These findings clearly indicate that VPD and VCD are distinctly less teratogenic than VPA in the induction of not only neural tube defects, but also skeletal abnormalities. A structure-teratogenicity relationship of VPA on the skeleton is suspected.

To determine expression and localization of receptors for estrogen (ER), progesterone (PR) and androgen (AR), detailed immunohistochemical evaluations were performed in the Sprague-Dawley rat oviduct during pre-and neonatal development, estrous cycle and pre-implantation period. In addition, real-time RT-PCR studies were conducted to evaluate changes in ERα, ERβ, total PR (PR-A+B), PR-B and AR mRNA expressions. All receptors except for ERβ were detected in epithelial, and stromal or mesenchymal cells of the fetal and neonatal oviduct, and increased with development. During the estrous cycle and early pregnancy, ERα and PR-A+B were expressed in epithelial, stromal and muscle cells throughout the oviduct region, and showed changes in expression predominantly in the isthmus. Only a few epithelial cells in the infundibulum (INF) and ampulla (AMP) showed ERβ staining. AR was detected in stromal and muscle cells throughout the oviduct region, and in epithelial cells of the INF/AMP. Taken together, ERα, PR-A+B and AR were detected in the epithelium of the INF/AMP region, but all of these receptors were expressed in a distinct subset of epithelial cells which were negative for β-tubulin IV, a ciliated epithelial cell marker. These results contribute to a better understanding of the respective roles of ERs, PRs and AR in the rat oviduct.

Estrogen regulates proliferation and differentiation of epithelial cells in the mammalian oviduct, but pathways for cell-specific differentiation are not well understood. In the epithelial cells of the developing rat oviduct, we found estrogen receptor (ER) is expressed at birth and persists in all cells through neonatal day (ND) 7 when ciliated cells appear. To determine a specific function of ER and foxj1, a transcription factor known to have fundamental roles in ciliogenesis in the lung, in differentiation of the ciliated epithelial cells, we treated newborn rats from ND 0 to 5 with estradiol-17 (E2) with and without a selective ER antagonist. E2 enhanced the number of proliferating cells and accelerated the process of epithelial cell differentiation resulting in ciliogenesis by ND 5, and co-treatment with an ER antagonist inhibited these changes. Foxj1 was expressed only in the infundibulum and ampulla (INF/AMP). That expression preceded the appearance of cilia and was induced by E2. Cilia were absent in oviducts of foxj1-deficient mice, indicating that foxj1 plays a critical role in oviductal ciliogenesis. However, we found the presence of cilia in the ER -deficient mouse oviduct. The widespread expression of ER in oviductal epithelium, but restriction of cilia to the INF/AMP regions, and importantly, the presence of cilia in the ER -deficient mice, suggested ER signaling is not essential for ciliated epithelial cell differentiation. These observations demonstrate that, although E2 stimulates the differentiation process of ciliated epithelial cells, foxj1 is directly required for epithelial cell ciliogenesis of the neonatal oviduct.

No abstract

-Many chemicals released into the environment potentially disrupt the endocrine system in wildlife and humans. Some of these chemicals exhibit estrogenic activity by binding to the estrogen receptors. The developing organism is particularly sensitive to estrogenic chemicals during the critical period in which the induction of long-term changes and persistent molecular alterations in female reproductive tracts occur. Perinatal mouse and rat models can be utilized as indicators for determining the consequences of exposure to exogenous estrogenic agents, including possible xenoestrogens or environmental endocrine disruptors. Estrogen receptors (ER) and estrogen responsive genes, therefore, need to be identified in order to understand the molecular basis of estrogenic actions. Recent identifications of ER subtypes and isoforms make understanding target organ responses to these estrogenic chemicals even more difficult. Indeed, many reports suggest that these chemicals do affect the reproductive and developmental processes of female laboratory rodents that had been perinatally exposed, and that interactions between sex steroid hormone receptors occur. Much information concerning the expression of sex steroid receptors in rodents has been reported concerning the normal development of the Müllerian duct. Thus, accumulated information on the expression of ER subtypes and isoforms as well as that of progesterone and androgen receptors in laboratory rodents is herein reviewed, in addition to the presentation of our own data.