Development of Vaginal Adenosis-like Lesions and Uterine Epithelial Stratification in Mice Exposed Perinatally to Diethylstilbestrol

Abstract

Abstracf. Pregnant ICR/JCL mice were given either four daily subcutaneous injections of 20-2000 pg diethylstilbestrol (DES)/day or a 4-day intravenous infusion of 20-200 pg DES/day starting on Day 15 of gestation. Female mice were injected with 0.01-50 pg DES/day for 5 days starting on the day of birth. Females given oil injections during the neonatal period and offspring of mothers given injections of an infusion of respective vehicles alone served as controls when corresponding ages were attained. Incidence of adenosis-like lesions (ADL) in the vaginal epithelium and stratification of the uterine epithelium (UST) were determined in both offspring and neonatally exposed mice at 30 days of age. Injections of 0.1-50 pg DES/day during the neonatal period induced ADL in the fornical epithelium of vagina (36-70%), but not UST. A high incidence of ADL (80-8870) was found in the fornical and upper-vaginal epithelia in offspring of mothers given injections of 200-2000 pg DES/day, and UST was encountered in 38-70% of these mice. Offspring of mothers given an infusion of 20 pg DES/day had low incidences of ADL ( 1 1%) and UST (22%). whereas offspring of mothers infused with 200 pg DES/day exhibited high incidences of ADL (71%) and UST (86%). In offspring of mothers given injections of 2000 pg DES/day, ADL appeared in the fornical and upper-vaginal epithelia as early as I5 days of age. Thus, the present study revealed that ADL and UST occur at a high incidence in infantile mice exposed prenatally to high doses of DES. Previous studies failed to detect such effects perhaps due to the strain of mice, methods, duration. and/or dose of DES used. G 1986 Society for Experimental Biology and Medicine. 59

Fetal exposure to DES results in de-regulation of Wnt7a during uterine morphogenesis

“…Haematoxylin and eosinstained sections of DES-exposed and Wnt7a −/− FRTs displayed lesions including Wolffian duct (w) remnants (a,b). Wnt7a −/− FRTs displayed concretions (con) forming in the vaginal fornices (c) and epithelial inclusions in the vagina stroma (adenosis, d), lesions that have been described in DES-exposed mice 9,11,12 . e, Control (oil treated) uteri had simple columnar epithelium (inset), stroma (s) populated by glands (g) and compact layers of smooth muscle (h).…”

“…DESexposed mice had shallow vaginal fornices, malformed oviducts that lacked coils, Wolffian duct remnants (Fig. 1a), vaginal concretions and adenotic lesions in the vagina 9,11,12 . Wnt7a −/− mice also had shallow vaginal fornices (data not shown) and malformed oviducts 8 .…”

“…To directly compare the effects of loss of Wnt7a with the effects of DES in the FRT, we generated mice with DES-induced malformed FRTs using an established protocol 9,10 . DESexposed mice had shallow vaginal fornices, malformed oviducts that lacked coils, Wolffian duct remnants (Fig.…”

“…Prenatal DES treatment mimics the phenotype of the Wnt7a −/− female reproductive tract. Pregnant CD-1 mice were treated with 200 μg/day of DES (Sigma) suspended in sesame oil, or with oil alone, on days 15-18 of gestation 9,10 . The exposed female offspring were analysed on the day of birth (day 0) and at subsequent time points.…”

Neonatal Exposure to Diethylstilbestrol Alters Expression of DNA Methyltransferases and Methylation of Genomic DNA in the Mouse Uterus

“…Our results indicated that DES altered the expression levels of Dnmts and DNA methylation. [3][4][5], and DES is now widely known as an estrogenic endocrine disruptor. In our previous studies, we showed that mice treated neonatally with DES or the phytoestrogen, genistein, developed altered expression levels of various genes in male reproductive organs, even during adulthood [6][7][8][9][10].…”