Neonatal diethylstilbestrol exposure disrupts female reproductive tract structure/function via both direct and indirect mechanisms in the hamster

Abstract

We assessed neonatal diethylstilbestrol (DES)-induced disruption at various endocrine levels in the hamster. In particular, we used organ transplantation into the hamster cheek pouch to determine whether abnormalities observed in the post-pubertal ovary are due to: a) a direct (early) mechanism; or b) an indirect (late) mechanism that involves altered development and function of the hypothalamus and/or pituitary. Of the various disruption endpoints and attributes assessed: 1) some were consistent with the direct mechanism (altered uterine and cervical dimensions/organization, ovarian polyovular follicles, vaginal hypospadius, endometrial hyperplasia/dysplasia); 2) some were consistent with the indirect mechanism (ovarian/oviductal salpingitis, cystic ovarian follicles); 3) some were consistent with a combination of the direct and indirect mechanisms (altered endocrine status); and 4) the mechanism(s) for one (lack of corpora lutea) was uncertain. This study also generated some surprising observations regarding vaginal estrous assessments as a means to monitor periodicity of ovarian function in the hamster.

Altered gene expression patterns during the initiation and promotion stages of neonatally diethylstilbestrol-induced hyperplasia/dysplasia/neoplasia in the hamster uterus

“…Co.; St. Louis, MO) (O+E2). According to previous determinations [5, 6], that procedure maintains serum E2 levels at approximately 200 pg/ml for at least 5 mo. Tissues were harvested (see below) from the O+E2 animals when they were 2 months of age (Promotion Stage or PS).…”

“…A particularly striking observation very early in the system was that, in mature (postpubertal) hamsters, 100% of the neonatally DES-exposed uteri developed hyperplasia and a large proportion progressed to neoplasia (endometrial adenocarcinoma) [5]. We subsequently determined that, consistent with the two-stage model of carcinogenesis [10], neonatal DES exposure directly and permanently alters (re-programs) the developing hamster uterus (initiating event) such that it responds abnormally later in life to stimulation (promoting event) with the natural estrogen, estradiol [5, 6]. We are now probing the mechanism of this two-stage phenomenon at the molecular level.…”

Endocrine Active Compounds Actions during Neonatal Period: Effect on the Ovary

“…Studies on neonatal rodents injected with diethylstilbestrol demonstrated results similar to those of bisphenol A. Neonatal exposure to diethylstilbestrol of mice and hamster inhibited germ cell nest breakdown and induced MOFs formation, likely by interfering with the ERβ pathway and inhibiting programmed oocyte death and germ cell loss [78,79]. Rodríguez et al [75] used a relatively low concentration of diethylstilbestrol (20 μg/kg body weight) in the rat and found that primordial follicle activation was increased compared to studies of Karavan et al [80] on mice, where the higher diethylstilbestrol concentration (100 μg/kg body weight) decreased the follicle activation.…”

Altered microRNA expression patterns during the initiation and promotion stages of neonatal diethylstilbestrol-induced dysplasia/neoplasia in the hamster (Mesocricetus auratus) uterus

“…All procedures including neonatal treatment, anesthesia, ovariectomy, chronic estrogen stimulation, sacrificing, and tissue collections followed IACUC-approved and established protocols (Alwis et al, 2011, Hendry et al, 2004, Hendry et al, 2014, Hendry et al, 2002). In all cases, tissue collections were performed at mid-day.…”

“…The Syrian hamster uterus is also particularly susceptible to the development of hyperplastic, dysplastic, and neoplastic lesions as a result of perinatal or neonatal DES-exposure (Rustia and Shubik, 1979). Indeed, we determined that such lesions are due to the fact that neonatal DES exposure directly and permanently disrupts early development of the hamster uterus (Initiation Stage) such that it responds abnormally later in life (Promotion Stage) to estrogenic stimulation (Alwis et al, 2011, Hendry et al, 1999, Hendry and Leavitt, 1993, Hendry et al, 2002, Hendry et al, 1997, Leavitt et al, 1982). …”