“
“The prototype dioxin congener 2,3,7,8-tetrachlorodibenzo-p-dioxin

(TCDD) is a highly toxic and persistent organic pollutant, which is ubiquitously found in the environment. There is extensive evidence in vivo and in vitro that TCDD exerts anti-estrogenic effects via activation of the arylhydrocarbon receptor (AhR) by interfering with the regulation of estrogen homeostasis and the estrogen receptor α (ERα) signaling pathway (reviewed in [1]). A number of mechanisms were proposed to describe dioxin-mediated AhR/ERα cross-talk ( [2] and [3]; Safe et al., 2000). It was hypothesized that TCDD may interfere with the regulation of estrogen homeostasis resulting in reduced concentrations of circulating estrogens. This is MS-275 cost thought to result from enhanced oxidative metabolism of 17β-estradiol (E2) via AhR-mediated induction of cytochromes P450 (CYPs), particularly CYP1A1 and CYP1B1 [4]. The latter also serve as general surrogate markers for AhR activation [5]. Furthermore, TCDD may also prevent binding of the E2/ER-complex to the estrogen response element (ERE) and instead recruit Panobinostat molecular weight the hormone receptor to AhR target genes via an indirect protein-protein interaction [6] and [7]. It was shown that E2-dependent expression of genes and proteins such as

pS2, cathepsin D and vitellogenin. were inhibited by the action of TCDD [8]. Furthermore, TCDD was reported to inhibit E2-induced cell proliferation and

DNA synthesis by specifically blocking the E2-induced transition from G1 to S phase [9]. TCDD also induced the degradation of ERα through activation of the proteasome as observed in breast cancer cell lines [10] and it mediated the down-regulation of ER levels via a repressor site in the promoter region of ER-regulated genes [3]. Most of these studies were performed using breast cancer cell lines or other hormone-related cells and focused on AhR agonists which directly affected ERα-dependent pathways [11], [12] and [13]. In contrast, TCDD did not show direct activation of ERα in a competitive binding assay [14]. TCDD has been classified as a human carcinogen by the International Agency for Research on Cancer [15], its carcinogenic effect in rodent liver being most probably related to its mode of action as a liver tumour Carbohydrate promoter [5]. AhR signaling-dependent suppression of apoptosis of preneoplastic hepatocytes seems to play a central role in this effect [16]. Interestingly, TCDD was found to be a more potent liver carcinogen in female rats compared to male rats and it reduced age-related spontaneous hormone-dependent tumours, suggesting a role of estrogens [17] and [18]. Exposure to E2 is primarily associated with increased risk of breast cancer [19]. However, E2 was also related to liver carcinogenesis and it has been postulated to promote ER-mediated growth stimulation via co-mitogenic effects [20].