Estrogen Receptors, Estradiol, and Diethylstilbestrol in Early Development: The Mouse as a Model for the Study of Estrogen Receptors and Estrogen Sensitivity in Embryonic Development of Male and Female Reproductive Tracts*

Abstract

To date, there is no conclusive evidence that ERs are present in preimplantation embryos. There are reports that estrogen is made by the rabbit blastocyst (61), and estrogens have been used to induce implantation in mice (62), but whether estrogens act through ERs in the embryo or in the maternal uterus is not known. ERs may be present in early embryos, but if so, levels are below the methods of detection used thus far. Perhaps with more sensitive immunodetection methods, it may be possible to detect ERs in embryos if they are present. Using PCR, messenger RNA for ER has been detected as early as the oocyte stage in mouse embryos (Q. Hou and J. Gorski, unpublished results). This was confirmed recently by Wu et al. (83a). Figure 7 shows a model for the pattern of ER expression in the developing mouse fetus based on the various reports discussed in this review. ERs are present in the 10-day mouse fetus, possibly in the developing ambisexual reproductive tract. Analysis of seven individual 10-day-old fetuses taken from the same litter showed similar levels of an immunostained protein the size of the ER in each fetus (57). The pattern of expression of ER between implantation and the development of the reproductive tract may be the same in male and female mice. Estrogen, acting through ERs, may be one factor (of many) that determines which cells are destined to be part of the indifferent reproductive tract. We were not able to isolate fetal mouse reproductive tracts at an indifferent stage (day 10) due to their very small size. One way to study ER in the indifferent reproductive tract would be to examine these tissues in a larger animal, such as the bovine, using similar immunodetection methods. The distribution of ER in the fetal mouse reproductive tract on fetal days 13 (before sexual differentiation) and 15 (initiation of sexual differentiation) is similar in males and females (71, 72). Thus, estrogen does not appear to be responsible for the initiation of sexual differentiation. Early experiments by Jost (41) showed that removal of the gonad from male or female rabbit fetuses resulted in the female phenotype, which lent weight to the hypothesis that ovarian hormones are not critical in the development of the female phenotype, whereas testicular hormones are essential for the development of the male phenotype.(ABSTRACT TRUNCATED AT 400 WORDS)

Stromal estrogen receptors mediate mitogenic effects of estradiol on uterine epithelium

“…Cunha et al (5) used steroid autoradiography (ARG) to demonstrate that ER are undetectable in uterine epithelium (UtE) of neonatal BALB͞c mice, but are present in the mesenchyme͞stroma. Subsequent immunohistochemical studies confirmed that ER are undetectable in UtE from neonatal mice (1,6,7).…”

Potency of Combined Estrogenic Pesticides

“…One of our working hypotheses is that under conditions in which the ER tends to exist as a monomer, the binding characteristics of two interacting molecules are different from that observed at high receptor concentrations. We contend that this low ER experimental condition better approximates ER concentrations found during early development [the ER content of uterine epithelial cells is low in fetal or newborn mouse (6) or rat (7), a period critical for estrogen-associated disorders (8)]. During these sensitive periods, chemical interactions resulting in synergy may occur at conditions in which critical ligand-receptor or receptorreceptor combinations occur.…”

The effects of environmental hormones on reproduction

“…Nonetheless, the foetal rabbit ovary has been shown to produce oestradiol at the same age as the testis was able to synthesize testosterone [134]. Oestrogen receptors are present in the mouse embryo at the ambisexual stage [135], and they are also present in early embryos of other species [136,137]. Therefore, it is likely that oestrogens are involved in the differentiation of structures derived from the Mü llerian ducts, and they may affect differentiation of Wolffian derivatives.…”

“…During the critical period of sexual differentiation, one might anticipate that exposure of a chromosomal male to antiandrogenic xenobiotics would interfere with the androgen-dependent differentiation of the Wolffianderived structures and/or with the normal development of the male genitalia. Since oestrogen receptors are present in the male reproductive tract [54,55,57,135,[137][138][139][140], xenooestrogens could also interfere with the proper development of these structures. Likewise, xenoandrogens could masculinize the developing female foetuses, since the structures of their reproductive tracts contain androgen receptors [141].…”

“…The development of a mutant mouse model that lacks responsiveness to oestradiol because of insertional disruption of the oestrogen receptor gene by gene targeting [the oestrogen receptor knockout (ERKO) mouse] [145] and the expectation that so-called environmental oestrogens might have deleterious effects in the male [9,10] have renewed interest in oestrogen action in the male. Recent papers on oestrogen action in the male [54,55,135] tend to neglect the extensive older literature which reported such effects as histological alterations of the reproductive tract [98,144] and effects on protein synthesis [146,147]. A recent paper by Hess et al [57] using the ERKO mouse model [145] determined that oestradiol regulates the absorption of fluid by the efferent ducts of the testis, thus providing direct evidence for a specific, physiological role for oestrogens in the male.…”