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Archives of Toxicology

, Volume 78, Issue 6, pp 309–315 | Cite as

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

  • Kei Takemoto
  • Miki Nakajima
  • Yuto Fujiki
  • Miki Katoh
  • Frank J. Gonzalez
  • Tsuyoshi Yokoi
Molecular Toxicology

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.

Keywords

Cyp1b1 Aryl hydrocaron receptor Estrogen receptor 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) Antiestrogenic activity 

Notes

Acknowledgements

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

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Copyright information

© Springer-Verlag 2004

Authors and Affiliations

  • Kei Takemoto
    • 1
  • Miki Nakajima
    • 1
  • Yuto Fujiki
    • 1
  • Miki Katoh
    • 1
  • Frank J. Gonzalez
    • 2
  • Tsuyoshi Yokoi
    • 1
  1. 1.Division of Drug Metabolism, Faculty of Pharmaceutical SciencesKanazawa UniversityKanazawa Japan
  2. 2.National Cancer InstituteBethesdaUSA

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