TRANSCRIPTIONAL SUPPRESSION OF ESTROGEN-RECEPTOR GENE-EXPRESSION BY 2,3,7,8-TETRACHLORODIBENZO-P-DIOXIN (TCDD)

TCDD, the most potent congener of the polychlorinated dioxins, has bee n shown to be an antiestrogen. The mechanisms of TCDD-induced antiestr ogenicity are still under investigation. In this study, we investigate d the effects of TCDD on the expression of the estrogen receptor (ER) gene. We studied the levels of un-spliced ER transcript (hnRNA) as wel l as the ER mRNA in ovary, uterus and Liver of TCDD-treated mice with different genetic backgrounds. To quantitate the ER hnRNA levels, the intron and exon boundary of ER hnRNA was amplified by competitive RT-P CR. The ER mRNA from these mice was quantitated by competitive RT-PCR amplifying exons separated by an intron. ER hnRNA and ER mRNA levels w ere quantitated 4 days after a single i.p. dose of TCDD (5 mu g/kg) in female C57BL/6J (B6) mice, which carry the responsive allele to TCDD. TCDD treatment significantly (p < 0.05) suppressed the levels of ER h nRNA in the ovary (27.4%) and uterus (21.9%). The decreases in ER hnRN A were coordinated with significant (p < 0.01) decreases in ER mRNA in ovary (57.7%) and uterus (37.6%). There was a significant decrease (2 0.3%, p < 0.05) in liver ER mRNA, however, the changes of ER hnRNA in liver were not significant. The coordinated decreases in ER hnRNA and mRNA in TCDD-treated mice suggest a suppression of transcription of th e ER gene. We performed the same study on DBA/2J (D2) mice, which poss ess the ''non-responsive'' allele of the aryl hydrocarbon receptor (Ah R). These mice demonstrated no significant decrease in either the ER m RNA or hnRNA after TCDD treatment. Overall, these results suggest that TCDD suppresses the gene expression of the ER receptor by decreasing its transcription, and the AhR plays an important role in mediating th is response. (C) 1998 Elsevier Science Ltd. All rights reserved.