2,3,7,8-Tetrachlorodibenzo-p-dioxin increases glycodelin gene and protein expression in human endometrium

Context: Glycodelin (GdA) is an immunosuppressive endometrial glycoprotein critical for embryonic implantation and pregnancy establishment. Objective: The aim of the present study was to examine the effect of dioxin [2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)] on GdA production in human endometrial cells. Design: Controlled endometrial explant (EE) and cell cultures were used in this study. Setting: Work was conducted at university hospital research laboratories in Bern, Switzerland, and in San Francisco, California. Patients: Ovulatory women provided endometrial biopsies in the proliferative or secretory phase. Intervention(s): EEs and cells were cultured without and with TCDD. Main Outcome Measure( s): GdA protein and gene expression were quantified. Results: A 2.5- fold increase in GdA production was demonstrated in EEs treated with 10 nM TCDD for 9 d. Fluorography revealed a 3- to 4- fold increase in new GdA biosynthesis and secretion in TCDD-treated endometrial epithelial cells. Because the action of dioxin is mediated by the aryl hydrocarbon receptor (AhR), we ascertained that primary epithelial and Ishikawa cells express AhR. Dose responses to TCDD and expressed AhR were established in transiently transfected Ishikawa cells using luciferase fusion vectors containing 1.0 kb of 5' flanking DNA relative to the GdA transcriptional start site but not when shorter promoter constructs were used. A dioxin response element was mapped to nucleotides -539 to -533 of the gene promoter and verified by site-directed mutagenesis. Conclusions: We demonstrated a direct AhR-mediated effect of dioxin on GdA gene transcription and protein secretion that might influence human female fertility.