Novel Mechanisms of Tumor Promoter Activity by Estrogenic Xenobiotics
Abstract
Tumor promoter activity of the xenoestrogens, o,p'-DDT and beta-hexachlorocyclohexane (beta-HCH), is under investigation using three model systems: 1) the MNU-initiated rat; 2) mouse xenografts of human breast tumors; 3) cells transfected with estrogen receptor and estrogen-responsive reporter genes. Continuous estrogen stimulation of ovariectomized rats causes growth of mammary glands but only fractionally replaces the ovary in promoting tumorigenesis. The weaker estrogen, estrone is more effective than estradiol. Further tests with lower doses of estrone are being pursued; experiments with xenoestrogens are underway. Studies in mice revealed that o,p'-DDT and beta-HCH elicit estrogenic effects in reproductive tract tissues at blood levels that are within 10-fold of non-exposed, human levels. Further studies are required to determine the minimal blood level associated with estrogenic effects. The mouse xenograft model has proved difficult to reestablish. In a single experiment, the tumors did not respond to estradiol as dramatically as in our earlier experiments; this may be due to a change in the procedure used to establish the xenografts. Transfection experiments have been completed as originally designed. Transcriptional activation by all xenoestrogens tested requires the presence of ER. Compared to natural estrogens, xenoestrogens are generally more dependent upon the N-terminal transactivation domain of ER (AF-1).
Document Details
- Document Type
- Technical Report
- Publication Date
- Apr 01, 1999
- Accession Number
- ADA370180
Entities
People
- Robert M. Bigsby
Organizations
- Indiana University Bloomington