Induction of estrogen receptor, peroxidase activity, and epithelial abnormalities in the mouse uterovaginal epithelium after neonatal treatment with diethylstilbestrol

Abstract

Neonatal female NMRI mice were treated with daily doses of 10(-2) or 5 micrograms diethylstilbestrol (DES) on one or more of days 1-5 after birth. Using immunohistochemical techniques and a monoclonal antibody to the estrogen receptor, we demonstrated an estrogen-induced precocious appearance of receptor protein in the nuclei of the uterovaginal epithelium. High levels of peroxidase activity and a pronounced stromal infiltration with peroxidase positive cells occurred in the uterine cervix and upper vagina after estrogen treatment. This regional restriction in peroxidase activity was similar to the regional restriction for estrogen-induced epithelial abnormalities (heterotopic columnar epithelium, adenosis). A combined treatment with DES and corticosterone depressed peroxidase activity but not to the control level. The distribution of abnormal epithelium was similar in DES- and DES-corticosterone-treated females. The conclusion is that neonatal estrogen treatment induces an epithelial receptor for estrogen and a high level of cervical peroxidase activity, but the relationship between these parameters and the appearance of abnormal cervicovaginal epithelial changes could not be settled in the present study.

Genotoxic effects of estrogens in epithelial cells from the neonatal mouse uterine cervix: Modifications by metabolic modifiers

“…DES is metabolized by uterine peroxidase into Z,Zdienestrol via reactive intermediates that bind to DNA and proteins [ 15,26,27]. However, we found no reduced appearance of HCE after corticosteroneinduced depression of estrogen-induced peroxidase activity [25], which raises doubts about the relationship between peroxidase-mediated DES metabolism and epithelial aberrations.…”

“…Neonatal estrogen treatment results in a pronounced region-restricted infiltration with peroxidase-containing cells in the stroma of the uterine cervix and upper vagina [25]. DES is metabolized by uterine peroxidase into Z,Zdienestrol via reactive intermediates that bind to DNA and proteins [ 15,26,27].…”

Estrogen effects on chromosome number and sister chromatid exchanges in uterine epithelial cells and kidney cells from neonatal mice

“…We described earlier a pronounced estrogen-induced peroxidase activity in the cervical region in strong contrast to the slight effect seen in the uterine horns [ 5 ] . Even though it is tempting to speculate about an association between estrogen-induced epithelial abnormalities, high peroxidase activity, and genomic plasticity in the cervical region, we have no proof for this hypothesis.…”

“…The synthetic estrogen diethylstilbestrol (DES) is a potent drug, which, when used in the neonatal life of female mice, induces permanent disturbances at different sites such as the genital epithelium, endocrine glands, and immune system [ 1-41. We have analyzed different mechanisms whereby DES may change the normal differentiation pathway of the epithelium in the uterine cervix and upper vagina, resulting in the appear-ance of an heterotopic columnar epithelium, adenosis, and even, in old mice, morphologically malignant changes [2]. Findings related to the organotropic localization of DES induced changes have been reported [ 5 ] . We have further studied the genotoxic potential, evident as an effect on the incidence of sister chromatid exchanges (SCEs), of DES in stromal and epithelial cells from the neonatal uterine cervix, cultured in vitro in the presence of the drug and metabolic modifiers with postulated effects on DES metabolizing enzymes [6,7].…”

Failure to Detect a Second-Generation Effect in Female Mice after Neonatal Treatment with an Estrogen (Diethylstilbestrol)

“…While estrogen effects at the receptor level were not restricted to the cervical part of the uterovaginal tract, a pronounced peak of estrogen-induced peroxidase activity was | Andersson and Forsberg, 1988]. The cervical epithelium had a greater sensitivity towards an estrogen genotoxic effect [increased incidence of cells with a high number of sister chromatid exchanges (SCEs)| than that in the uterine horns [Forsberg.…”