Novel Mechanisms of Tumor Promoter Activity by Estrogenic Xenobiotics
Abstract
Ovariectomized, adult rats, were injected with the tumor initiator methylnitrosourea (MNU). Tumor incidence without hormone replacement was 3%. Continuous estradiol or estrone replacement for 8 months yielded 24% or 54% tumor incidence, respectively. when progesterone was included with estrone, tumor incidence was 88%, significantly greater (p - 0.042) than the incidence with estrone alone. Thus, progesterone synergizes with estrone to induce tumorigenesis. Synergistic stimulation of glandular growth was associated with this increase in tumor incidence. Ovariectomized mice were treated with Beta-hexachlorocyclohexane or o,p'-DDT by continuous, slow release capsule; the lowest blood levels required to produce an estrogenic effect were 42 ng/ml or 18 ng/ml, respectively. These concentrations are only slightly higher than those found in humans, suggesting that these compounds may pose a risk at current exposure levels. Transfection studies using mutant forms of estrogen receptor and a luciferase reporter expression vector showed that the two activation domains within the receptor, AF-1 and AF-2 are required for full activity of xenoestrogens. With wildtype receptor, xenoestrogens were as effective as estradiol. when either activation domain was mutated, the xenoestrogens were 33-50% less effective than estradiol. Thus, xenoestrogens depend on the combined effects of AF-1 and AF-2 for their full effect.
Document Details
- Document Type
- Technical Report
- Publication Date
- Apr 01, 2001
- Accession Number
- ADA391904
Entities
People
- Robert M. Bigsby
Organizations
- Indiana University