Summary
The molecular mechanisms of toxic agents are rarely likely to be the result of change in the expression of a single gene. Even apparently simple actions of chemicals are probably the consequence of genetically variable multigene expression. One strategy for attacking this problem is to take advantage of the genetic variation of response in mice to search for susceptibility genes using genetic linkage analysis in combination with comparisons of gene expression in the parent strains by cDNA microarray technology. Genetic variation in mice and toxicogenomics were used to explore mechanisms of gene interaction leading to cell malfunction and injury in the liver caused by dioxin. This demonstrated susceptibility loci, other than the Ahr gene, pertinent to the development of porphyria (a disruption of heme synthesis) and liver injury. cDNA arrays of 4000 IMAGE clones pertinent to toxicology were used to compare candidate multiple gene expression in strains relative to their initial hepatic response e.g. induction of drug metabolism enzymes, and to their subsequent development of porphyria and liver injury. Phenotypic response was compared with gene expression by metabolic system including groups of genes for heme and iron metabolism, the AH battery and oxidative stress.
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References
Alizadeh AA, Elsen MB, Davis E, Ma C, Lossos IS, Rosenwald A, Boldrick JC, Sabet H, Tran T, Yu X, Powell JI, Yang Liming, Marti GE, Moore T, Hudson J Jr, Lu L, Lewis DB, Tibshirani R, Sherlock G, Chan WC, Greiner TC, Weisenburger DD, Armitage JO, Warnke R, Levy R, Wilson W, Grever MR, Byrd JC, Botstein D, Brown PO, Staudt LM (2000) Distinct types of diffuse large B-cell lymphoma identified by gene expression profiling. Nature 403: 503–511.
Fernandez-Salguero PM, Hilbert DM, Rudikoff S, Ward JM, Gonzalez FJ (1996) Arylhydrocarbon receptor-deficient mice are resistant to 2,3,7,8-tetrachlorodibenzo-p-dioxin-induced toxicity. Toxicol Appl Pharmacol 140: 173–179.
Fleming RE, Holden CC, Tamatsu S, Waheed A, Brunt EM, Britton RS, Bacon BR, Roopenian DC, Sly WS (2001) Mouse strain differences determine severity of iron accumulation in Hfe knockout model of hereditary hemochromatosis. PNAS 98: 2707–2711.
Greig AG, Francis JE, Kay SJE, Lovell DP, Smith AG (1984) Incomplete correlation of 2,3,7,8-tetrachlorodibenzo-p-dioxin hepatotoxicity with Ah phenotype in mice. Toxicol Appl Pharmacol 74: 17–25.
Gu Y-Z, Hogenesch JB, Bradfield CA (2000) The PAS superfamily: Sensors of environmental and developmental signals. Annu Rev Pharmacol Toxicol 40: 519–561.
Ikeda M, Ishii Y, Kato H, Akazawa D, Hatsumura M, Ishida T, Matsusue K, Yamada H, Oguri K (2000) Suppression of carbonic anhydrase 111 in rat liver by a dioxin-related toxic compound, coplanar polychlorinated biphenyl, 3,3’,4,4’,5-pentachlorobiphenyl. Arch Biochem Biophys 380: 159–164.
Meyer UA, Zanger UM (1997) Molecular mechanisms of genetic polymorphisms of drug metabolism. Annu Rev Pharmacol Toxicol 37: 269–296.
Nebert DW, Puga A, Vasiliou V (1993) Role of the Ah receptor and the dioxin-inducible [Ah gene battery in toxicity, cancer, and signal transduction. Ann N Y Acad Sci 685: 624–640.
Oscarson M, Ingelman-Sundberg M, Daly AK, Nebert DW (2001) Human Cytochrome P450 (CYP) Alleles. http://www.imm.ki.se/CYPalleles/.
Shertzer HG, Nebert DW, Puga A, Ary M, Sonntag D, Dixon K, Robinson LJ, Cianciolo E, Dalton TP (1998) Dioxin causes a sustained oxidative stress response in the mouse. Biochem Biophys Res Commun 253: 44–48.
Smith AG, Clothier B, Robinson S, Scullion MJ, Carthew P, Edwards R, Luo J, Lim CK (1998) Interaction between iron metabolism and 2,3,7,8-tetrachlorodibenzo-p-dioxin in mice with variants of the Ahr gene: A heptic oxidative mechanism. Mol Pharmacol 53: 52–61.
Smith AG, Clothier B, Carthew P, Childs NL, Sinclair PR, Nebert DW, Dalton TP (2001) Protection of the Cypla2(-/-) null mouse against uroporphyria and hepatic injury following exposure to 2,3,7,8-Tetrachlorodibenzo-p-dioxin. Toxicol Appl Pharmacol 173: 89–98.
Turton NJ, Judah DJ, Riley J, Davies R, Lipson D, Styles JA, Smith AG, Gant TW (2001) Gene expression and amplification in breast carcinoma cells with intrinsic and acquired doxorubicin resistance. Oncogene 20: 1300–1306.
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Smith, A.G. et al. (2003). Use of reverse genetics and cDNA arrays to understand ‘dioxin’ toxicity. In: Inoue, T., Pennie, W.D. (eds) Toxicogenomics. Springer, Tokyo. https://doi.org/10.1007/978-4-431-66999-9_5
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DOI: https://doi.org/10.1007/978-4-431-66999-9_5
Publisher Name: Springer, Tokyo
Print ISBN: 978-4-431-67001-8
Online ISBN: 978-4-431-66999-9
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