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.

Impact of Polychlorinated Biphenyls Contamination on Estrogenic Activity in Human Male Serum

“…Besides CYP1A1, 1A2, and 1B1 iso-enzymes, CYP3A4 has been suggested to play a major role in hydroxylation of E 2 (Badawi et al 2000; Hayes et al 1996; Pang et al 1999; Spink et al 1990; Takemoto et al 2004; Yamazaki et al 1998). Induction of CYP3A4 is a consequence of exposure to prevalent nondioxin-like PCBs (Gillette et al 2002; Parkinson et al 1981).…”

CYP1A in TCDD Toxicity and in Physiology–with Particular Reference to CYP Dependent Arachidonic Acid Metabolism and other Endogenous Substrates

“…Two estrogen-related effects of TCDD, suppression of uterine weight and uterine peroxidase activity, were seen in CYP1A2 − / − mice, indicating that CYP1A2 is not involved in those effects of TCDD (Takemoto et al, 2004).…”

Regulation of Estrogen Sulfotransferase Expression by Confluence of MCF10A Breast Epithelial Cells: Role of the Aryl Hydrocarbon Receptor

“…Our results add to the growing number of mechanisms whereby the AhR modulates estrogenic activity. Antiestrogenic effects of AhR ligands, in particular, have been extensively studied, and several mechanisms underlying such effects have been reported (for review, see Safe and Wormke, 2003), including the following; 1) AhR-mediated induction of enzymes (e.g., CYP1B1) that metabolize estrogens and thereby reduce tissue estrogen concentrations (Takemoto et al, 2004); 2) AhR-mediated induction of a transcription inhibitory factor (Rogers and Denison, 2002); 3) an inhibitory action mediated by the nonproductive binding of liganded AhR to an ER target gene, which prevents ER from binding (Krishnan et al, 1995); 4) AhR-mediated reduction of cellular ER levels by either suppression of ER transcription (Tian et al, 1998) or acceleration of ER degradation ; and 5) AhR-mediated transcriptional activation of its target genes, resulting in competition for recruitment of the limited pool of coactivators that are shared by the AhR and ER. In this regard, ARNT is said to function as a coactivator for ER, but with selectivity for ER␤.…”