Transgenic animal models in toxicology: Historical perspectives and future outlook

Toxicological Sciences

Volumn 121, Issue 2, 2011, Pages 207-233

  Boverhof, Darrell R ^a   Chamberlain, Mark P ^b   Elcombe, Clifford R ^b   Gonzalez, Frank J ^c   Heflich, Robert H ^d   Hernández, Lya G ^e   Jacobs, Abigail C ^f   Jacobson Kram, David ^f   Luijten, Mirjam ^e   Maggi, Adriana ^g   Manjanatha, Mugimane G ^d   van Benthem, Jan ^e   Gollapudi, B Bhaskar ^a  

^a DOW CHEMICAL COMPANY   (United States)

^b CXR Biosciences Ltd   (United Kingdom)

^c NATIONAL CANCER INSTITUTE   (United States)

^d NATIONAL CENTER FOR TOXICOLOGICAL RESEARCH   (United States)

^e NATIONAL INSTITUTE FOR PUBLIC HEALTH AND THE ENVIRONMENT   (Netherlands)

^f CENTER FOR DRUG EVALUATION AND RESEARCH   (United States)

^g UNIVERSITY OF MILAN   (Italy)

Author keywords

Humanized models; Knock out models; Risk assessment; Transgenic models

Indexed keywords

BETA GALACTOSIDASE; CONSTITUTIVE ANDROSTANE RECEPTOR; CYTOCHROME P450 1A1; CYTOCHROME P450 1A2; CYTOCHROME P450 2E1; CYTOCHROME P450 3A4; PEROXISOME PROLIFERATOR ACTIVATED RECEPTOR ALPHA; PREGNANE X RECEPTOR; XENOBIOTIC AGENT;

CARCINOGENESIS; DNA MODIFICATION; ENZYME METABOLISM; GENE MUTATION; HAZARD ASSESSMENT; KNOCKOUT MOUSE; MOUSE MUTANT; MUTAGENICITY; MUTATIONAL ANALYSIS; NONHUMAN; REVIEW; RISK ASSESSMENT; RODENT; TOXICITY TESTING; TRANSGENE; TRANSGENIC ANIMAL; TRANSGENIC MOUSE;

ANIMALIA;

EID: 79957795559     PISSN: 10966080     EISSN: 10960929     Source Type: Journal    
DOI: 10.1093/toxsci/kfr075     Document Type: Review

References (214)

1. Abdel-Rahman, W. M., Mecklin, J. P., and Peltomaki, P. (2006). The genetics of HNPCC: application to diagnosis and screening. Crit. Rev. Oncol. ematol. 58, 208-220.
2. Aidoo, A., Lyn-Cook, L. E., Mittelstaedt, R. A., Heflich, R. H., and Casciano, D. A. (1991). Induction of 6-thioguanine-resistant lymphocytes in Fischer 344 rats following in vivo exposure to N-ethyl-N-nitrosourea and cyclophosphamide. Environ. Mol. Mutagen 17, 141-151.
3. Aiges, H. W., Daum, F., Olson, M., Kahn, E., and Teichberg, S. (1980). The effects of phenobarbital and diphenylhydantoin on liver function and morphology. . Pediatr. 97, 22-26.
4. Andersen, M. E., and Krewski, D. (2010). The vision of toxicity testing in the 21st century: moving from discussion to action. Toxicol. Sci. 117, 17-24.
5. Athirakul, K., Bradbury, J. A., Graves, J. P., DeGraff, L. M., Ma, J., Zhao, Y., Couse, J. F., Quigley, R., Harder, D. R., Zhao, X., et al. (2008). Increased blood pressure in mice lacking cytochrome P450 2J5. FASEB J. 22, 4096-4108.
6. Biertumpfel, C., Zhao, Y., Kondo, Y., Ramon-Maiques, S., Gregory, M., Lee, J. Y., Masutani, C., Lehmann, A. R., Hanaoka, F., and Yang, W. (2010). Structure and mechanism of human DNA polymerase eta. Nature 465, 1044-1048.
7. Blakey, D. H., Douglas, G. R., Huang, K. C., and Winter, H. J. (1995). Cytogenetic mapping of lambda gt10 lacZ sequences in the transgenic mouse strain 0.6 (Muta Mouse). Mutagenesis 10, 145-148.
8. Boley, S. E., Anderson, E. E., French, J. E., Donehower, L. A., Walker, D. B., and Recio, L. (2000). Loss of p53 in benzene-induced thymic lymphomas in p53+/- mice: evidence of chromosomal recombination. Cancer Res. 60, 2831-2835.
9. Bondesson, M., Jonsson, J., Pongratz, I., Olea, N., Cravedi, J. P., Zalko, D., Hakansson, H., Halldin, K., Di Lorenzo, D., Behl, C., et al. (2009). A CASCADE of effects of bisphenol A. Reprod. Toxicol. 28, 563-567.
10. Boobis, A. R., Cohen, S. M., Dellarco, V., McGregor, D., Meek, M. E., Vickers, C., Willcocks, D., and Farland, W. (2006). IPCS framework for analyzing the relevance of a cancer mode of action for humans. Crit. Rev.Toxicol. 36, 781-792.
11. Borresen, A. L. (1992). Oncogenesis in ovarian cancer. Acta Obstet. Gynecol. Scand. (Suppl. 155), 25-30.
12. Buters, J., Quintanilla-Martinez, L., Schober, W., Soballa, V. J., Hintermair, J., Wolff, T., Gonzalez, F. J., and Greim, H. (2003). CYP1B1 determines susceptibility to low doses of 7,12-dimethylbenz[a]anthracene-induced ovarian cancers in mice: correlation of CYP1B1-mediated DNA adducts with carcinogenicity. arcinogenesis 24, 327-334.
13. Buters, J. T., Sakai, S., Richter, T., Pineau, T., Alexander, D. L., Savas, U., Doehmer, J., Ward, J. M., Jefcoate, C. R., and Gonzalez, F. J. (1999). Cytochrome P450 CYP1B1 determines susceptibility to 7, 12-dimethylbenz[a]anthracene-induced lymphomas. Proc. Natl. Acad. Sci. U. S. A. 96, 1977-1982.
14. Calvert, P. M., and Frucht, H. (2002). The genetics of colorectal cancer. Ann. Intern. Med. 137, 603-612.
15. Candido, E. P., and Jones, D. (1996). Transgenic Caenorhabditis elegans strains as biosensors. Trends Biotechnol. 14, 125-129.
16. Capecchi, M. R. (1989). Altering the genome by homologous recombination. Science 244, 1288-1292.
17. Capecchi, M. R. (2005). Gene targeting in mice: functional analysis of the mammalian genome for the twenty-first century. Nat. Rev. Genet. 6, 507-512.
18. Carbery, I. D., Ji, D., Harrington, A., Brown, V., Weinstein, E. J., Liaw, L., and Cui, X. (2010). Targeted genome modification in mice using zinc-finger ucleases. Genetics 186, 451-459.
19. Chang, C., Smith, D. R., Prasad, V. S., Sidman, C. L., Nebert, D. W., and Puga, A. (1993). Ten nucleotide differences, five of which cause amino acid changes, are associated with the Ah receptor locus polymorphism of C57BL/ 6 and DBA/2 mice. Pharmacogenetics 3, 312-321.
20. Charreau, B., Tesson, L., Soulillou, J. P., Pourcel, C., and Anegon, I. (1996). Transgenesis in rats: technical aspects and models. Transgenic Res. 5, 223-34.
21. Chen, S., Beaton, D., Nguyen, N., Senekeo-Effenberger, K., Brace-Sinnokrak, E., Argikar, U., Remmel, R. P., Trottier, J., Barbier, O., and Ritter, J. K., et al. (2005). Tissue-specific, inducible, and hormonal control of the human UDP-glucuronosyltransferase-1 (UGT1) locus. J. Biol. Chem. 280, 37547-37557.
22. Chen, T., Dean, S., Douglas, G. R., Heddle, J. A., Lambert, I. B., Nohmi, T., Sykes, P. J., Thybaud, V., Valentine, C. R., Van Benthem, J., et al. (2006). Environmental Health Criteria: Number 233. Transgenic Animal Mutagenicity Assays. WHO, Geneva, Switzerland.
23. Cheng, J., Ma, X., and Gonzalez, F. J. (2010a). Pregnane X receptor and CYP3A4 humanized mouse models and their applications. Br. J. Pharmacol. Advance access published on November 22, 2010; doi:10.1111/j.1476-5381.2010.01129.x.
24. Cheng, J., Ma, X., Krausz, K. W., Idle, J. R., and Gonzalez, F. J. (2009). Rifampicin-activated human pregnane X receptor and CYP3A4 induction enhance acetaminophen-induced toxicity. Drug Metab. Dispos. 37, 1611-1621.
25. Cheng, J., Shah, Y. M., Ma, X., Pang, X., Tanaka, T., Kodama, T., Kristopher, K. W., and Gonzalez, F. J. (2010b). Therapeutic role of rifaximin in inflammatory bowel disease: clinical implication of human pregnane X receptor activation. J. Pharmacol. Exp. Ther. 335, 32-41.
26. Cheung, C., Akiyama, T. E., Ward, J. M., Nicol, C. J., Feigenbaum, L., Vinson, C., and Gonzalez, F. J. (2004). Diminished hepatocellular proliferation in mice humanized for the nuclear receptor peroxisome proliferator-activated receptor alpha. Cancer Res. 64, 3849-3854.
27. Cheung, C., and Gonzalez, F. J. (2008). Humanized mouse lines and their application for prediction of human drug metabolism and toxicological risk ssessment. J. Pharmacol. Exp. Ther. 327, 288-299.
28. Cheung, C., Ma, X., Krausz, K. W., Kimura, S., Feigenbaum, L., Dalton, T. P., Nebert, D. W., Idle, J. R., and Gonzalez, F. J. (2005a). Differential metabolism of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) in mice humanized for CYP1A1 and CYP1A2. Chem. Res. Toxicol. 18, 1471-1478.
29. Cheung, C., Yu, A. M., Chen, C. S., Krausz, K. W., Byrd, L. G., Feigenbaum, L., Edwards, R. J., Waxman, D. J., and Gonzalez, F. J. (2006). Growth hormone determines sexual dimorphism of hepatic cytochrome P450 3A4 expression in transgenic mice. J. Pharmacol. Exp. Ther. 316, 1328-1334.
30. Cheung, C., Yu, A. M., Ward, J. M., Krausz, K. W., Akiyama, T. E., Feigenbaum, L., and Gonzalez, F. J. (2005b). The cyp2e1-humanized transgenic mouse: role of cyp2e1 in acetaminophen hepatotoxicity. Drug Metab. Dispos. 33, 449-457.
31. Ciana, P., Raviscioni, M., Mussi, P., Vegeto, E., Que, I., Parker, M. G., Lowik, C., and Maggi, A. (2003). In vivo imaging of transcriptionally active estrogen eceptors. Nat. Med. 9, 82-86.
32. Cohen, S. M. (2001). Alternative models for carcinogenicity testing: weight of evidence evaluations across models. Toxicol. Pathol. 29(Suppl.), 183-190.
33. Cohen, S. M., Meek, M. E., Klaunig, J. E., Patton, D. E., and Fenner-Crisp, P. A. (2003). The human relevance of information on carcinogenic modes of ction: overview. Crit. Rev. Toxicol. 33, 581-589.
34. Corchero, J., Granvil, C. P., Akiyama, T. E., Hayhurst, G. P., Pimprale, S., Feigenbaum, L., Idle, J. R., and Gonzalez, F. J. (2001). The CYP2D6 humanized mouse: effect of the human CYP2D6 transgene and HNF4alpha on the disposition of debrisoquine in the mouse. Mol. Pharmacol. 60, 1260-1267.
35. Cruet-Hennequart, S., Gallagher, K., Sokol, A. M., Villalan, S., Prendergast, A. M., and Carty, M. P. (2010). DNA polymerase eta, a key protein in translesion synthesis in human cells. Subcell Biochem. 50, 189-209.
36. Cui, X., Ji, D., Fisher, D. A., Wu, Y., Briner, D. M., and Weinstein, E. J. (2011). Targeted integration in rat and mouse embryos with zinc-finger nucleases. at. Biotechnol. 29, 64-67.
37. Dalton, T. P., Dieter, M. Z., Matlib, R. S., Childs, N. L., Shertzer, H. G., Genter, M. B., and Nebert, D. W. (2000). Targeted knockout of Cyp1a1 gene does not alter hepatic constitutive expression of other genes in the mouse [Ah] battery. Biochem. Biophys. Res. Commun. 267, 184-189.
38. Derkenne, S., Curran, C. P., Shertzer, H. G., Dalton, T. P., Dragin, N., and Nebert, D. W. (2005). Theophylline pharmacokinetics: comparison of Cyp1a1(_/_) and Cyp1a2(_/_) knockout mice, humanized hCYP1A1_1A2 knock-in mice lacking either the mouse Cyp1a1 or Cyp1a2 gene, and Cyp1(+/+) wild-ype mice. Pharmacogenet. Genomics 15, 503-511.
39. Di Lorenzo, D., Rando, G., Ciana, P., and Maggi, A. (2008). Molecular imaging, an innovative methodology for whole-body profiling of endocrine disrupter ction. Toxicol. Sci. 106, 304-311.
40. Di Lorenzo, D., Villa, R., Biasiotto, G., Belloli, S., Ruggeri, G., Albertini, A., Apostoli, P., Raviscioni, M., Ciana, P., and Maggi, A. (2002). Isomerspecific activity of dichlorodyphenyltrichloroethane with estrogen receptor in adult and suckling estrogen reporter mice. Endocrinology 143, 4544-4551.
41. Dickins, M. (2004). Induction of cytochromes P450. Curr. Top. Med. Chem. 4, 1745-1766.
42. Dobrovolsky, V. N., Miura, D., Heflich, R. H., and Dertinger, S. D. (2010). The in vivo Pig-a gene mutation assay, a potential tool for regulatory safety ssessment. Environ. Mol. Mutagen. 51, 825-835.
43. Dolle, M. E., Snyder, W. K., van Orsouw, N. J., and Vijg, J. (1999). Background mutations and polymorphisms in lacZ-plasmid transgenic mice. Environ. ol. Mutagen 34, 112-120.
44. Donehower, L. A., Harvey, M., Slagle, B. L., McArthur, M. J., Montgomery, C. A., Jr., Butel, J. S., and Bradley, A. (1992). Mice deficient for p53 are developmentally normal but susceptible to spontaneous tumours. Nature 356, 215-221.
45. Dragin, N., Uno, S., Wang, B., Dalton, T. P., and Nebert, D. W. (2007). Generation of 'humanized' hCYP1A1_1A2_Cyp1a1/1a2(_/_) mouse line. Biochem. Biophys. Res. Commun. 359, 635-642.
46. Dycaico, M. J., Provost, G. S., Kretz, P. L., Ransom, S. L., Moores, J. C., and Short, J. M. (1994). The use of shuttle vectors for mutation analysis in transgenic mice and rats. Mutat Res. 307, 461-478.
47. EC (2006). Regulation (EC) No. 1907/2006 of the European Parliament and of the Council of 18 December 2006 concerning the Registration. Evaluation, Authorisation and Restriction of Chemicals (REACH), establishing a European Chemicals Agency, amending Directive 1999/45/EC and repealing Council Regulation (EEC) No 793/93 and Commission Regulation (EC) No 1488/94 as well as Council Directive 76/769/EEC and Commission Directive 91/155/EEC, 93/67/EEC, 93/105/EC and 2000/21/EC.
48. Ema, M., Ohe, N., Suzuki, M., Mimura, J., Sogawa, K., Ikawa, S., and Fujii-Kuriyama, Y. (1994). Dioxin binding activities of polymorphic forms of mouse and human arylhydrocarbon receptors. J. Biol. Chem. 269, 27337-27343.
49. Feil, S., Valtcheva, N., and Feil, R. (2009). Inducible Cre mice. Methods Mol. Biol. 530, 343-363.
50. Fernandez-Salguero, P., Pineau, T., Hilbert, D. M., McPhail, T., Lee, S. S., Kimura, S., Nebert, D. W., Rudikoff, S., Ward, J. M., and Gonzalez, F. J. (1995). Immune system impairment and hepatic fibrosis in mice lacking the dioxin-binding Ah receptor. Science. 268, 722-726.
51. Flaveny, C. A., Murray, I. A., Chiaro, C. R., and Perdew, G. H. (2009). Ligand selectivity and gene regulation by the human aryl hydrocarbon receptor in ransgenic mice. Mol. Pharmacol. 75, 1412-1420.
52. Flaveny, C. A., Murray, I. A., and Perdew, G. H. (2010). Differential gene regulation by the human and mouse aryl hydrocarbon receptor. Toxicol. Sci. 114, 17-225.
53. Flaveny, C. A., and Perdew, G. H. (2009). Transgenic humanized AHR mouse reveals differences between human and mouse AHR ligand selectivity. Mol. ell. Pharmacol. 1, 119-123.
54. Foster, J. R. (2000). Cell death and cell proliferation in the control of normal and neoplastic tissue growth. Toxicol. Pathol. 28, 441-446.
55. Geurts, A. M., Cost, G. J., Freyvert, Y., Zeitler, B., Miller, J. C., Choi, V. M., Jenkins, S. S., Wood, A., Cui, X., Meng, X., et al. (2009). Knockout rats via mbryo microinjection of zinc-finger nucleases. Science 325, 433.
56. Gonzalez, F. J. (2002). Transgenic models in xenobiotic metabolism and toxicology. Toxicology 181-182, 237-239.
57. Gonzalez, F. J. (2007). The 2006 Bernard B. Brodie Award Lecture. Cyp2e1. Drug Metab. Dispos. 35, 1-8.
58. Gonzalez, F. J., and Shah, Y. M. (2008). PPARalpha: mechanism of species differences and hepatocarcinogenesis of peroxisome proliferators. Toxicology 46, 2-8.
59. Gorelick, N. J., and Mirsalis, J. C. (1996). A strategy for the application of transgenic rodent mutagenesis assays. Environ. Mol. Mutagen 28, 434-442.
60. Gossen, J. A., de Leeuw, W. J., Molijn, A. C., and Vijg, J. (1993). Plasmid rescue from transgenic mouse DNA using LacI repressor protein conjugated to agnetic beads. Biotechniques 14, 624-629.
61. Gossen, J. A., Martus, H. J., Wei, J. Y., and Vijg, J. (1995). Spontaneous and X-ray-induced deletion mutations in a LacZ plasmid-based transgenic mouse odel. Mutat Res. 331, 89-97.
62. Granvil, C. P., Yu, A. M., Elizondo, G., Akiyama, T. E., Cheung, C., Feigenbaum, L., Krausz, K. W., and Gonzalez, F. J. (2003). Expression of the human CYP3A4 gene in the small intestine of transgenic mice: In vitro metabolism and pharmacokinetics of midazolam. Drug Metab. Dispos. 31, 548-558.
63. Grippo, P. J., Nowlin, P. S., Cassaday, R. D., and Sandgren, E. P. (2002). Cellspecific transgene expression from a widely transcribed promoter using Cre/lox in mice. Genesis 32, 277-286.
64. Guengerich, F. P., and Shimada, T. (1998). Activation of procarcinogens by human cytochrome P450 enzymes. Mutat. Res. 400, 201-213.
65. Gulezian, D., Jacobson-Kram, D., McCullough, C. B., Olson, H., Recio, L., Robinson, D., Storer, R., Tennant, R., Ward, J. M., and Neumann, D. A. (2000). Use of transgenic animals for carcinogenicity testing: considerations and implications for risk assessment. Toxicol. Pathol. 28, 482-499.
66. Hanahan, D. (1989). Transgenic mice as probes into complex systems. Science 246, 1265-1275.
67. Hansen, L. A., and Tennant, R. W. (1994). Follicular origin of epidermal papillomas in v-Ha-ras transgenic TG.AC mouse skin. Proc. Natl. Acad. Sci. .S.A. 91, 7822-7826.
68. Hanson, K. D., and Sedivy, J. M. (1995). Analysis of biological selections for high-efficiency gene targeting. Mol. Cell. Biol. 15, 45-51.
69. Hartung, T., and Daston, G. (2009). Are in vitro tests suitable for regulatory use? Toxicol. Sci. 111, 233-237.
70. Hasmall, S. C., and Roberts, R. A. (1999). The perturbation of apoptosis and mitosis by drugs and xenobiotics. Pharmacol. Ther. 82, 63-70.
71. Hayashi, H., Kondo, H., Masumura, K., Shindo, Y., and Nohmi, T. (2003). Novel transgenic rat for in vivo genotoxicity assays using 6-thioguanine and Spi- election. Environ. Mol. Mutagen 41, 253-259.
72. Heddle, J. A., Martus, H. J., and Douglas, G. R. (2003). Treatment and sampling protocols for transgenic mutation assays. Environ. Mol. Mutagen 41, 1-6.
73. Heideman, J. (1991). Transgenic rats: a discussion. Biotechnology 16, 325-332.
74. Henderson, C. J., Smith, A. G., Ure, J., Brown, K., Bacon, E. J., and Wolf, C. R. (1998). Increased skin tumorigenesis in mice lacking pi class glutathione S-ransferases. Proc. Natl. Acad. Sci. U.S.A. 95, 5275-5280.
75. Holla, V. R., Adas, F., Imig, J. D., Zhao, X., Price, E., Jr., Olsen, N., Kovacs, W. J., Magnuson, M. A., Keeney, D. S., Breyer, M. D., et al. (2001). Alterations in the regulation of androgen-sensitive Cyp 4a monooxygenases cause hypertension. Proc. Natl. Acad. Sci. U.S.A. 98, 5211-5216.
76. Holsapple, M. P., Pitot, H. C., Cohen, S. M., Boobis, A. R., Klaunig, J. E., Pastoor, T., Dellarco, V. L., and Dragan, Y. P. (2006). Mode of action in relevance of rodent liver tumors to human cancer risk. Toxicol. Sci. 89, 51-56.
77. Huang, W., Zhang, J., Washington, M., Liu, J., Parant, J. M., Lozano, G., and Moore, D. D. (2005). Xenobiotic stress induces hepatomegaly and liver tumors via the nuclear receptor constitutive androstane receptor. Mol. Endocrinol. 19, 1646-1653.
78. Hurley, P. J., and Bunz, F. (2007). ATM and ATR: components of an integrated circuit. Cell Cycle 6, 414-417.
79. Hussain, S. P., and Harris, C. C. (2000). Molecular epidemiology and carcinogenesis: endogenous and exogenous carcinogens. Mutat. Res. 462, 311-322.
80. Hussain, S. P., Hollstein, M. H., and Harris, C. C. (2000). p53 tumor suppressor gene: at the crossroads of molecular carcinogenesis, molecular epidemiology, and human risk assessment. Ann. N.Y. Acad. Sci. 919, 79-85.
81. International Conference on Harmonization (ICH) (1997). International Conference on Harmonization, Expert Working Group on Safety; Guidance for Industry S1B Testing for Carcinogencity of Pharmaceuticals. Switzerland, ICH, Geneva.
82. International Conference on Harmonization (ICH) (2007). The International Conference on Harmonization of Technical Requirements of Pharmaceuticals for Human Use (ICH). Available at: http://www.ich.org/cache/compo/276-254-1.html. Accessed December 2010.
83. International Conference on Harmonization (ICH) (2008). International Conference on Harmonization. S2 (R1) Genotoxicity Testing and Data Interpretation for Pharmaceuticals Intended for Human Use. Available at: http://www.fda.gov/downloads/drugs/guidancecomplianceregulatory Information/Guidances/ucm129117.pdf. Accessed December 2010.
84. Jaenisch, R. (1976). Germ line integration and Mendelian transmission of the exogenous Moloney leukemia virus. Proc. Natl. Acad. Sci. U.S.A. 73, 1260-264.
85. Jaenisch, R. (1988). Transgenic animals. Science 240, 1468-1474.
86. Jaenisch, R., and Mintz, B. (1974). Simian virus 40 DNA sequences in DNA of healthy adult mice derived from preimplantation blastocysts injected with viral NA. Proc. Natl. Acad. Sci. U.S.A. 71, 1250-1254.
87. Jakubczak, J. L., Merlino, G., French, J. E., Muller, W. J., Paul, B., Adhya, S., and Garges, S. (1996). Analysis of genetic instability during mammary tumor progression using a novel selection-based assay for in vivo mutations in a bacteriophage lambda transgene target. Proc. Natl. Acad. Sci. U.S.A. 93, 9073-9078.
88. James, N. H., and Roberts, R. A. (1996). Species differences in response to peroxisome proliferators correlate in vitro with induction of DNA synthesis rather han suppression of apoptosis. Carcinogenesis 17, 1623-1632.
89. Jiang, X. L., Gonzalez, F. J., and Yu, A. M. (2010). Drug-metabolizing enzyme, transporter, and nuclear receptor genetically modified mouse models. Drug etab. Rev 43, 27-40.
90. Jiang, Z., Dalton, T. P., Jin, L., Wang, B., Tsuneoka, Y., Shertzer, H. G., Deka, R., and Nebert, D. W. (2005). Toward the evaluation of function in genetic variability: characterizing human SNP frequencies and establishing BAC-transgenic mice carrying the human CYP1A1_CYP1A2 locus. Hum. Mutat. 25, 196-206.
91. Jones, H. B., Orton, T. C., and Lake, B. G. (2009). Effect of chronic phenobarbitone administration on liver tumour formation in the C57BL/10J mouse. ood Chem. Toxicol. 47, 1333-1340.
92. Jones, I. M., Burkhart-Schultz, K., and Carrano, A. V. (1985). A method to quantify spontaneous and in vivo induced thioguanine-resistant mouse ymphocytes. Mutat. Res. 147, 97-105.
93. Jyrkkarinne, J., Windshugel, B., Makinen, J., Ylisirnio, M., Perakyla, M., Poso, A., Sippl, W., and Honkakoski, P. (2005). Amino acids important for ligand specificity of the human constitutive androstane receptor. J. Biol. Chem. 280, 5960-5971.
94. Kawamata, M., and Ochiya, T. (2010). Generation of genetically modified rats from embryonic stem cells. Proc. Natl. Acad. Sci. U.S.A. 107, 14223-4228.
95. Kliewer, S. A., Goodwin, B., and Willson, T. M. (2002). The nuclear pregnane X receptor: a key regulator of xenobiotic metabolism. Endocr. Rev. 23, 687-02.
96. Kliewer, S. A., Moore, J. T., Wade, L., Staudinger, J. L., Watson, M. A., Jones, S.A.,McKee, D. D.,Oliver, B.B.,Wilson, T.M., and Zetterstrom, R. H., et al. (1998). An orphan nuclear receptor activated by pregnanes defines a novel steroid signaling pathway. Cell 92, 73-82.
97. Klungland, A., Rosewell, I., Hollenbach, S., Larsen, E., Daly, G., Epe, B., Seeberg, E., Lindahl, T., and Barnes, D. E. (1999). Accumulation of premutagenic DNA lesions in mice defective in removal of oxidative base damage. Proc. Natl. Acad. Sci. U.S.A. 96, 13300-13305.
98. Kohler, S. W., Provost, G. S., Fieck, A., Kretz, P. L., Bullock, W. O., Putman, D. L., Sorge, J. A., and Short, J. M. (1991). Analysis of spontaneous and induced mutations in transgenic mice using a lambda ZAP/lacI shuttle vector. Environ. Mol. Mutagen. 18, 316-321.
99. Kohler, S. W., Provost, G. S., Kretz, P. L., Dycaico, M. J., Sorge, J. A., and Short, J. M. (1990). Development of a short-term, in vivo mutagenesis assay: the effects of methylation on the recovery of a lambda phage shuttle vector from transgenic mice. Nucleic Acids Res. 18, 3007-3013.
100. Kolaja, K. L., Stevenson, D. E., Walborg, E. F., Jr., and Klaunig, J. E. (1996). Reversibility of promoter induced hepatic focal lesion growth in mice. arcinogenesis 17, 1403-1409.
101. Lambert, I. B., Singer, T. M., Boucher, S. E., and Douglas, G. R. (2005). Detailed review of transgenic rodent mutation assays. Mutat Res. 590, 1-280.
102. Lambert, I. B., Singer, T. M., Boucher, S. E., and Douglas, G. R. (2008). Detailed review paper on transgenic rodent mutation assays. OECD Environment, Health and Safety Publications Series on Testing and Assessment. Environment Directorate, Organisation for Economic Cooperation and Development, 2nd draft-May 2008 (final document under review).
103. Lavin, M. F. (2008). Ataxia-telangiectasia: from a rare disorder to a paradigm for cell signalling and cancer. Nat. Rev. Mol. Cell. Biol. 9, 759-769.
104. Leder, A., Kuo, A., Cardiff, R. D., Sinn, E., and Leder, P. (1990). v-Ha-ras transgene abrogates the initiation step in mouse skin tumorigenesis: effects of phorbol esters and retinoic acid. Proc. Natl. Acad. Sci. U.S.A. 87, 9178-9182.
105. Lee, S. S., Buters, J. T., Pineau, T., Fernandez-Salguero, P., and Gonzalez, F. J. (1996). Role of CYP2E1 in the hepatotoxicity of acetaminophen. J. Biol. hem. 271, 12063-12067.
106. Lee, S. S., Pineau, T., Drago, J., Lee, E. J., Owens, J. W., Kroetz, D. L., Fernandez-Salguero, P. M., Westphal, H., and Gonzalez, F. J. (1995). Targeted disruption of the alpha isoform of the peroxisome proliferatoractivated receptor gene in mice results in abolishment of the pleiotropic effects of peroxisome proliferators. Mol. Cell. Biol. 15, 3012-3022.
107. Lehmann, J. M., McKee, D. D., Watson, M. A., Willson, T. M., Moore, J. T., and Kliewer, S. A. (1998). The human orphan nuclear receptor PXR is activated by compounds that regulate CYP3A4 gene expression and cause drug interactions. J. Clin. Invest. 102, 1016-1023.
108. Li, P., Tong, C., Mehrian-Shai, R., Jia, L., Wu, N., Yan, Y., Maxson, R. E., Schulze, E. N., Song, H., Hsieh, C. L., et al. (2008). Germline competent embryonic stem cells derived from rat blastocysts. Cell 135, 1299-1310.
109. Liang, H. C., Li, H., McKinnon, R. A., Duffy, J. J., Potter, S. S., Puga, A., and Nebert, D. W. (1996). Cyp1a2(-/-) null mutant mice develop normally but show deficient drug metabolism. Proc. Natl. Acad. Sci. U. S. A. 93, 1671-1676.
110. Lin, J. H. (2006). CYP induction-mediated drug interactions: in vitro assessment and clinical implications. Pharmacol. Res. 23, 1089-1116.
111. Lowy, D. R., Johnson, M. R., DeClue, J. E., Cen, H., Zhang, K., Papageorge, A. G., Vass, W. C., Willumsen, B. M., Valentine, M. B., and Look, A. T. (1993). Cell transformation by ras and regulation of its protein product. Ciba Found. Symp. 176, 67- 80; discussion 80-164.
112. Lowy, D. R., and Willumsen, B. M. (1993). Function and regulation of ras. Annu. Rev. Biochem. 62, 851-891.
113. Lofgren, S., Baldwin, R. M., Hiratsuka, M., Lindqvist, A., Carlberg, A., Sim, S. C., Schulke, M., Snait, M., Edenro, A., and Fransson-Steen, R., et al. (2008). Generation of mice transgenic for human CYP2C18 and CYP2C19: characterization of the sexually dimorphic gene and enzyme expression. Drug. Metab. ispos. 36, 955-962.
114. Luecke, S., Backlund, M., Jux, B., Esser, C., Krutmann, J., and Rannug, A. (2010). The aryl hydrocarbon receptor (AHR), a novel regulator of human elanogenesis. Pigment Cell Melanoma Res. 23, 828-833.
115. Ma, X., Cheung, C., Krausz, K. W., Shah, Y. M., Wang, T., Idle, J. R., and Gonzalez, F. J. (2008a). A double transgenic mouse model expressing human pregnane X receptor and cytochrome P450 3A4. Drug Metab. Dispos. 36, 2506-2512.
116. Ma, X., Idle, J. R., and Gonzalez, F. J. (2008b). The pregnane X receptor: from bench to bedside. Expert Opin. Drug Metab. Toxicol. 4, 895-908.
117. Ma, X., Shah, Y., Cheung, C., Guo, G. L., Feigenbaum, L., Krausz, K. W., Idle, J. R., and Gonzalez, F. J. (2007). The PREgnane X receptor genehumanized mouse: a model for investigating drug-drug interactions mediated by cytochromes P450 3A. Drug Metab. Dispos. 35, 194-200.
118. Maggi, A., Ottobrini, L., Biserni, A., Lucignani, G., and Ciana, P. (2004). Techniques: reporter mice-a new way to look at drug action. Trends Pharmacol. ci. 25, 337-342.
119. Malling, H. V., Burkhart, J. G., Fater, M. C., Hardies, S. C., Hutchinson, C. A., III, and Edgell, M. H. (1983). Development towards the ultimate hostmediated assay. Environ Mol. Mutagen. 5, 416.
120. Manson, J. C., and Tuzi, N. L. (2001). Transgenic models of the transmissible spongiform encephalopathies. Expert Rev. Mol. Med. 2001, 1-15.
121. Martignoni, M., Groothuis, G. M., and de Kanter, R. (2006). Species differences between mouse, rat, dog, monkey and human CYP-mediated drug metabolism, inhibition and induction. Expert Opin. Drug Metab. Toxicol. 2, 875-894.
122. Masumura, K., Matsui, K., Yamada, M., Horiguchi, M., Ishida, K., Watanabe, M., Ueda, O., Suzuki, H., Kanke, Y., Tindall, K. R., et al. (1999). Mutagenicity of 2-amino-1-methyl-6-phenylimidazo [4,5-b]pyridine (PhIP) in the new gpt delta transgenic mouse. Cancer Lett. 143, 241-244.
123. McCarroll, N., Keshava, N., Cimino, M., Chu, M., Dearfield, K., Keshava, C., Kligerman, A., Owen, R., Protzel, A., Putzrath, R., et al. (2008). An evaluation of the mode of action framework for mutagenic carcinogens case study: cyclophosphamide. Environ. Mol. Mutagen. 49, 117-131.
124. McMillan, B. J., and Bradfield, C. A. (2007). The aryl hydrocarbon receptor sans xenobiotics: endogenous function in genetic model systems. Mol. harmacol. 72, 487-498.
125. Minowa, O., Arai, T., Hirano, M., Monden, Y., Nakai, S., Fukuda, M., Itoh, M., Takano, H., Hippou, Y., Aburatani, H., et al. (2000). Mmh/Ogg1 gene inactivation results in accumulation of 8-hydroxyguanine in mice. Proc. Natl. Acad. Sci. U.S.A. 97, 4156-4161.
126. Miyata, M., Kudo, G., Lee, Y. H., Yang, T. J., Gelboin, H. V., Fernandez-Salguero, P., Kimura, S., and Gonzalez, F. J. (1999). Targeted disruption of the microsomal epoxide hydrolase gene. Microsomal epoxide hydrolase is required for the carcinogenic activity of 7,12-dimethylbenz[a]anthracene. J. Biol. Chem. 274, 3963-23968.
127. Modica, S., Bellafante, E., and Moschetta, A. (2009). Master regulation of bile acid and xenobiotic metabolism via the FXR, PXR and CAR trio. Front. iosci. 14, 4719-4745.
128. Montani, C., Penza, M., Jeremic, M., Biasiotto, G., La Sala, G., De Felici, M., Ciana,P.,Maggi,A., andDi Lorenzo,D. (2008). Genistein is an efficient estrogen in the whole-body throughout mouse development. Toxicol. Sci. 103, 57-67.
129. Moore, J. T., Moore, L. B., Maglich, J. M., and Kliewer, S. A. (2003). Functional and structural comparison of PXR and CAR. Biochim. Biophys. Acta 619, 235-238.
130. Moore, L. B., Parks, D. J., Jones, S. A., Bledsoe, R. K., Consler, T. G., Stimmel, J. B., Goodwin, B., Liddle, C., Blanchard, S. G., Willson, T. M., et al. (2000). Orphan nuclear receptors constitutive androstane receptor and pregnane X receptor share xenobiotic and steroid ligands. J. Biol. Chem. 275, 15122-5127.
131. Moore, M. M., Heflich, R. H., Haber, L. T., Allen, B. C., Shipp, A. M., and Kodell, R. L. (2008). Analysis of in vivo mutation data can inform cancer risk ssessment. Regul. Toxicol. Pharmacol. 51, 151-161.
132. Moriguchi, T., Motohashi, H., Hosoya, T., Nakajima, O., Takahashi, S., Ohsako, S., Aoki, Y., Nishimura, N., Tohyama, C., Fujii-Kuriyama, Y., et al. (2003). Distinct response to dioxin in an arylhydrocarbon receptor (AHR)-humanized mouse. Proc. Natl. Acad. Sci. U.S.A. 100, 5652-5657.
133. Morimura, K., Cheung, C., Ward, J. M., Reddy, J. K., and Gonzalez, F. J. (2006). Differential susceptibility of mice humanized for peroxisome proliferator-activated receptor alpha to Wy-14,643-induced liver tumorigenesis. Carcinogenesis 27, 1074-1080.
134. Nakagawa, K., Holla, V. R., Wei, Y., Wang, W. H., Gatica, A., Wei, S., Mei, S., Miller, C. M., Cha, D. R., Price, E., Jr., et al. (2006). Salt-sensitive hypertension is associated with dysfunctional Cyp4a10 gene and kidney epithelial sodium channel. J. Clin. Invest. 116, 1696-1702.
135. Nguyen, L. P., and Bradfield, C. A. (2008). The search for endogenous activators of the aryl hydrocarbon receptor. Chem. Res. Toxicol. 21, 102-116.
136. Nohmi, T., Katoh, M., Suzuki, H., Matsui, M., Yamada, M., Watanabe, M., Suzuki, M., Horiya, N., Ueda, O., Shibuya, T., et al. (1996). A new transgenic mouse mutagenesis test system using Spi- and 6-thioguanine selections. Environ. Mol. Mutagen. 28, 465-470.
137. National Research Council (NRC) (2007). Toxicity Testing in the 21st Century: A Vision and a Strategy. National Academies Press, Washington, DC.
138. Organization for Economic Cooperation and Development (OECD) (2010). Guideline for the Testing of Chemicals; Draft Proposal for a New Guideline XXX: Transgenic Rodent Gene Mutation Assay. Available at: http://www.oecd.org/dataoecd/6/18/46161214.pdf.
139. Olsen, J. H., Boice, J. D., Jr., Jensen, J. P., and Fraumeni, J. F., Jr. (1989). Cancer among epileptic patients exposed to anticonvulsant drugs. J. Natl. ancer Inst. 81, 803-808.
140. Olsen, J. H., Schulgen, G., Boice, J. D., Whysner, J., Travis, L. B., Williams, G. M., Johnson, F. B., and McGee, J. O. (1995). Antiepileptic treatment and risk for hepatobiliary cancer and malignant lymphoma. Cancer Res. 55, 294-297.
141. Palmiter, R. D., Norstedt, G., Gelinas, R. E., Hammer, R. E., and Brinster, R. L. (1983). Metallothionein-human GH fusion genes stimulate growth of mice. cience 222, 809-814.
142. Parzefall, W., Erber, E., Sedivy, R., and Schulte-Hermann, R. (1991). Testing for induction of DNA synthesis in human hepatocyte primary cultures by rat liver umor promoters. Cancer Res. 51, 1143-1147.
143. Penza, M., Bonetti, E., Villa, R., Ganzerla, S., Bergonzi, R., Biasiotto, G., Caimi, L., Apostoli, P., Ciana, P., Maggi, A., et al. (2004). Whole body action of xenoestrogens with different chemical structures in estrogen reporter male mice. Toxicology 205, 65-73.
144. Peters, J. M. (2006). Use of transgenic and knockout mice to study gene regulation. In Regulation of Gene Expression (G. H. Perdew, J. P. Vanden Heuvel, nd J. M. Peters, Eds). Humana Press Inc., Totowa, NJ.
145. Peters, J. M., Cattley, R. C., and Gonzalez, F. J. (1997). Role of PPAR alpha in the mechanism of action of the nongenotoxic carcinogen and peroxisome roliferator Wy-14,643. Carcinogenesis 18, 2029-2033.
146. Pirttiaho, H. I., Sotaniemi, E. A., Ahlqvist, J., Pitkanen, U., and Pelkonen, R. O. (1978). Liver size and indices of drug metabolism in alcoholics. Eur. J. Clin. harmacol. 13, 61-67.
147. Pirttiaho, H. I., Sotaniemi, E. A., Pelkonen, R. O., and Pitkanen, U. (1982). Hepatic blood flow and drug metabolism in patients on enzyme-inducing nticonvulsants. Eur. J. Clin. Pharmacol. 22, 441-445.
148. Pineau, T., Fernandez-Salguero, P., Lee, S. S., McPhail, T., Ward, J. M., and Gonzalez, F. J. (1995). Neonatal lethality associated with respiratory distress in mice lacking cytochrome P450 1A2. Proc. Natl. Acad. Sci. U. S. A. 92, 5134-5138.
149. Plant, N. J., Horley, N. J., Dickins, M., Hasmall, S., Elcombe, C. R., and Bell, D. R. (1998). The coordinate regulation of DNA synthesis and suppression of apoptosis is differentially regulated by the liver growth agents, phenobarbital and methylclofenapate. Carcinogenesis 19, 1521-1527.
150. Pozniak, A., Muller, L., Salgo, M., Jones, J. K., Larson, P., and Tweats, D. (2009). Elevated ethyl methanesulfonate (EMS) in nelfinavir mesylate (Viracept, oche): overview. AIDS Res. Ther. 6, 18.
151. Pozzi, A., Popescu, V., Yang, S., Mei, S., Shi, M., Puolitaival, S. M., Caprioli, R. M., and Capdevila, J. H. (2010). The anti-tumorigenic properties of peroxisomal proliferator-activated receptor alpha are arachidonic acid epoxygenase-mediated. J. Biol. Chem. 285, 12840-12850.
152. Qian, Y. M., Sun, X. J., Tong, M. H., Li, X. P., Richa, J., and Song, W. C. (2001). Targeted disruption of the mouse estrogen sulfotransferase gene reveals a role of estrogen metabolism in intracrine and paracrine estrogen regulation. Endocrinology 142, 5342-5350.
153. Radjendirane, V., Joseph, P., Lee, Y. H., Kimura, S., Klein-Szanto, A. J., Gonzalez, F. J., and Jaiswal, A. K. (1998). Disruption of the DT diaphorase (NQO1) gene in mice leads to increased menadione toxicity. J. Biol. Chem. 273, 7382-7389.
154. Ramadoss, P., and Perdew, G. H. (2004). Use of 2-azido-3-[125I]iodo-7,8-dibromodibenzo-p-dioxin as a probe to determine the relative ligand affinity of human versus mouse aryl hydrocarbon receptor in cultured cells. Mol. Pharmacol. 66, 129-136.
155. Rando, G., Biserni, A., Ciana, P., and Maggi, A. (2010a). Profiling of drug action using reporter mice and molecular imaging. Methods Mol. Biol. 602, 79-2.
156. Rando, G., Casiraghi, E., Arca, S., Campadelli, P., and Maggi, A. (2009a). Automatic segmentation of mouse images. In Proceedings of the10th European Congress of International Society for Stereology, 22-26 June, 2009, Bologna, Italy, p. 60.
157. Rando, G., Horner, D., Biserni, A., Ramachandran, B., Caruso, D., Ciana, P., Komm, B., and Maggi, A. (2010b). An innovative method to classify SERMs based on the dynamics of estrogen receptor transcriptional activity in living animals. Mol. Endocrinol. 24, 735-744.
158. Rando, G., Ramachandran, B., Rebecchi, M., Ciana, P., and Maggi, A. (2009b). Differential effect of pure isoflavones and soymilk on estrogen receptor ctivity in mice. Toxicol. Appl. Pharmacol. 237, 288-297.
159. Recio, L., Bauer, A., and Faiola, B. (2005). Use of genetically modified mouse models to assess pathways of benzene-induced bone marrow cytotoxicity and enotoxicity. Chem. Biol. Interact. 153-154, 159-164.
160. Riou, G. F. (1988). Proto-oncogenes and prognosis in early carcinoma of the uterine cervix. Cancer Surv. 7, 441-456.
161. Robinson, D. E., and MacDonald, J. S. (2001). Background and framework for ILSI's collaborative evaluation program on alternative models for carcinogenicity assessment. International Life Sciences Institute. Toxicol. Pathol. 29(Suppl.) 13-19.
162. Ross, J., Plummer, S. M., Rode, A., Scheer, N., Bower, C. C., Vogel, O., Henderson, C. J., Wolf, C. R., and Elcombe, C. R. (2010). Human constitutive androstane receptor (CAR) and pregnane X receptor (PXR) support the hypertrophic but not the hyperplastic response to the murine nongenotoxic hepatocarcinogens phenobarbital and chlordane in vivo. Toxicol. Sci. 116, 452-466.
163. Rowlands, J. C., and Gustafsson, J. A. (1997). Aryl hydrocarbon receptormediated signal transduction. Crit. Rev. Toxicol. 27, 109-134.
164. Ryu, B. Y., Orwig, K. E., Oatley, J. M., Lin, C. C., Chang, L. J., Avarbock, M. R., and Brinster, R. L. (2007). Efficient generation of transgenic rats through the male germline using lentiviral transduction and transplantation of spermatogonial stem cells. J. Androl. 28, 353-360.
165. Saitoh, A., Kimura, M., Takahashi, R., Yokoyama, M., Nomura, T., Izawa, M., Sekiya, T., Nishimura, S., and Katsuki, M. (1990). Most tumors in transgenic mice with human c-Ha-ras gene contained somatically activated transgenes. Oncogene 5, 1195-1200.
166. Sauer, B., and Henderson, N. (1988). Site-specific DNA recombination in mammalian cells by the Cre recombinase of bacteriophage P1. Proc. Natl. Acad. ci. U.S.A. 85, 5166-5170.
167. Scheer, N., Ross, J., Kapelyukh, Y., Rode, A., and Wolf, C. R. (2010). In vivo responses of the human and murine pregnane X receptor to dexamethasone in ice. Drug Metab. Dispos. 38, 1046-1053.
168. Scheer, N., Ross, J., Rode, A., Zevnik, B., Niehaves, S., Faust, N., and Wolf, C. R. (2008). A novel panel of mouse models to evaluate the role of human pregnane X receptor and constitutive androstane receptor in drug response. J. Clin. Invest. 118, 3228-3239.
169. Shah, Y. M., Morimura, K., Yang, Q., Tanabe, T., Takagi, M., and Gonzalez, F. J. (2007). Peroxisome proliferator-activated receptor alpha regulates a microRNA-mediated signaling cascade responsible for hepatocellular proliferation. Mol. Cell. Biol. 27, 4238-4247.
170. Shibata, A., Kamada, N., Masumura, K., Nohmi, T., Kobayashi, S., Teraoka, H., Nakagama, H., Sugimura, T., Suzuki, H., and Masutani, M. (2005). Parp-1 deficiency causes an increase of deletion mutations and insertions/rearrangements in vivo after treatment with an alkylating agent. Oncogene 24, 1328-1337.
171. Sinal, C. J., Miyata, M., Tohkin, M., Nagata, K., Bend, J. R., and Gonzalez, F. J. (2000). Targeted disruption of soluble epoxide hydrolase reveals a role in blood pressure regulation. J. Biol. Chem. 275, 40504-40510.
172. Sinn, E., Muller, W., Pattengale, P., Tepler, I., Wallace, R., and Leder, P. (1987). Coexpression of MMTV/v-Ha-ras and MMTV/c-myc genes in transgenic ice: synergistic action of oncogenes in vivo. Cell 49, 465-475.
173. Slijepcevic, P. (2006). The role of DNA damage response proteins at telomeres-an "integrative" model. DNA Repair 5, 1299-1306.
174. Sonich-Mullin, C., Fielder, R., Wiltse, J., Baetcke, K., Dempsey, J., Fenner-Crisp, P., Grant, D., Hartley, M., Knaap, A., Kroese, D., et al. (2001). IPCS conceptual framework for evaluating a mode of action for chemical carcinogenesis. Regul. Toxicol. Pharmacol. 34, 146-152.
175. Soriano, P. (1999). Generalized lacZ expression with the ROSA26 Cre reporter strain. Nat. Genet. 21, 70-71.
176. Spalding, J. W., French, J. E., Stasiewicz, S., Furedi-Machacek, M., Conner, F., Tice, R. R., and Tennant, R. W. (2000). Responses of transgenic mouse lines p53(+/-) and Tg.AC to agents tested in conventional carcinogenicity bioassays. Toxicol. Sci. 53, 213-223.
177. Staudinger, J. L., Goodwin, B., Jones, S. A., Hawkins-Brown, D., MacKenzie, K. I., LaTour, A., Liu, Y., Klaassen, C. D., Brown, K. K., Reinhard, J., et al. (2001). The nuclear receptor PXR is a lithocholic acid sensor that protects against liver toxicity. Proc. Natl. Acad. Sci. U.S.A. 98, 3369-3374.
178. Stockinger, B. (2009). Beyond toxicity: aryl hydrocarbon receptor-mediated functions in the immune system. J. Biol. 8, 61.
179. Tennant, R. W., Spalding, J., and French, J. E. (1996). Evaluation of transgenic mouse bioassays for identifying carcinogens and noncarcinogens. Mutat. Res. 65, 119-127.
180. Thorpe, E., and Walker, A. I. (1973). The toxicology of dieldrin (HEOD). II. Comparative long-term oral toxicity studies in mice with dieldrin, DDT, phenobarbitone, -BHC and -BHC. Food Cosmet. Toxicol. 11, 433-442.
181. Thybaud, V., Dean, S., Nohmi, T., de Boer, J., Douglas, G. R., Glickman, B. W., Gorelick, N. J., Heddle, J. A., Heflich, R. H., Lambert, I., et al. (2003). In vivo transgenic mutation assays. Mutat. Res. 540, 141-151.
182. U.S. Environmental Protection Agency (EPA). (2005). Guidelines for Carcinogen Risk Assessment. EPA/630/P-03/001B. U.S. Environmental Protection Agency. Available at: http://www.epa.gov/ttn/atw/cancer_guidelines_final_3-25-05.pdf. Accessed December 2010.
183. U.S. Environmental Protection Agency (EPA). (2007). Framework for Determining a Mutagenic Mode of Action for Carcinogenicity. Available from http://www.epa.gov/osa/mmoaframework/pdfs/MMOA-ERD-FINAL-83007.pdf. Accessed December 2010.
184. U.S. Environmental Protection Agency (EPA) (2009). The U.S. Environmental Protection Agency's Strategic Plan for Evaluating the Toxicity of Chemicals. U.S. Environmental Protection Agency, Washington, DC. Available at: http://wwww.epa.gov/spc/toxicitytesting/. Accessed December 2010.
185. U.S. Environmental Protection Agency (EPA) (2010a). IRIS Toxicological Review of Acrylamide. Available from: http://www.epa.gov/iris/toxreviews/286tr.pdf. Accessed December 2010.
186. U.S. Environmental Protection Agency (EPA). (2010b). IRIS Toxicological Review of Hexavalent Chromium. Available from: http://cfpub.epa.gov/ncea/iris_drafts/recordisplay.cfm?deid=221433. Accessed December 2010.
187. Ueda, A., Hamadeh, H. K., Webb, H. K., Yamamoto, Y., Sueyoshi, T., Afshari, C. A., Lehmann, J. M., and Negishi, M. (2002). Diverse roles of the nuclear orphan receptor CAR in regulating hepatic genes in response to phenobarbital. Mol. Pharmacol. 61, 1-6.
188. Uno, S., Dalton, T. P., Derkenne, S., Curran, C. P., Miller, M. L., Shertzer, H. G., and Nebert, D. W. (2004). Oral exposure to benzo[a]pyrene in the mouse: detoxication by inducible cytochrome P450 is more important than metabolic activation. Mol. Pharmacol. 65, 1225-1237.
189. Uno, S., Dalton, T. P., Dragin, N., Curran, C. P., Derkenne, S., Miller, M. L., Shertzer, H. G., Gonzalez, F. J., and Nebert, D. W. (2006). Oral benzo[a]pyrene in Cyp1 knockout mouse lines: CYP1A1 important in detoxication, CYP1B1 metabolism required for immune damage independent of total-body urden and clearance rate. Mol. Pharmacol. 69, 1103-1114.
190. Valentine, J. L., Lee, S. S., Seaton, M. J., Asgharian, B., Farris, G., Corton, J. C., Gonzalez, F. J., and Medinsky, M. A. (1996). Reduction of benzene metabolism and toxicity in mice that lack CYP2E1 expression. Toxicol. Appl. Pharmacol. 141, 205-213.
191. van Kreijl, C. F., McAnulty, P. A., Beems, R. B., Vynckier, A., van Steeg, H., Fransson-Steen, R., Alden, C. L., Forster, R., van der Laan, J. W., and Vandenberghe, J. (2001). Xpa and Xpa/p53+/- knockout mice: overview of available data. Toxicol. Pathol. 29(Suppl.), 117-127.
192. van Steeg, H., de Vries, A., van Oostrom, C., van Benthem, J., Beems, R. B., and van Kreijl, C. F. (2001). DNA repair-deficient Xpa and Xpa/p53+/_ knock-out mice: nature of the models. Toxicol. Pathol. 29(Suppl.) 109-116.
193. van Waterschoot, R. A., Rooswinkel, R. W., Sparidans, R. W., van Herwaarden, A. E., Beijnen, J. H., and Schinkel, A. H. (2009). Inhibition and stimulation of intestinal and hepatic CYP3A activity: studies in humanized CYP3A4 transgenic mice using triazolam. Drug Metab. Dispos. 37, 2305-2313.
194. Veldhoen, M., and Duarte, J. H. (2010). The aryl hydrocarbon receptor: finetuning the immune-response. Curr. Opin. Immunol. 22, 747-752.
195. Venkatachalam, S., Tyner, S. D., Pickering, C. R., Boley, S., Recio, L., French, J. E., and Donehower, L. A. (2001). Is p53 haploinsufficient for tumor suppression? Implications for the p53+/_ mouse model in carcinogenicity testing. Toxicol. Pathol. 29(Suppl.), 147-154.
196. Vijg, J., Dolle, M. E., Martus, H. J., and Boerrigter, M. E. (1997). Transgenic mouse models for studying mutations in vivo: applications in aging research. ech. Ageing Dev. 98, 189-202.
197. Vijg, J., and Douglas, G. R. (1996). Bacteriophage Lambda and Plasmid lacZ Transgenic Mice for Studying Mutations In Vivo. Plenum Press, New York, Y.
198. Vogelstein, B., and Kinzler, K. W. (1993). The multistep nature of cancer. Trends Genet. 9, 138-141.
199. Watson, P., and Lynch, H. T. (2001). Cancer risk in mismatch repair gene mutation carriers. Fam. Cancer 1, 57-60.
200. Wei, P., Zhang, J., Egan-Hafley, M., Liang, S., and Moore, D. D. (2000). The nuclear receptor CAR mediates specific xenobiotic induction of drug etabolism. Nature 407, 920-923.
201. Wells, M. Y., and Williams, E. S. (2009). The transgenic mouse assay as an alternative test method for regulatory carcinogenicity studies-implications for EACH. Regul. Toxicol. Pharmacol. 53, 150-155.
202. Whysner, J., Ross, P. M., and Williams, G. M. (1996). Phenobarbital mechanistic data and risk assessment: enzyme induction, enhanced cell proliferation, and umor promotion. Pharmacol. Ther. 71, 153-191.
203. Wight, D. C., and Wagner, T. E. (1994). Transgenic mice: a decade of progress in technology and research. Mutat. Res. 307, 429-440.
204. Wijnhoven, S. W., and van Steeg, H. (2003). Transgenic and knockout mice for DNA repair functions in carcinogenesis and mutagenesis. Toxicology 193, 71-187.
205. Wijnhoven, S. W., Zwart, E., Speksnijder, E. N., Beems, R. B., Olive, K. P., Tuveson, D. A., Jonkers, J., Schaap, M. M., van den Berg, J., Jacks, T., et al. (2005). Mice expressing a mammary gland-specific R270H mutation in the p53 tumor suppressor gene mimic human breast cancer development. Cancer Res 65, 166-8173.
206. Wu, Y., and Luo, Y. (2005). Transgenic C. elegans as a model in Alzheimer's research. Curr. Alzheimer Res. 2, 37-45.
207. Xie, W., Barwick, J. L., Downes, M., Blumberg, B., Simon, C. M., Nelson, M. C., Neuschwander-Tetri, B. A., Brunt, E. M., Guzelian, P. S., and Evans, R. M. (2000). Humanized xenobiotic response in mice expressing nuclear receptor SXR. Nature 406, 435-439.
208. Yamamoto, Y., Moore, R., Goldsworthy, T. L., Negishi, M., and Maronpot, R. R. (2004). The orphan nuclear receptor constitutive active/androstane receptor is essential for liver tumor promotion by phenobarbital in mice. Cancer Res 64, 7197-7200.
209. Yang, L., Ho, N. Y., Alshut, R., Legradi, J., Weiss, C., Reischl, M., Mikut, R., Liebel, U., Muller, F., and Strahle, U. (2009). Zebrafish embryos as models for embryotoxic and teratological effects of chemicals. Reprod Toxicol 28, 245-253.
210. Yang, Q.,Nagano, T., Shah, Y., Cheung, C., Ito, S., andGonzalez, F. J. (2008). The PPARalpha-humanized mouse: amodel to investigate species differences in liver toxicity mediated by PPAR alpha. Toxicol Sci 101, 132-139.
211. Yatagai, F., Kurobe, T., Nohmi, T., Masumura, K., Tsukada, T., Yamaguchi, H., Kasai-Eguchi, K., and Fukunishi, N. (2002). Heavy-ioninduced mutations in the gpt delta transgenic mouse: effect of p53 gene knockout. Environ. Mol. Mutagen. 40, 216-225.
212. Yu, A. M., Fukamachi, K., Krausz, K. W., Cheung, C., and Gonzalez, F. J. (2005). Potential role for human cytochrome P450 3A4 in estradiol homeostasis. ndocrinology 146, 2911-2919.
213. Zaher, H., Buters, J. T., Ward, J. M., Bruno, M. K., Lucas, A. M., Stern, S. T., Cohen, S. D., and Gonzalez, F. J. (1998). Protection against acetaminophen toxicity in CYP1A2 and CYP2E1 double-null mice. Toxicol. Appl. Pharmacol. 152, 193-199.
214. Zhang, J., Huang, W., Chua, S. S., Wei, P., and Moore, D. D. (2002). Modulation of acetaminophen-induced hepatotoxicity by the xenobiotic receptor CAR. cience 298, 422-424.