Skip to main content

Advertisement

SpringerLink
Log in

Role of the aryl hydrocarbon receptor and Cyp1b1 in the antiestrogenic activity of 2,3,7,8-tetrachlorodibenzo-p-dioxin

  • Molecular Toxicology
  • Published:
Archives of Toxicology Aims and scope Submit manuscript

Abstract

The role of aryl hydrocarbon receptor (AhR) and cytochrome P450 (Cyp) 1 family in the antiestrogenic activity of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) was investigated in vivo. Immature (21 days old) AhR, Cyp1a2, or Cyp1b1 knockout (−/−) mice were treated intraperitoneally with estradiol (E2, 20 ng/mouse per day, for 14 consecutive days) and/or TCDD (200 ng/mouse per day, on days 7, 9, 11, and 13). Uterine wet weight and uterine peroxidase activity (UPA) were measured as markers of estrogen responsiveness. UPA was a better marker of estrogen responsiveness than the uterine wet weight. In AhR wild-type (+/+) mice, UPA (208.1±81.6 units/g tissue) was increased by the administration of E2 (to 297.2±178.7 units/g). The administration of TCDD significantly (p<0.01) decreased the UPA (10.5±3.4 units/g) compared with that in the control mice. Co-administration of TCDD with E2 also significantly (p<0.05) decreased the UPA (18.8±19.9 units/g) compared with that in E2-treated mice. In AhR(−/−) mice, UPA (162.9±146.7 units/g) was significantly (p<0.01) increased by the administration of E2 (486.8±108.2 units/g). In contrast to the results in AhR(+/+) mice, UPA was not affected by the administration of TCDD (51.8±70.6 units/g) compared with control, and co-administration of TCDD with E2 (545.8±189.4 units/g) compared with that in E2-treated mice. In Cyp1a2/1b1(+/+) mice, UPA was significantly (p<0.05) increased by the administration of E2 (70.0±36.4 units/g). Co-administration of TCDD with E2 significantly (p<0.05) decreased the UPA (29.6±22.2 units/g) compared with that in E2-treated mice. In Cyp1a2(−/−) mice, co-administration of TCDD with E2 significantly (p<0.01) decreased the UPA (6.8±5.1 units/g) compared with that in E2-treated mice. In Cyp1b1(−/−) mice, UPA (5.5±8.1 units/g) was significantly (p<0.05) increased by the administration of E2 (56.6±34.1 units/g). In contrast to the results in Cyp1a2/1b1(+/+) mice or Cyp1a2(−/−) mice, UPA was not affected by the co-administration of TCDD and E2 (52.6±30.1 units/g) compared with that in E2-treated mice. This is the first demonstration that Cyp1b1 as well as AhR is involved in the antiestrogenic effects of TCDD.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1A, B
Fig. 2
Fig. 3

Similar content being viewed by others

References

  • Abbott BD, Schmid JE, Pitt JA, Buckalew AR, Wood CR, Hel, GA, Diliberto JJ (1999) Adverse reproductive outcomes in the transgenic Ah receptor-deficient mouse. Toxicol Appl Pharmacol 155:62–70

    Article  CAS  PubMed  Google Scholar 

  • Aoyama T, Korzekwa K, Nagata K, Gillette J, Gelboin HV, Gonzalez FJ (1990) Estradiol metabolism by cDNA expressed human cytochrome P450s. Endocrinology 126:3101–3106

    CAS  PubMed  Google Scholar 

  • Astroff B, Eldridge B, Safe S (1991) Inhibition of the 17β-estradiol-induced and constitutive expression of the cellular protooncogene c-fos by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in the female rat uterus. Toxicol Lett 56:305–315

    Article  CAS  PubMed  Google Scholar 

  • Bradford A (1976) Rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem 72:248–254

    Article  CAS  PubMed  Google Scholar 

  • Brodie A (1991) Aromatase and its inhibitors—an overview. J Steroid Biochem Mol Biol 40:255–261

    Article  CAS  PubMed  Google Scholar 

  • Buchanan DL, Sato T, Peterson RE, Cooke PS (2000) Antiestrogenic effects of 2,3,7,8-tetrachlordibenzo-p-dioxin in mouse uterus: critical role of the aryl hydrocarbon receptor in stromal tissue. Toxicol Sci 57:302–311

    Article  CAS  PubMed  Google Scholar 

  • Bunyagidj C, MaLachlan JA (1988) Catechol estrogen formation in mouse uterus. J Steroid Biochem 31:795–801

    Article  CAS  PubMed  Google Scholar 

  • Buters JT, Sakai S, Richter T, Pineau, T, Alexander DL, Savas U, Doehmer J, Ward JM, Jefcoate CR, Gonzalez FJ (1999) Cytochrome P450 CYP1B1 determines susceptibility to 7,12-dimethylbenz[a]anthracene-induced lymphomas. Proc Natl Acad Sci USA 96:1977–1982

    Article  CAS  PubMed  Google Scholar 

  • Dannan GA, Porubek DJ, Nelson SD, Waxman DJ, Guengerich FP (1986)17β-Estradiol 2- and 4-hydroxylation catalyzed by rat hepatic cytochrome P-450: roles of individual forms, inductive effects, developmental patterns, and alterations by gonadectomy and hormone replacement. Endocrinology 118:1952–1960

    CAS  PubMed  Google Scholar 

  • Fernandez-Salguero P, Pineau T, Hilbert DM, McPhail T, Lee SS, Kimura S, Nebert DW, Rudikoff S, Ward JM, Gonzalez FJ (1995) Immune system impairment and hepatic fibrosis in mice lacking the dioxin-binding Ah receptor. Science 268:722–726

    CAS  PubMed  Google Scholar 

  • Fishman J (1976) The cathechol estrogens. Neuroendocrinology 22:363–374

    CAS  PubMed  Google Scholar 

  • Gale SK, Sclafani A (1977) Comparison of ovarian and hypothalamic obesity syndromes in the female rat: effects of diet palatability on food intake and body weight. J Comp Physiol Psychol 91:381–392

    CAS  PubMed  Google Scholar 

  • Gallo MA, Hesse EJ, Macdonald GJ, Umbreit TH (1986) Interactive effects of estradiol and 2,3,7,8-tetrachlordibenzo-p-dioxin on hepatic cytochrome P-450 and mouse uterus. Toxicol Lett 32:123–132

    Article  CAS  PubMed  Google Scholar 

  • Gierthy JF, Lincoln DW, Gillespie MB, Seeger JI, Martinez HL, Dickerman HW, Kumar SA (1987) Suppression of estrogen-related extracellular tissue plasminogen activator activity of MCF-7 cells by 2,3,7,8-tetrachlordibenzo-p-dioxin. Cancer Res 47:6198–6203

    CAS  PubMed  Google Scholar 

  • Hankinson O (1995) The aryl hydrocarbon receptor complex. Annu Rev Pharmacol Toxicol 35:307–340

    Google Scholar 

  • Hayes CL, Spink DC, Spink BC, Cao JQ, Walker NJ, Sutter TR (1996) 17β-Estradiol hydroxylation catalyzed by human cytochrome P4501B1. Proc Natl Acad Sci USA 93:9776–9781

    CAS  PubMed  Google Scholar 

  • Jellinck PH, Newcombe A, Keeping HS (1979) Peroxidase as a marker enzyme in estrogen-responsive tissues. Adv Enzyme Regul 17:325–331

    Article  CAS  Google Scholar 

  • Kharat I, Saatcioglu F (1996) Antiestrogenic effects of 2,3,7,8-tetrachlordibenzo-p-dioxin are mediated by direct transcriptional interference with the liganded estrogen receptor. Cross-talk between aryl hydrocarbon- and estrogen-mediated signaling. J Biol Chem 271:10533–10537

    Article  CAS  PubMed  Google Scholar 

  • Krishnan V, Porter W, Santostefano M, Wang X, Safe S (1995) Molecular mechanism of inhibition of estrogen-induced cathepsin D gene expression by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in MCF-7 cells. Mol Cell Biol 15:6710–6719

    CAS  PubMed  Google Scholar 

  • Lee AJ, Cai MX, Thomas PE, Conney AH, Zhu BT (2003) Characterization of the oxidative metabolites of 17β-estradiol and estrone formed by 15 selectively expressed human cytochrome P450 isoforms. Endocrinology 144:3382–3398

    Article  CAS  PubMed  Google Scholar 

  • Lyttle CR, DeSombre ER (1977a) Generality of oestrogen stimulation of peroxidase activity in growth responsive tissues. Nature 268:337–339

    CAS  PubMed  Google Scholar 

  • Lyttle CR, DeSombre ER (1977b) Uterine peroxidase as a marker for estrogen action. Proc Natl Acad Sci USA 74:3162–3166

    CAS  PubMed  Google Scholar 

  • Nutter LM, Wu YY, Ngo EO, Sierra EE, Gutierrez PL, Abul-Hajj YJ (1994) An o-quinone form of estrogen produces free radicals in human breast cancer cells: correlation with DNA damage. Chem Res Toxicol 7:23–38

    CAS  PubMed  Google Scholar 

  • Ohtake F, Takeyama K, Matsumono T, Kitagawa H, Yamamoto Y, Nohara K, Tohyama C, Krust A, Mimura J, Chambon P, Yanagisawa J, Fujii-Kuriyama Y, Kato S (2003) Modulation of oestrogen receptor signaling by association with the activated dioxin receptor. Nature 423:545–550

    Article  CAS  PubMed  Google Scholar 

  • Pineau T, Fernandez-Salguero P, Lee SS, McPhail T, Ward JM, Gonzalez FJ (1995) Neonatal lethality associated with respiratory distress in mice lacking cytochrome P450 1A2. Proc Natl Acad Sci USA 92:5134–5138

    CAS  PubMed  Google Scholar 

  • Poland A, Knutson JC (1987) 2,3,7,8-Tetrachlorodibenzo-p-dioxin and related halogenated aromatic hydrocarbons: examination of the mechanism of toxicity. Annu Rev Pharmacol Toxicol 22:517–554

    Article  Google Scholar 

  • Safe SH (1986) Comparative toxicology and mechanism of action of polychlorinated dibenzo-p-dioxins and dibenzofurans. Annu Rev Pharmacol Toxicol 26:371–399

    Google Scholar 

  • Safe SH (1995) Modulation of gene expression and endocrine response pathways by 2,3,7,8-tetrachlordibenzo-p-dioxin and related compounds. Pharmacol Ther 67:247–281

    CAS  PubMed  Google Scholar 

  • Safe S, Krishnan V (1995) Chlorinated hydrocarbons: estrogens and antiestrogens. Toxicol Lett 82–83:731–736

    Google Scholar 

  • Safe S, Astroff B, Harris M, Zacharewski T, Dickerson R, Romkes M, Biegel L (1991) 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) and related compounds as antiestrogens: characterization and mechanism of action. Pharmacol Toxicol 69:400–409

    CAS  PubMed  Google Scholar 

  • Savas U, Christou M, Jefcoate CR (1993) Mouse endometrium stromal cells express a polycyclic aromatic hydrocarbon-inducible cytochrome P450 that closely resembles the novel P450 in mouse embryo fibroblasts (P450EF). Carcinogenesis 14:2013–2018

    CAS  PubMed  Google Scholar 

  • Savas U, Bhattacharyya KK, Christou M, Alexander DL, Jefcoate CR (1994) Mouse cytochrome P-450EF, representative of a new 1B subfamily of cytochrome P-450s. Cloning, sequence determination, and tissue expression. J Biol Chem 269:14905–14911

    CAS  PubMed  Google Scholar 

  • Sesardic D, Pasanen M, Pelkonen O, Boobis AR (1990) Differential expression and regulation of the cytochrome P450IA gene subfamily in human tissues. Carcinogenesis 11:1183–1188

    CAS  PubMed  Google Scholar 

  • Shimada T, Inoue K, Suzuki Y, Kawai T, Azuma E, Nakajima T, Shindo M, Kurose K, Sugie A, Yamagishi Y, Fujii-Kuriyama Y, Hashimoto M (2002) Arylhydrocarbon receptor-dependent induction of liver and lung cytochrome P450 1A1, 1A2, and 1B1 by polycyclic aromatic hydrocarbons and polychlorinated biphenyls in genetically engineered C57BL/6 J mice. Carcinogenesis 23:1199–1207

    Article  CAS  PubMed  Google Scholar 

  • Simpson E, Rubin G, Clyne C, Robertson K, O’Donnell L, Davis S, Jones M (1999) Local estrogen biosynthesis in males and females. Endocr Relat Cancer 6:131–137

    CAS  PubMed  Google Scholar 

  • Umbreit TH, Hesse EJ, Macdonald GJ, Gallo MA (1988) Effects of TCDD–estradiol interactions in three strains of mice. Toxicol Lett 40:1–9

    Article  CAS  PubMed  Google Scholar 

  • White TE, Gasiewics TA (1993) The human estrogen receptor structural gene contains a DNA sequence that binds activated mouse and human Ah receptors: a possible mechanism of estrogen receptor regulation by 2,3,7,8-tetrachlordibenzo-p-dioxin. Biochem Biophys Res Commun 193:956–962

    Article  CAS  PubMed  Google Scholar 

  • Wormke M, Stoner M, Saville B, Safe S (2000) Crosstalk between estrogen receptor α and the aryl hydrocarbon receptor in breast cancer cells involves unidirectional activation of proteasomes. FEBS Lett 478:109–112

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We thank Mr. Brent Bell for reviewing the manuscript. The experiments in the present study complied with the current laws in Japan.

Author information

Authors and Affiliations

  1. Division of Drug Metabolism, Faculty of Pharmaceutical Sciences, Kanazawa University, Takara-machi 13-1, 920-0934, Kanazawa , Japan

    Kei Takemoto, Miki Nakajima, Yuto Fujiki, Miki Katoh & Tsuyoshi Yokoi

  2. National Cancer Institute, Bethesda, MD 20892, USA

    Frank J. Gonzalez

Authors
  1. Kei Takemoto
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Miki Nakajima
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Yuto Fujiki
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Miki Katoh
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Frank J. Gonzalez
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Tsuyoshi Yokoi
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Tsuyoshi Yokoi.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Takemoto, K., Nakajima, M., Fujiki, Y. et al. Role of the aryl hydrocarbon receptor and Cyp1b1 in the antiestrogenic activity of 2,3,7,8-tetrachlorodibenzo-p-dioxin. Arch Toxicol 78, 309–315 (2004). https://doi.org/10.1007/s00204-004-0550-7

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00204-004-0550-7

Keywords

Search

Navigation