Oestrogen-independent actions of environmentally relevant AhR-agonists in human endometrial epithelial cells

The human endometrium is a cyclically regenerating organ under the influence of ovarian steroid hormones; disturbances in this highly coordinated regulation of endometrial proliferation and differentiation may result in infertility and diseases such as, endometriosis and endometrial cancer. Environmental toxins belonging to the group of poly-halogenated aromatics hydrocarbons (PAHs) are lipophilic xenobiotics, which accumulate in biological systems. PAHs have been implicated in the aetiology of uterine pathologies, including infertility, endometriosis and endometrial cancer. However, suitable cellular models of the endometrium are lacking and the molecular mechanism of PAH action in the endometrium is not fully understood. In this study, the authors have characterised a previously established immortalised human telomerase reverse transcriptase (hTERT) endometrial epithelial cell (hTERT-EEC) model as a responsive in vitro cell model to investigate the cellular and molecular mechanisms of selected environmentally relevant PAH in human EECs. The authors demonstrated that dioxin-type PAHs activate the endogenous aryl hydrocarbon receptor (AhR) signalling pathway in hTERT-EEC in a time-, concentration- and congener-specific manner and that the induction of AhR target genes is modulated by oestrogen. Strikingly, AhR activation did not interfere with estrogenic actions in these EECs. Independent of their ability to bind to AhR, the PAHs investigated here increased cell migration by hTERTEEC. Furthermore, several candidates were identified by proteomic analysis, which are involved in heat shock responses and protein modification and turnover. The authors concluded that the findings suggest that AhR-activating environmental pollutants directly alter endometrial cell stress responses and metabolism independent of estrogenic actions.

Authors: Willing, Cornelia; Peich, Marco; Danescu, Adrian; Kehlen, Astrid; Fowler, Paul A.; Hombach-Klonisch, Sabine ;Full Source: Molecular Human Reproduction 2011, 17(2), 115-126 (Eng) ;