract

Mutant mouse which show dwarfism has been developed by N-ethyl-N-nitrosourea (ENU) mutagenesis using BALB/c mice. The mutant mouse was inherited as autosomal recessive trait and named Small Body Size (SBS) mouse. The phenotype of SBS mouse was not apparent at birth, but it was possible to distinguish mutant phenotype from normal mice 1 week after birth. In this study, we examined body weight changes and bone mineral density (BMD), and we also carried out genetic linkage analysis to map the causative gene(s) of SBS mouse. Body weight changes were observed from birth to 14 weeks of age in both affected (n = 30) and normal mice (n = 24). BMD was examined in each five SBS and normal mice between 3 and 6 weeks of age, respectively. For the linkage analysis, we produced backcross progeny [(SBS${\times}$C57BL/6J) $F_1{\times}$ SBS] $N_2$ mice (n = 142), and seventy-four microsatellite markers were used for primary linkage analysis. Body weight of affected mice was consistently lower than that of the normal mice, and was 43.7% less than that of normal mice at 3 weeks of age (P < 0.001). As compared with normal mice at 3 and 6 weeks of age, BMD of the SBS mice was significantly low. The results showed 15.5% and 14.1 % lower in total body BMD, 15.3% and 8.7% lower in forearm BMD, and 29.7% and 20.1% lower in femur BMD, respectively. The causative gene was mapped on chromosome 10. The map order and the distance between markers were D10Mit248 - 2.1 cM - D10Mit51 - 4.2 cM - sbs - 0.7 cM - D10Mit283 - 1.4cM - D10Mit106 - 11.2cM - D10Mit170.

Keywords

References

  1. Argentin, G. and Cicchetti, R. (2000). In vitro proliferation of achondroplastic and normal mouse chondrocytes, before and after basic fibroblast growth factor stimulation. Cell Prolif., 33, 397-405 https://doi.org/10.1046/j.1365-2184.2000.00185.x
  2. Beamer, W.G., Shultz, K.L., Churchill, G.A. and Donahue, L.R. (1999). Quantitative trait loci for bone density in C57BL/6J and CAST/EiJ inbred mice. Mamm. Genome., 10, 1043-1049 https://doi.org/10.1007/s003359901159
  3. Beamer, W.G., Shultz, K.L., Donahue, L.R. and Rosen, C.J. (2001). Quantitative trait loci for femoral and lumbar vertebral bone mineral density in C57BL/6J and C3H/HeJ inbred strains of mice. J. Bone Miner. Res., 16, 1195-1206 https://doi.org/10.1359/jbmr.2001.16.7.1195
  4. Benes, H., Weinstein, R.S., Zheng, W., Thaden, J.J. and Shmookler, R.R.J. (2000). Chromosomal mapping of osteopenia-associated quantitative trait loci using closely related mouse strains. J. Bone Miner. Res., 15, 626-633 https://doi.org/10.1359/jbmr.2000.15.4.626
  5. Braga, V., Sangalli, A., Malerba, G., Mottes, M., Mirandola, S., Gatti, D., Rossini, M., Zamboni, M. and Adami, S. (2002). Relationship among VDR (BsmI and FokI), COLIA1, and CTR polymorphisms with bone mass, bone turnover markers, and sex hormones in men. Calcif. Tissue Int., 70, 457-462 https://doi.org/10.1007/s00223-001-1088-9
  6. Braverman, N., Steel, G., Obie, C., Moser, A., Moser, H., Gould, S.J. and Valle, D. (1997). Human PEX7 encodes the peroxisomal PTS2 receptor and is responsible for rhizomelic chondrodysplasia punctata. Nat. Genet., 15, 369-376 https://doi.org/10.1038/ng0497-369
  7. Brites, P., Motley, A.M., Gressens, P., Mooyer, P.A., Ploegaert, I., Everts, V., Evrard, P., Carmeliet, P., Dewerchin, M., Schoonjans, L., Duran, M., Waterham, H.R., Wanders, R.J. and Baes, M. (2003). Impaired neuronal migration and endochondral ossification in Pex7knockout mice: a model for rhizomelic chondrodysplasia punctata. Hum. Mol. Genet., 12, 2255-2267 https://doi.org/10.1093/hmg/ddg236
  8. Brown, S.D.M. and Hardisty, R.E. (2003). Mutagenesis strategies for identifying novel loci associated with disease phenotypes. Semin. Cell Dev. Biol., 14, 19-24 https://doi.org/10.1016/S1084-9521(02)00168-4
  9. Cheverud, J.M., Routman, E.J., Duarte, F.A., van Swinderen, B., Cothran, K. and Perel, C. (1996). Quantitative trait loci for murine growth. Genetics, 142, 1305-1319
  10. Cho, J.W., Yoo, J.K., Cho, K.H., Han, S.S. and Song, C.W. (2003). The Devlopment of Dwarfism Mice Using ENU Mutagenesis. Kor. J. Lab. Ani. Sic., 19, 65-69
  11. Davis, A.P., Woychik, R.P. and Justice, M.J. (1999). Effective chemical mutagenesis in FVB/N mice requires low dose s of ethylnitrosourea. Mamm. Genome, 10, 308-310 https://doi.org/10.1007/s003359900992
  12. Deng, H.W., Shen, H., Xu, F.H., Deng, H.Y., Conway, T., Zhang, H.T. and Recker, R.R. (2002). Tests of linkage and/or association of genes for vitamin D receptor, osteocalcin, and parathyroid hormone with bone mineral density. J. Bone Miner. Res., 17, 678-686 https://doi.org/10.1359/jbmr.2002.17.4.678
  13. Deng, H.W. and Recker, R.R. (2004). Gene mapping and identification for osteoporosis. J. Musculoskelet. Neuronal Interact., 4, 91-100
  14. Dietrich, W.F., Miller, J., Steen, R., Merchant, M.A., Damron-Boles, D., Husain, Z., Dredge, R., Daly, M.J., Ingalls, K.A. and O'Connor, T.J. (1996). A comprehensive genetic map of the mouse genome. Nature, 380, 149-152 https://doi.org/10.1038/380149a0
  15. Drake, T.A., Schadt, E., Hannani, K. and Lusis, A.J. (2001). Genetic loci determining bone density in mice with dietinduced atherosclerosis. Physiol. Genom., 5, 205-215 https://doi.org/10.1152/physiolgenomics.2001.5.4.205
  16. Duncan, E..L, Brown, M.A., Sinsheimer, J., Bell, J., Carr, A.J., Wordsworth, B.P. and Wass, J.A. (1999). Suggestive linkage of the parathyroid receptor type 1 to osteoporosis. J. Bone Miner. Res., 14, 1993-1999 https://doi.org/10.1359/jbmr.1999.14.12.1993
  17. Eason, J., Hall, C.M. and Trounce, J.Q. (1995). Renal tubular leakage complicating microcephalic osteodysplastic primordial dwarfism. J. Med. Genet., 32, 234-235 https://doi.org/10.1136/jmg.32.3.234
  18. Gibbs, R.A., Weinstock, G.M., Metzker, M.L., Muzny, D.M., Sodergren, E.J., Scherer, S., Scott, G. and Rat Genome Sequencing Project Consortium (2004). Genome sequence of the Brown Norway rat yields insights into mammalian evolution. Nature, 428, 493-521 https://doi.org/10.1038/nature02426
  19. Godfrey, P., Rahal, J.O., Beamer, W.G., Copeland, N.G., Jenkins, N.A. and Mayo, K.E. (1993). GHRH receptor of little mice contains a missense mutation in the extracellular domain that disrupts receptor function. Nat. Genet., 4, 227-232 https://doi.org/10.1038/ng0793-227
  20. Hitotsumachi, S., Carperter, D.A. and Russel, W.L. (1985). Dose repetition increases the mutagenic effectiveness of N-ethyl-N-nitrosourea in mouse spermatogonia. Proc. Matl. Acad. Sci., 82, 6619-6621
  21. Hrabe de Angelis, M.H., Flaswinkel, H., Fuchs, H., Balling, R. and Balling, R. (2000). Genome-wide, large-scale production of mutant mice by ENU mutagenesis. Nat. Genet., 25, 444-447 https://doi.org/10.1038/78146
  22. Hu, C.T. and O'shaughnessy, K.M. (2001). Glycerol-enhanced mini-polyacrylamide gel electrophoresis for the separation of differentially expressed DNA fragments in cDNA representational difference analysis. Electrophoresis, 22, 1063-1068 https://doi.org/10.1002/1522-2683()22:6<1063::AID-ELPS1063>3.0.CO;2-S
  23. Hwang, Q.Y., Recker, R.R. and Deng, H.W. (2003). Searching for osteoporosis genes in the post-genome era: progress and challenges. Osteoporos. Int., 14, 701-715 https://doi.org/10.1007/s00198-003-1445-9
  24. Ishikawa, A. and Namikawa, T. (2004). Mapping major quantitative trait loci for postnatal growth in an intersubspecific backcross between C57BL/6J and Philippine wild mice by using principal component analysis. Genes Genet. Syst., 79, 27-39 https://doi.org/10.1266/ggs.79.27
  25. Jansson, J.O., Downs, T.R., Beamer, W.G. and Frohman, L.A. (1986). Receptor-associated resistance to growth hormonereleasing factor in dwarf 'little' mice. Science, 232, 511-512 https://doi.org/10.1126/science.3008329
  26. Justice, M.J. and Bode, V.C. (1986). Induction of new mutations in a mouse t-haplotype using ethylnitrosourea mutagenesis. Gene Res., 47, 187-192 https://doi.org/10.1017/S0016672300023119
  27. Justice, M.J., Noveroske, J.K., Weber, J.S., Zheng, B. and Bradley, A. (1999). Mouse ENU mutagenesis. Hum. Mol. Genetics, 8, 1955-1963 https://doi.org/10.1093/hmg/8.10.1955
  28. Justice, M.J., Carpenter, D.A., Favor, J., Neuhauser, K.A., Hrabe de Angelis, M., Soewarto, D. and Bode, V.C. (2000). Effects of ENU doseage on mouse strains. Mamm. Genome, 11, 484-488 https://doi.org/10.1007/s003350010094
  29. Kim, J.C., Shin, D.H., Kim, S.H., Yang, Y.S., Oh, K.S., Jiang, C.Z. and Chung, M.K. (2006). Teratogenicity evaluation of 2-bromopropane using rat whole embryo culture. J. Toxicol. Pub. Health, 22, 127-133
  30. Klein, R.F., Mitchell, S.R., Phillips, T.J., Belknap, J.K. and Orwoll, E.S. (1998). Quantitative trait loci affecting peak bone mineral density in mice. J. Bone Miner. Res., 13, 1648-1656 https://doi.org/10.1359/jbmr.1998.13.11.1648
  31. Klein, R.F., Carlos, A.S., Vartanian, K.A., Chambers, V.K. and Orwoll, E.S. (2001). Confirmation and fine mapping of chromosomal regions influencing peak bone mass in mice. J. Bone Miner. Res., 16, 1953-1961 https://doi.org/10.1359/jbmr.2001.16.11.1953
  32. Kwack, S.J. and Cho, D.H. (2005). The recommended approaches and recent trends in reproductive and developmental toxicology. J. Toxicol. Pub. Health, 21, 271-278
  33. Lander, E.S., Linton, L.M., Birren, B., Nusbaum, C., Zody, M.C., Baldwin, J., Devon, K., Dewar, K. and Wyman, D. (2001). Initial sequencing and analysis of the human genome. Nature, 409, 860-921 https://doi.org/10.1038/35057062
  34. Li, S., Crenshaw III, E.B., Rawson, E.J., Simmonds, D.M., Swanson, L.V. and Rosenfeld, M.G. (1990). Dwarf locus mutants lacking three pituitary cell types result from mutations in the POU-domain gene pit-1. Nature, 347, 528-533 https://doi.org/10.1038/347528a0
  35. Li, X., Masinde, G., Gu, W., Wergedal, J., Mohan, S. and Baylink, D.J. (2002). Genetic dissection of femur breaking strength in a large population (MRL/MpJ x SJL/J) of F2 mice: single QTL effects, epistasis, and pleiotropy. Genomics, 79, 734-740 https://doi.org/10.1006/geno.2002.6760
  36. Lin, S.C., Lin, C.R., Gukovsky, I., Lusis, A.J., Sawchenco, P.E. and Rosenfeld, M.G. (1993). Molecular basis of the little mouse phenotype and implications for cell-type specific growth. Nature, 364, 209-214
  37. Lira, S.A., Kalla, K.A., Glass, C.K., Drolet, D.W. and Rosenfeld, M.G. (1993). Synergistic interactions between Pit-1 and other elements are required for effective somatotroph rat growth hormone gene expression in transgenic mice. Mol. Endocrinol., 7, 694-701 https://doi.org/10.1210/me.7.5.694
  38. Masinde, G.L., Li, X., Gu, W., Wergedal, J., Mohan, S. and Baylink, D.J. (2002). Quantitative trait loci for bone density in mice: the genes determining total skeletal density and femur density show little overlap in F2 mice. Calcif. Tissue Int., 71, 421-428 https://doi.org/10.1007/s00223-001-1113-z
  39. Meyer, C.W., Korthaus, D., Jagla, W., Cornali, E., Grosse, J., Fuchs, H., Klingenspor, M., Roemheld, S., Tschop, M., Heldmaier, G., De Angelis, M.H. and Nehls, M. (2004). A novel missense mutation in the mouse growth hormone gene causes semidominant dwarfism, hyperghrelinemia, and obesity. Endocrinology, 145, 2531-2541 https://doi.org/10.1210/en.2003-1125
  40. Noveroske, J.K., Weber, J.S. and Justice, M.J. (2000). The mutagenic action of ENU in the mouse. Mamm. Genome, 11, 478-483 https://doi.org/10.1007/s003350010093
  41. Purchase, I.F.H. (2001). Assessment of the risk of exposure to chemical carcinogens. J. Toxicol. Pub. Health, 17, 41-45
  42. Purdue, P.E., Zhang, J.W., Skoneczny, M. and Lazarow, P.B. (1997). Rhizomelic chondrodysplasia punctata is caused by deficiency of human PEX7, a homologue of the yeast PTS2 receptor. Nat. Genet., 15, 381-384 https://doi.org/10.1038/ng0497-381
  43. Russel, W.L., Kelly, E.M., Hunsicker, P.R., Bangham, J.W., Maddux, S.C. and Phipps, E.L. (1979). Specific-locus test shows ethylnitrosourea to be the most potent mutagen in the mouse. Proc. Matl. Acad. Sci., 76, 5818-5819
  44. Russel, W.L., Hunsicker, P.R., Carpenter, D.A., Cornett, C.V. and Guinn, G.M. (1982a). Effect of dose fractionation on the ethylnitrosourea induction of specificlocus mutations in mouse spermatogonia. Proc. Matl. Acad. Sci., 79, 3589-3591
  45. Russel, W.L., Hunsicker, P.R., Raymer, G.D., Steele, M.H., Stelzmer, K.F. and Thompson, H.M. (1982b). Doseresponse curve for the ethylnitrosourea-inducted specificlocus mutations in mouse spermatogonia. Proc. Matl. Acad. Sci., 79, 3589-3591
  46. Ressell, L.B. and Russell, W.L. (1992). Frequency and nature of specific-locus mutations induced in female mice by radiations and chemicals: a review. Mutat. Res., 296, 107-127 https://doi.org/10.1016/0165-1110(92)90035-8
  47. Rosen, C.J., Beamer, W.G. and Donahue, L.R. (2001). Defining the genetics of osteoporosis: Using the mouse to understand man. Osteoporos. Int., 12, 803-810 https://doi.org/10.1007/s001980170030
  48. Shelovsky, A., McDonald, J.D., Symula, D.M. and Dove, W.F. (1993). Mouse models of human phenylketonuria. Genetics, 134, 1205-1210
  49. Shibayama, K., Ohyama, Y., Ono, M. and Furudate, S. (1993). Expression of mRNA coding for pituitary hormones and pituitary-specific transcription factor in the pituitary gland of the rdw rat with hereditary dwarfism. J. Endocrinol., 138, 307-313 https://doi.org/10.1677/joe.0.1380307
  50. Shimizu, M., Higuchi, K., Bennett, B., Xia, C. and Hosokawa, M. (1999). Identification of peak bone mass QTL in spontaneously osteoporotic mouse strain. Mamm. Genome, 10, 81-87 https://doi.org/10.1007/s003359900949
  51. Shimizu, M., Higuchi, K., Kasai, S., Nakamura, T. and Hosokawa, M. (2001). Chromosome 13 locus, Pbd2, regulates bone density in mice. J. Bone Miner. Res., 12, 1972-1982
  52. Soewarto, D., Fella, C., Teubner, A., Rathkolb, B., Pargent, W., Heffner, S. and Angelis, M.H. (2000). The large-scale Munich ENU-mouse-mutagenesis screen. Mamm. Genome, 11, 507-510 https://doi.org/10.1007/s003350010097
  53. Sornson, M.W., Wu, W. and Dasen, J.S. (1996). Pituitary lineage determination by the Prophet of Pit-1 homeodomain factor defective in Ames dwarfism. Nature, 384, 327-333 https://doi.org/10.1038/384327a0
  54. Tsuji, T. and Kunieda, T. (2005). A loss-of-function mutation in natriuretic peptide receptor 2 (Npr2) gene is responsible for disproportionate dwarfism in cn/cn mouse. J. Biol. Chem., 280, 14288-14292 https://doi.org/10.1074/jbc.C500024200
  55. Takeuchi, T., Suzuki, H., Sakurai, S., Nogami, H., Okuma, S. and Ishikawa, H. (1990). Molecular mechanism of growth hormone (GH) deficiency in the spontaneous dwarf rat: detection of abnormal splicing of GH messenger ribonucleic acid by polymerase chain reaction. Endocrinology, 126, 31-38 https://doi.org/10.1210/endo-126-1-31
  56. Wang, Y., Spatz, M.K., Kannan, K., Hayk, H., Avivi, A., Gorivodsky, M., Pines, M., Yayon, A., Lonai, P. and Givol, D. (1999). A mouse model for achondroplasia produced by targeting fibroblast growth factor receptor 3. Proc. Natl. Acad. Sci., 96, 4455-4460
  57. Waterston, R.H., Lindblad-Toh, K., Birney, E., Rogers, J., Abril, J.F., Agarwal, P., Agarwala, R. and Mouse Genome sequencing Consortium (2002). Initial sequencing and comparative analysis of the mouse genome. Nature, 420, 520-562 https://doi.org/10.1038/nature01262
  58. WHO (1994). Assessment of fracture risk and its application to screening for postmenopausal osteoporosis. World Health Organ Tech. Report Series No. 843, Geneva: WHO, 1-129
  59. Wynne, F., Drummond, F., O'Sullivan, K., Daly, M., Shanahan, F., Molloy, M.G. and Quane, K.A. (2002). Investigation of the genetic influence of the OPG, VDR (Fok1), and COLIA1 Sp1 polymorphisms on BMD in the Irish population. Calcif. Tissue Int., 71, 26-35 https://doi.org/10.1007/s00223-001-2081-z
  60. Zhou, X., Benson, K.F., Ashar, H.R. and Chada, K. (1995). Mutation responsible for the mouse pygmy phenotype in the developmentally regulated factor HMGI-C. Nature, 376, 771-774 https://doi.org/10.1038/376771a0