Potential endocrine-modulating effects of various phytoestrogens in the diet.
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Biomedical subjects
R R Newbold
Publications and source records attributed to R R Newbold.
A recessive mutation causing imperforate vagina in mice.
A recessive mutation (ipv) causing imperforate vagina was discovered in a line of mice selected for low lean tissue mass as a proportion of body weight. Two full sisters were found to have marked swelling of the perineum and complete closure of the vagina. Crosses of heterozygotes identified by progeny testing produced a female progeny ratio not different from the 3 normal: 1 affected (chi 2 = 0.695; p less than .3) expected on the basis of a recessive allele at a single autosomal locus. As a consequence of the imperforate vagina, the uterus and vagina were greatly distended by fluid. The uterus of affected females displayed a swollen uterine lumen and thin endometrial stroma and muscularis. Ovarian tissue of affected females was similar to that of normal mice, and affected females produced ova that were normal in appearance. The mutation causing an imperforate vagina may present a useful model for studying the basis of abnormal vaginal development in other species and increasing the understanding of normal vaginal development in the mouse.
Animals↗
Abnormal cell differentiation and p21 expression of endometrial epithelial cells following developmental exposure to diethylstilbestrol (DES).
Gene expression relevant to abnormal cell differentiation and altered cell cycle in endometrial epithelial cells was investigated immunohistochemically in developing mouse uteri exposed neonatally to diethylstilbestrol (DES). Female CD-1 mice were given daily s.c. injections of 2 microg of DES in corn oil or were given corn oil alone (control) at 1-5 days of age and euthanatized at 5, 6, 7, 8, 15, and 22 days of age. The endometrial epithelial cells of DES-treated mice at 5-8 days of age showed enhanced staining intensity for the estrogen receptor alpha (ER alpha), whereas the stromal cells showed decreased staining reaction; the epithelial cells showed that the protein encoded by the c-fos proto-oncogene, which plays a key role in regulating diverse estrogen-related cellular differentiation patterns, was enhanced. These cells also showed increased expression of lactoferrin, a sensitive protein marker of estrogen exposure, although the staining intensity decreased after exposure ended. The stain for p21 protein, a mitotic inhibitor which suppresses cyclin-dependent kinase activity, showed frequent positively stained cells in DES-treated mice at 5-15 days of age, whereas no accumulation of p53 protein of either wild or mutant type was detected immunohistochemically in these cells. These results indicate that suppressed cell cycle activity of endometrial epithelial cells and abnormal estrogen-related differentiation at the developmental stage following neonatal DES exposure may be caused, in part, by transient altered expression of ER alpha and expression of the p21 gene, which appears to be induced by a p53-independent mechanism.
Animals↗
Effects of neonatal diethylstilbestrol (DES) exposure on morphology and growth patterns of endometrial epithelial cells in CD-1 mice.
The effects of neonatal diethylstilbestrol (DES) exposure on the morphology and proliferating patterns of endometrial epithelial cells were investigated at various stages of development in mice. Female CD-1 mice were given daily subcutaneous injections of 2 micrograms of DES in corn oil or corn oil alone (control) at 1-5 days of age and were killed at 5, 6, 7, 8, 15, and 22 days of age. At 5 days of age, the uteri of DES-treated mice had expanded lumina and undulated luminal surfaces lined by slightly elongated epithelial cells. At 6-8 days of age, marked infolding of clusters of hypertrophic elongated luminal epithelial cells was present; uteri had disorganized endometrial stromal and myometrial layers. At 15 and 22 days of age, the tissues from DES-treated mice had decreased numbers of endometrial glands, minimal stromal fibrosis, and smaller uterine horns than did the controls. Ultrastructurally, the endometrial epithelial cells of DES-treated mice at 5 and 8 days of age had distorted nuclei with condensed matrix and abundant secretory granules associated with rough endoplasmic reticulum and Golgi apparatus. At 8 days of age, an accumulation of fingerlike cytoplasmic processes that extended into the separated intercellular spaces and along the basal aspects of the endometrial epithelial cells were also observed. At 5-8 days of age, the proliferative activity of endometrial epithelial cells in DES-treated mice, identified by bromodeoxyuridine labeling, was significantly lower (10.5-1.7%) than that of the controls (25.5-19.8%). In situ analysis of endometrial luminal epithelial cells for DNA fragmentation representing apoptosis revealed < or = 0.1% and > 10% in the DES-treated and control mice at 5-8 days of age, respectively. The data show that cell cycle kinetics, in addition to changes in morphology, are altered in the developing mouse uterus following neonatal exposure to DES.
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