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

Although an association between dioxin exposure and endometriosis has been proposed, the effects of this environmental toxin on human endometriosis are not known. To understand the potential underlying molecular mechanisms we studied the expressions of cytochrome P-450 genes (CYP1A1, CYP1A2, and CYP1B1 ), which are induced by dioxin, and the expressions of cytosolic receptor for dioxin, aryl hydrocarbon receptor, and its nuclear translocator, aryl hydrocarbon receptor nuclear translocator protein, in endometriotic and eutopic endometrial tissues.

Levels of transcripts of CYP1A1, CYP1A2, CYP1B1, aryl hydrocarbon receptor, and aryl hydrocarbon receptor nuclear translocator protein were determined by a quantitative reverse transcriptase-polymerase chain reaction and Southern blot assay in total ribonucleic acid samples from endometriotic and eutopic endometrial tissues. Eutopic endometrial tissue samples (n = 33) and endometriotic tissue samples (n = 10) were obtained at the time of uterine curettage and laparoscopy from disease-free women and from patients with endometriosis. Portions of these eutopic endometrial and endometriotic tissues were obtained simultaneously from the same patients (n = 8 pairs of samples). Levels of transcripts of CYP1A1, CYP1A2, CYP1B1, aryl hydrocarbon receptor, and aryl hydrocarbon receptor nuclear translocator protein were determined in endometrial and endometriotic tissues during follicular and luteal phases of the cycle and in cultured endometriotic stromal cells treated with forskolin, phorbol diacetate, medroxyprogesterone acetate,and serum.

Transcripts of dioxin receptor, its nuclear translocator, and two dioxin-induced target genes (CYP1A2 and CYP1B1) were demonstrated during follicular and luteal phases of the cycle in both eutopic endometrial tissues and tissues affected by pelvic endometriosis, with no readily detectable differences 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 endometriotic tissues were 8.7 times those found in eutopic endometrium. Various hormonal treatments of endometriotic stromal cells did not significantly alter these levels.

We demonstrated for the first time the expression of dioxin-related transcription factors aryl hydrocarbon receptor and aryl hydrocarbon receptor nuclear translocator protein and target genes CYP1A1, CYP1A2, and CYP1B1 in endometriotic tissues and stromal cells. Strikingly elevated CYP1A1 transcripts in endometriosis may give rise to significantly increased P-4501A1 enzyme activity and thus promote the development and growth of endometriosis by either activating procarcinogens or inducing the formation of catechol estrogens or both. In fact, the proposed link between dioxin exposure and endometriosis may be explained in part by the up-regulation of the CYP1A1 gene expression in endometriotic tissues.