Expression of Estrogen-Regulated Genes During Development in the Mouse Uterus Exposed to Diethylstilbestrol Neonatally

Abstract

Neonatal diethylstilbestrol (DES) exposure elicits a wide range of abnormalities in the female mouse genital tract. This animal model system is suitable for investigating the mechanism of DES syndrome in humans. Accumulated evidence has shown that critical periods in development are present for distinct and permanent alterations in the female genital tract of mice exposed to DES neonatally (DES-mice). These effects of DES and other estrogens are mainly mediated by estrogen receptor alpha (ER alpha) through multiple pathways. Induction of ER alpha by DES exposure in neonatal stromal and epithelial cells, and successive premature activation of estrogen-regulated genes are thought to be essential to induce the abnormalities. Induction of malformation, permanent changes in estrogen-regulated genes, such as protooncogenes and growth factors, and carcinogenesis are assumed to be interdependent. This review focuses the following topics to discuss the molecular basis of DES-induced abnormalities mainly based on the results by histochemical techniques in the uterus: spatiotemporal expression of ER alpha and coactivators, proteins relating morphogenesis, and estrogen-regulated protooncogenes and growth factors.

Estrogen-mediated effects on cognition and synaptic plasticity: What do estrogen receptor knockout models tell us?

“…In this regard, an early study demonstrated that application of estrogen to normal hippocampal slices produces a rapid increase in synaptic transmission that is muted in hippocampal slices prepared from male and female ERαKO mice [55]. However, because ERα is critical during development [56] the early ERα knockout mouse cannot be used to separate adult versus developmental effects of ERα. An important recent study in which lentiviral delivery of the gene encoding ERα was delivered to the hippocampus of adult ER-α-knockout (ERαKO) has separated developmental from ERα specific effects on synaptic function and behavior [57].…”

Exposure to diethylstilbestrol during sensitive life stages: A legacy of heritable health effects

“…Rodent models have been utilized to evaluate DESinduced infertility, breast cancer susceptibility, reproductive tract abnormalities, and cancer development, as well as investigate the mechanisms involved in disease development later in life. Murine genital tract development at birth is similar to human fetal development at the end of the first trimester (Sato et al, 2004;Yamashita 2006;Ma, 2009). Doses of DES given to pregnant mice or rats varied between 0.2 and 12,000 mg/ day, or approximately 1 mg/kg to 60 mg/kg DES per day in the rat (Hilakivi-Clarke et al, 2013), and these doses were typically oral or via subcutaneous injection in oil.…”

“…DES affects the methylation patterns of genes that are associated with proliferation ( c‐jun, c‐fos, c‐myc, ltf ), genes associated with apoptosis ( bcl‐2, bcl‐x ), and growth factors associated with proliferation and differentiation, including epidermal growth factor (EGF) and transforming growth factor (TGF)‐α (Sato et al, ; Newbold, 2006; LeBaron et al, ). This change in methylation is referred to as estrogen imprinting (Yamashita, ). Estrogen imprinting is an epigenetic mechanism where early‐life exposure to estrogens (i.e., DES, Bisphenol A) permanently alters DNA methylation and gene expression of estrogen‐responsive genes.…”

“…Changes in hox gene expression have led to abnormalities in tissues that depend on their expression for normal developmental signaling (Newbold et al, 2007;Bromer et al, 2009). Down regulation of hoxa11 (which is found in the stroma and epithelial cells of the uterus) may be partly responsible for DES-induced uterine malformations, as similar malformations are seen in hoxa11-null mice (Yamashita, 2006). Hoxa10 (which is expressed in the uterine horns) controls uterine organogenesis and its expression is increased in cultured human endometrial cells but repressed in mice after in utero exposure to DES (Newbold et al, 2007;Bromer et al, 2009).…”

Editorial [Hot Topic:Recent Advances in Developmental and Reproductive Toxicology (Executive Editor: Gian Mario Tiboni )]

“…In the paper by Yamashita [7] the current understanding on the molecular basis of diethylstilbestrol-induced uterus anomalies is reviewed. In utero exposure to diethylstilbestrol has been causally linked to clear cell adenocarcinoma of the vagina, breast cancer, and reproductive anomalies.…”