Neonatal Estrogen Receptor β Is Important in the Permanent Inhibition of Epithelial Cell Proliferation in the Mouse Uterus

Nakajima, Tasuku; Tanimoto, Yuki; Tanaka, Masami; Chambon, Pierre; Watanabe, Hidenobu; Iguchi, Taisen; Satō, Tomomi

doi:10.1210/en.2015-1012

Cited by 10 publications

(3 citation statements)

References 68 publications

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“…The lack of overlapping signaling between E2 and SPI is perhaps not surprising given that isoflavones such as genistein have a much higher affinity for ER than ER whereas E2 has comparable affinity for both receptors. However, it should be noted that ER is only expressed at low levels in the adult rat uterus (Nakajima et al, 2015). The combination of E2 treatment and SPI-feeding resulted in significant regulation of 679 fewer mRNAs than E2 alone and 20 fewer mRNAs than SPI alone.…”

Section: Discussionmentioning

confidence: 94%

Uterine responses to feeding soy protein isolate and treatment with 17β-estradiol differ in ovariectomized female rats

Ronis

Gómez-Acevedo

Blackburn

et al. 2016

Toxicology and Applied Pharmacology

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There are concerns regarding reproductive toxicity from consumption of soy foods, including an increased risk of endometriosis and endometrial cancer, as a result of phytoestrogen consumption. In this study, female rats were fed AIN-93G diets made with casein (CAS) or soy protein isolate (SPI) from postnatal day (PND) 30, ovariectomized on PND 50 and infused with 5 μg/kg/d 17β-estradiol (E2) or vehicle. E2 increased uterine wet weight (P<0.05). RNAseq analysis revealed that E2 significantly altered expression of 1991 uterine genes (P<0.05). SPI feeding had no effect on uterine weight and altered expression of far fewer genes than E2 at 152 genes (P<0.05). Overlap between E2 and SPI genes was limited to 67 genes. Functional annotation analysis indicated significant differences in uterine biological processes affected by E2 and SPI and little evidence for recruitment of estrogen receptor (ER)α to the promoters of ER-responsive genes after SPI feeding. The major E2 up-regulated uterine pathways were carcinogenesis and extracellular matrix organization, whereas SPI feeding up-regulated uterine peroxisome proliferator activated receptor (PPAR) signaling and fatty acid metabolism. The combination of E2 and SPI resulted in significant regulation of 504 fewer genes relative to E2 alone. The ability of E2 to induce uterine proliferation in response to the carcinogen dimethybenz(a)anthracene (DMBA) as measured by expression of PCNA and Ki67 mRNA was suppressed by feeding SPI (P<0.05). These data suggest that SPI is a selective estrogen receptor modulator (SERM) interacting with a small sub-set of E2-regulated genes and is anti-estrogenic in the presence of endogenous estrogens.

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Section: Discussionmentioning

confidence: 94%

Uterine responses to feeding soy protein isolate and treatment with 17β-estradiol differ in ovariectomized female rats

Ronis

Gómez-Acevedo

Blackburn

et al. 2016

Toxicology and Applied Pharmacology

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“…In the case of ERβ, it has been proposed with a protective role from the undesired effects induce through ERα. Almost all benign and malignant endometrial proliferative diseases show changes in the ERβ expression (Nakajima et al, ), highlighting its protective role.…”

Section: Discussionmentioning

confidence: 99%

Effects of a glyphosate‐based herbicide on the uterus of adult ovariectomized rats

Varayoud

Durando

Ramos

et al. 2016

Environmental Toxicology

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Glyphosate is the active ingredient of several herbicide formulations. Different reports suggest that glyphosate-based herbicides (GBHs) may act as endocrine disruptors. We evaluated the potential estrogenic effects of a GBH formulation using the uterotrophic assay. Adult ovariectomized rats were sc injected for 3 consecutive days with: saline solution (vehicle control), 2.10 g E /kg/day (uterotrophic dose; UE ), 2.10 g E /kg/day (nonuterotrophic dose; NUE ), or 0.5, 5, or 50 mg GBH/kg/day of the. Twenty-four hours after the last injection, the uterus was removed and weighed and processed for histopathology and mRNA extraction. Epithelial cell proliferation and height and expression of estrogen-responsive genes were evaluated (estrogen receptors, ERα and ERβ; progesterone receptor, PR; complement 3, C3). Uterine weight and epithelial proliferation were not affected by GBH. However, the luminal epithelial cell height increased at GBH0.5. ERα mRNA was downregulated by all GBH doses and E groups, whereas PR and C3 mRNA were diminished by GBH0.5. GBH5-, GBH50-, and UE -treated rats showed downregulated ERα protein expression in luminal epithelial cells, while the receptor was upregulated in the stroma. GBH upregulated ERβ (GBH0.5-50) and PR (GBH5) expressions in glandular epithelial cells, similar effect to that of NUE group. These results indicate that, although the uterine weight was not affected, GBH modulates the expression of estrogen-sensitive genes. © 2016 Wiley Periodicals, Inc. Environ Toxicol 32: 1191-1201, 2017.

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“…ESR2 is important for differentiation and growth of the uterine epithelium. In addition, loss of ESR2 function results in an enhanced uterine responsiveness to E2 in the neonatal and adult uterus, highlighting its role in the inhibition of epithelial cell proliferation (Wada-Hiraike et al 2006, Nakajima et al 2015. Besides this protective action in normal endometrial tissue, a completely different role has been proposed in benign and malignant proliferative endometrial pathologies.…”

Section: Discussionmentioning

confidence: 99%

Glyphosate-based herbicide enhances the uterine sensitivity to estradiol in rats

Schimpf

Milesi

Luque

et al. 2018

Journal of Endocrinology

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In a previous work, we detected that postnatal exposure to a glyphosate-based herbicide (GBH) alters uterine development in prepubertal rats causing endometrial hyperplasia and increasing cell proliferation. Our goal was to determine whether exposure to low-dose of a GBH during postnatal development might enhance the sensitivity of the uterus to an estrogenic treatment. Female Wistar pups were subcutaneously injected with saline solution (control) or GBH using the reference dose (2 mg/kg/day, EPA) on postnatal days (PND) 1, 3, 5, and 7. At weaning (PND21), female rats were bilaterally ovariectomized and treated with silastic capsules containing 17β-estradiol (E2, 1mg/ml) until they were two months of age. On PND60, uterine samples were removed and processed for histology, immunohistochemistry and mRNA extraction to evaluate: i) uterine morphology, ii) uterine cell proliferation by the detection of Ki67, iii) the expression of the estrogen receptors alpha (ESR1) and beta (ESR2), and iv) the expression of WNT7A and β-catenin. GBH-exposed animals showed increased luminal epithelial height and stromal nuclei density. The luminal and glandular epithelium were markedly hyperplastic in 43% of GBH-exposed animals. GBH exposure caused an increase in E2-induced cell proliferation in association with an induction of both ESR1 and ESR2. GBH treatment decreased membranous and cytoplasmic expression of β-catenin in luminal and glandular epithelial cells and increased WNT7A expression in the luminal epithelium. These results suggest that early postnatal exposure to a GBH enhances the sensitivity of the rat uterus to estradiol, and induces histomorphological and molecular changes associated with uterine hyperplasia.

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Neonatal Estrogen Receptor β Is Important in the Permanent Inhibition of Epithelial Cell Proliferation in the Mouse Uterus

Cited by 10 publications

References 68 publications

Uterine responses to feeding soy protein isolate and treatment with 17β-estradiol differ in ovariectomized female rats

Uterine responses to feeding soy protein isolate and treatment with 17β-estradiol differ in ovariectomized female rats

Effects of a glyphosate‐based herbicide on the uterus of adult ovariectomized rats

Glyphosate-based herbicide enhances the uterine sensitivity to estradiol in rats

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