ABSTRACT
Women exposed to diethylstilbestrol (DES) in utero frequently develop vaginal adenosis, from which clear cell adenocarcinoma can arise. Despite decades of extensive investigation, the molecular pathogenesis of DES-associated vaginal adenosis remains elusive. Here we report that DES induces vaginal adenosis by inhibiting the BMP4/Activin A-regulated vaginal cell fate decision through a downregulation of RUNX1. BMP4 and Activin A produced by vaginal mesenchyme synergistically activated the expression of ΔNp63, thus deciding vaginal epithelial cell fate in the Müllerian duct epithelial cells (MDECs) via direct binding of SMADs on the highly conserved 5' sequence of ΔNp63. Therefore, mice in which Smad4 was deleted in MDECs failed to express ΔNp63 in vaginal epithelium and developed adenosis. This SMAD-dependent ΔNp63 activation required RUNX1, a binding partner of SMADs. Conditional deletion of Runx1 in the MDECs induced adenosis in the cranial portion of vagina, which mimicked the effect of developmental DES-exposure. Furthermore, neonatal DES exposure downregulated RUNX1 in the fornix of the vagina, where DES-associated adenosis is frequently found. This observation strongly suggests that the downregulation of RUNX1 is the cause of vaginal adenosis. However, once cell fate was determined, the BMP/Activin-SMAD/RUNX1 signaling pathway became dispensable for the maintenance of ΔNp63 expression in vaginal epithelium. Instead, the activity of the ΔNp63 locus in vaginal epithelium was maintained by a ΔNp63-dependent mechanism. This is the first demonstration of a molecular mechanism through which developmental chemical exposure causes precancerous lesions by altering cell fate.
Subject(s)
Core Binding Factor Alpha 2 Subunit/metabolism , Diethylstilbestrol/adverse effects , Epithelium/drug effects , Mullerian Ducts/drug effects , Smad Proteins/metabolism , Vagina/embryology , Activins/metabolism , Animals , Cell Lineage , Crosses, Genetic , Estrogens, Non-Steroidal/adverse effects , Female , Gene Expression Regulation, Developmental , Mice , Mice, Inbred C57BL , Mice, Transgenic , Oligonucleotide Array Sequence Analysis , Phosphoproteins/metabolism , Protein Binding , Trans-Activators/metabolism , Uterus/embryology , Vagina/drug effects , Vaginal Diseases/chemically inducedABSTRACT
Exposure to exogenous hormones during development can result in permanent health problems. In utero exposure to diethylstilbestrol (DES) is probably the most well documented case in human history. DES, an orally active synthetic estrogen, was believed to prevent adverse pregnancy outcome and thus was routinely given to selected pregnant women from the 1940s to the 1960s. It has been estimated that 5 million pregnant women worldwide were prescribed DES during this period. In the early 1970s, vaginal clear cell adenocarcinomas (CCACs) were diagnosed in daughters whose mother took DES during pregnancy (known as DES daughters). Follow-up studies demonstrated that exposure to DES in utero causes a spectrum of congenital anomalies in female reproductive tracts and CCACs. Among those, cervical and vaginal adenoses are most commonly found, which are believed to be the precursors of CCACs. Transformation related protein 63 (TRP63/p63) marks the cell fate decision of Müllerian duct epithelium (MDE) to become squamous epithelium in the cervix and vagina. DES disrupts the TRP63 expression in mice and induces adenosis lesions in the cervix and vagina. This review describes mouse models that can be used to study the development of DES-induced anomalies, focusing on cervical and vaginal adenoses, and discusses their molecular pathogenesis.
Subject(s)
Adenocarcinoma, Clear Cell/chemically induced , Diethylstilbestrol/adverse effects , Estrogens, Non-Steroidal/adverse effects , Prenatal Exposure Delayed Effects , Uterine Cervical Neoplasms/chemically induced , Vaginal Neoplasms/chemically induced , Adenocarcinoma, Clear Cell/genetics , Animals , Female , Gene Expression Regulation, Neoplastic , Humans , Mice , Phosphoproteins/genetics , Pregnancy , Trans-Activators/genetics , Uterine Cervical Neoplasms/genetics , Vaginal Neoplasms/geneticsABSTRACT
The purpose of the current study was to identify initial effects of a coaching training intervention using Level of Assistance (LoA) strategies compared with traditional lecture techniques on the appropriateness of LoA use by certified nursing assistants (CNAs) and independence of dressing of nursing home residents with dementia. Seventeen CNA-resident dyads participated in this pilot randomized controlled trial (RCT). Control and experimental group CNAs received a 25-minute traditional lecture. Experimental group CNAs also underwent three coaching sessions over 4 weeks. There were significant between-group differences in the percentage of dyads who had improved scores for appropriateness of LoA use and dressing independence from pretest to posttest (experimental: n = 9, 100%; control: n = 8, 50%; p = 0.029). However, there were no statistically significant median differences between groups in appropriateness of LoA use by CNAs and resident dressing independence scores. There were significant within-group median improvements in appropriateness of LoA use (p = 0.004) and independence of dressing scores (p = 0.004) between pretest and posttest in the experimental group, but not in the control group. This initial pilot RCT supports coach training as a method to improve appropriate use of LoA strategies by CNAs and independence of resident dressing. [Res Gerontol Nurs. 2017; 10(6):267-276.].