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Proceedings of the National Academy of Sciences of the United States of America logoLink to Proceedings of the National Academy of Sciences of the United States of America
. 1996 Jun 25;93(13):6731–6736. doi: 10.1073/pnas.93.13.6731

Characterization of a murine Ahr null allele: involvement of the Ah receptor in hepatic growth and development.

J V Schmidt 1, G H Su 1, J K Reddy 1, M C Simon 1, C A Bradfield 1
PMCID: PMC39095  PMID: 8692887

Abstract

The Ah receptor (AHR) is a ligand-activated transcription factor that mediates a pleiotropic response to environmental contaminants such as benzo[a]pyrene and 2,3,7,8-tetrachlorodibenzo-p-dioxin. In an effort to gain insight into the physiological role of the AHR and to develop models useful in risk assessment, gene targeting was used to inactivate the murine Ahr gene by homologous recombination. Ahr-/- mice are viable and fertile but show a spectrum of hepatic defects that indicate a role for the AHR in normal liver growth and development. The Ahr-/- phenotype is most severe between 0-3 weeks of age and involves slowed early growth and hepatic defects, including reduced liver weight, transient microvesicular fatty metamorphosis, prolonged extramedullary hematopoiesis, and portal hypercellularity with thickening and fibrosis.

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Selected References

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  1. BROWN R. R., MILLER J. A., MILLER E. C. The metabolism of methylated aminoazo dyes. IV. Dietary factors enhancing demethylation in vitro. J Biol Chem. 1954 Jul;209(1):211–222. [PubMed] [Google Scholar]
  2. Bowdler A. J. Splenomegaly and hypersplenism. Clin Haematol. 1983 Jun;12(2):467–488. [PubMed] [Google Scholar]
  3. Bradfield C. A., Chang Y., Bjeldanes L. F. Effects of commonly consumed vegetables on hepatic xenobiotic-metabolizing enzymes in the mouse. Food Chem Toxicol. 1985 Oct;23(10):899–904. doi: 10.1016/0278-6915(85)90105-x. [DOI] [PubMed] [Google Scholar]
  4. Bradfield C. A., Kende A. S., Poland A. Kinetic and equilibrium studies of Ah receptor-ligand binding: use of [125I]2-iodo-7,8-dibromodibenzo-p-dioxin. Mol Pharmacol. 1988 Aug;34(2):229–237. [PubMed] [Google Scholar]
  5. Burbach K. M., Poland A., Bradfield C. A. Cloning of the Ah-receptor cDNA reveals a distinctive ligand-activated transcription factor. Proc Natl Acad Sci U S A. 1992 Sep 1;89(17):8185–8189. doi: 10.1073/pnas.89.17.8185. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Chan W. K., Chu R., Jain S., Reddy J. K., Bradfield C. A. Baculovirus expression of the Ah receptor and Ah receptor nuclear translocater. Evidence for additional dioxin responsive element-binding species and factors required for signaling. J Biol Chem. 1994 Oct 21;269(42):26464–26471. [PubMed] [Google Scholar]
  7. Dolwick K. M., Swanson H. I., Bradfield C. A. In vitro analysis of Ah receptor domains involved in ligand-activated DNA recognition. Proc Natl Acad Sci U S A. 1993 Sep 15;90(18):8566–8570. doi: 10.1073/pnas.90.18.8566. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Ema M., Sogawa K., Watanabe N., Chujoh Y., Matsushita N., Gotoh O., Funae Y., Fujii-Kuriyama Y. cDNA cloning and structure of mouse putative Ah receptor. Biochem Biophys Res Commun. 1992 Apr 15;184(1):246–253. doi: 10.1016/0006-291x(92)91185-s. [DOI] [PubMed] [Google Scholar]
  9. Favreau L. V., Pickett C. B. Transcriptional regulation of the rat NAD(P)H:quinone reductase gene. Identification of regulatory elements controlling basal level expression and inducible expression by planar aromatic compounds and phenolic antioxidants. J Biol Chem. 1991 Mar 5;266(7):4556–4561. [PubMed] [Google Scholar]
  10. Fernandez-Salguero P., Pineau T., Hilbert D. M., McPhail T., Lee S. S., Kimura S., Nebert D. W., Rudikoff S., Ward J. M., Gonzalez F. J. Immune system impairment and hepatic fibrosis in mice lacking the dioxin-binding Ah receptor. Science. 1995 May 5;268(5211):722–726. doi: 10.1126/science.7732381. [DOI] [PubMed] [Google Scholar]
  11. Gonzalez F. J., Tukey R. H., Nebert D. W. Structural gene products of the Ah locus. Transcriptional regulation of cytochrome P1-450 and P3-450 mRNA levels by 3-methylcholanthrene. Mol Pharmacol. 1984 Jul;26(1):117–121. [PubMed] [Google Scholar]
  12. Hoffman E. C., Reyes H., Chu F. F., Sander F., Conley L. H., Brooks B. A., Hankinson O. Cloning of a factor required for activity of the Ah (dioxin) receptor. Science. 1991 May 17;252(5008):954–958. doi: 10.1126/science.1852076. [DOI] [PubMed] [Google Scholar]
  13. Jones P. B., Galeazzi D. R., Fisher J. M., Whitlock J. P., Jr Control of cytochrome P1-450 gene expression by dioxin. Science. 1985 Mar 22;227(4693):1499–1502. doi: 10.1126/science.3856321. [DOI] [PubMed] [Google Scholar]
  14. Lamb J. G., Straub P., Tukey R. H. Cloning and characterization of cDNAs encoding mouse Ugt1.6 and rabbit UGT1.6: differential induction by 2,3,7,8-tetrachlorodibenzo-p-dioxin. Biochemistry. 1994 Aug 30;33(34):10513–10520. doi: 10.1021/bi00200a037. [DOI] [PubMed] [Google Scholar]
  15. Liang H. C., Li H., McKinnon R. A., Duffy J. J., Potter S. S., Puga A., Nebert D. W. Cyp1a2(-/-) null mutant mice develop normally but show deficient drug metabolism. Proc Natl Acad Sci U S A. 1996 Feb 20;93(4):1671–1676. doi: 10.1073/pnas.93.4.1671. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. MacKenzie S. A., Thomas T., Umbreit T. H., Gallo M. A. The potentiation of 2,3,7,8-tetrachlorodibenzo-p-dioxin toxicity by tamoxifen in female CD1 mice. Toxicol Appl Pharmacol. 1992 Sep;116(1):101–109. doi: 10.1016/0041-008x(92)90150-q. [DOI] [PubMed] [Google Scholar]
  17. Mansour S. L., Thomas K. R., Capecchi M. R. Disruption of the proto-oncogene int-2 in mouse embryo-derived stem cells: a general strategy for targeting mutations to non-selectable genes. Nature. 1988 Nov 24;336(6197):348–352. doi: 10.1038/336348a0. [DOI] [PubMed] [Google Scholar]
  18. McDonnell W. M., Chensue S. W., Askari F. K., Moseley R. H. Hepatic fibrosis in Ahr-/- mice. Science. 1996 Jan 12;271(5246):223–224. [PubMed] [Google Scholar]
  19. Nagy A., Rossant J., Nagy R., Abramow-Newerly W., Roder J. C. Derivation of completely cell culture-derived mice from early-passage embryonic stem cells. Proc Natl Acad Sci U S A. 1993 Sep 15;90(18):8424–8428. doi: 10.1073/pnas.90.18.8424. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Perdew G. H. Association of the Ah receptor with the 90-kDa heat shock protein. J Biol Chem. 1988 Sep 25;263(27):13802–13805. [PubMed] [Google Scholar]
  21. Pineau T., Fernandez-Salguero P., Lee S. S., McPhail T., Ward J. M., Gonzalez F. J. Neonatal lethality associated with respiratory distress in mice lacking cytochrome P450 1A2. Proc Natl Acad Sci U S A. 1995 May 23;92(11):5134–5138. doi: 10.1073/pnas.92.11.5134. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Pitot H. C., Goldsworthy T., Campbell H. A., Poland A. Quantitative evaluation of the promotion by 2,3,7,8-tetrachlorodibenzo-p-dioxin of hepatocarcinogenesis from diethylnitrosamine. Cancer Res. 1980 Oct;40(10):3616–3620. [PubMed] [Google Scholar]
  23. Pohl R. J., Fouts J. R. A rapid method for assaying the metabolism of 7-ethoxyresorufin by microsomal subcellular fractions. Anal Biochem. 1980 Sep 1;107(1):150–155. doi: 10.1016/0003-2697(80)90505-9. [DOI] [PubMed] [Google Scholar]
  24. Poland A., Glover E. Characterization and strain distribution pattern of the murine Ah receptor specified by the Ahd and Ahb-3 alleles. Mol Pharmacol. 1990 Sep;38(3):306–312. [PubMed] [Google Scholar]
  25. Poland A., Knutson J. C. 2,3,7,8-tetrachlorodibenzo-p-dioxin and related halogenated aromatic hydrocarbons: examination of the mechanism of toxicity. Annu Rev Pharmacol Toxicol. 1982;22:517–554. doi: 10.1146/annurev.pa.22.040182.002505. [DOI] [PubMed] [Google Scholar]
  26. Pollenz R. S., Sattler C. A., Poland A. The aryl hydrocarbon receptor and aryl hydrocarbon receptor nuclear translocator protein show distinct subcellular localizations in Hepa 1c1c7 cells by immunofluorescence microscopy. Mol Pharmacol. 1994 Mar;45(3):428–438. [PubMed] [Google Scholar]
  27. Quattrochi L. C., Vu T., Tukey R. H. The human CYP1A2 gene and induction by 3-methylcholanthrene. A region of DNA that supports AH-receptor binding and promoter-specific induction. J Biol Chem. 1994 Mar 4;269(9):6949–6954. [PubMed] [Google Scholar]
  28. Reyes H., Reisz-Porszasz S., Hankinson O. Identification of the Ah receptor nuclear translocator protein (Arnt) as a component of the DNA binding form of the Ah receptor. Science. 1992 May 22;256(5060):1193–1195. doi: 10.1126/science.256.5060.1193. [DOI] [PubMed] [Google Scholar]
  29. Robertson E., Bradley A., Kuehn M., Evans M. Germ-line transmission of genes introduced into cultured pluripotential cells by retroviral vector. Nature. 1986 Oct 2;323(6087):445–448. doi: 10.1038/323445a0. [DOI] [PubMed] [Google Scholar]
  30. Schmidt C., Bladt F., Goedecke S., Brinkmann V., Zschiesche W., Sharpe M., Gherardi E., Birchmeier C. Scatter factor/hepatocyte growth factor is essential for liver development. Nature. 1995 Feb 23;373(6516):699–702. doi: 10.1038/373699a0. [DOI] [PubMed] [Google Scholar]
  31. Southern E. M. Detection of specific sequences among DNA fragments separated by gel electrophoresis. J Mol Biol. 1975 Nov 5;98(3):503–517. doi: 10.1016/s0022-2836(75)80083-0. [DOI] [PubMed] [Google Scholar]
  32. Sutter T. R., Tang Y. M., Hayes C. L., Wo Y. Y., Jabs E. W., Li X., Yin H., Cody C. W., Greenlee W. F. Complete cDNA sequence of a human dioxin-inducible mRNA identifies a new gene subfamily of cytochrome P450 that maps to chromosome 2. J Biol Chem. 1994 May 6;269(18):13092–13099. [PubMed] [Google Scholar]
  33. Telakowski-Hopkins C. A., King R. G., Pickett C. B. Glutathione S-transferase Ya subunit gene: identification of regulatory elements required for basal level and inducible expression. Proc Natl Acad Sci U S A. 1988 Feb;85(4):1000–1004. doi: 10.1073/pnas.85.4.1000. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Tybulewicz V. L., Crawford C. E., Jackson P. K., Bronson R. T., Mulligan R. C. Neonatal lethality and lymphopenia in mice with a homozygous disruption of the c-abl proto-oncogene. Cell. 1991 Jun 28;65(7):1153–1163. doi: 10.1016/0092-8674(91)90011-m. [DOI] [PubMed] [Google Scholar]
  35. Törrönen R., Pelkonen K., Kärenlampi S. Enzyme-inducing and cytotoxic effects of wood-based materials used as bedding for laboratory animals. Comparison by a cell culture study. Life Sci. 1989;45(6):559–565. doi: 10.1016/0024-3205(89)90107-0. [DOI] [PubMed] [Google Scholar]
  36. Uehara Y., Minowa O., Mori C., Shiota K., Kuno J., Noda T., Kitamura N. Placental defect and embryonic lethality in mice lacking hepatocyte growth factor/scatter factor. Nature. 1995 Feb 23;373(6516):702–705. doi: 10.1038/373702a0. [DOI] [PubMed] [Google Scholar]
  37. Watanabe M., Osada J., Aratani Y., Kluckman K., Reddick R., Malinow M. R., Maeda N. Mice deficient in cystathionine beta-synthase: animal models for mild and severe homocyst(e)inemia. Proc Natl Acad Sci U S A. 1995 Feb 28;92(5):1585–1589. doi: 10.1073/pnas.92.5.1585. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. Whitlock J. P., Jr The regulation of gene expression by 2,3,7,8-tetrachlorodibenzo-p-dioxin. Pharmacol Rev. 1987 Jun;39(2):147–161. [PubMed] [Google Scholar]
  39. Wilhelmsson A., Cuthill S., Denis M., Wikström A. C., Gustafsson J. A., Poellinger L. The specific DNA binding activity of the dioxin receptor is modulated by the 90 kd heat shock protein. EMBO J. 1990 Jan;9(1):69–76. doi: 10.1002/j.1460-2075.1990.tb08081.x. [DOI] [PMC free article] [PubMed] [Google Scholar]

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