Expression of dioxin-related transactivating factors and target genes in human eutopic endometrial and endometriotic tissues

OBJECTIVE: Although an association between dioxin exposure and endometriosi s has been proposed, the effects of this environmental toxin on human endom etriosis are not known. To understand the potential underlying molecular me chanisms we studied the expressions of cytochrome P-450 genes (CYP1A1, CYP1 A2, and CYP1B1), which are induced by dioxin, and the expressions of cytoso lic receptor for dioxin, aryl hydrocarbon receptor, and its nuclear translo cator, aryl hydrocarbon receptor nuclear translocator protein, in endometri otic and eutopic endometrial tissues. STUDY DESIGN: Levels of transcripts of CYP1A1, CYP1A2, CYP1B1, aryl hydroca rbon receptor, and aryl hydrocarbon receptor nuclear translocator protein w ere determined by a quantitative reverse transcriptasepolymerase chain reac tion and Southern blot assay in total ribonucleic acid samples from endomet riotic and eutopic endometrial tissues. Eutopic endometrial tissue samples (n = 33) and endometriotic tissue samples (n = 10) were obtained at the tim e of uterine curettage and laparoscopy from disease-free women and from pat ients with endometriosis. Portions of these eutopic endometrial and endomet riotic tissues were obtained simultaneously from the same patients (n = 8 p airs of samples). Levels of transcripts of CYP1A1, CYP1A2, CYP1B1, aryl hyd rocarbon receptor, and aryl hydrocarbon receptor nuclear translocator prote in were determined in endometrial and endometriotic tissues during follicul ar and luteal phases of the cycle and in cultured endometriotic stromal cel ls treated with forskolin, phorbol diacetate, medroxyprogesterone acetate, and serum. RESULTS: Transcripts of dioxin receptor, its nuclear translocator, and two dioxin-induced target genes (CYP1A2 and CYP1B1) were demonstrated during fo llicular and luteal phases of the cycle in both eutopic endometrial tissues and tissues affected by pelvic endometriosis, with no readily detectable d ifferences between these tissues. On the other hand, levels of transcripts of another dioxin-induced gene. CYP1A1, were found to be strikingly higher in endometriotic tissues than in the eutopic endometrium. Mean levels in en dometriotic tissues were 8.7 times those found in eutopic endometrium. Vari ous hormonal treatments of endometriotic stromal cells did not significantl y alter these levels. CONCLUSION: We demonstrated for the first time the expression of dioxin-rel ated transcription factors aryl hydrocarbon receptor and aryl hydrocarbon r eceptor nuclear translocator protein and target genes CYP1A1, CYP1A2 and CY P1B1 in endometriotic tissues and stromal cells. Strikingly elevated CYP1A1 transcripts in endometriosis may give rise to significantly increased P-45 01A1 enzyme activity and thus promote the development and growth of endomet riosis by either activating procarcinogens or inducing the formation of cat echol estrogens or both. In fact, the proposed link between dioxin exposure and endometriosis may be explained in part by the up-regulation of the CYP 1A1 gene expression in endometriotic tissues.