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

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. © Springer-Verlag 2004.