Coumestrol Antagonizes Neuroendocrine Actions of Estrogen via the Estrogen Receptor α

2001 ◽  
Vol 226 (4) ◽  
pp. 301-306 ◽  
Author(s):  
Dena A. Jacob ◽  
Jennifer L. Temple ◽  
Heather B. Patisaul ◽  
Larry J. Young ◽  
Emilie F. Rissman
Keyword(s):  
Estrogen Receptor ◽  
Progesterone Receptors ◽  
Estrogen Receptor Α ◽  
Ventromedial Nucleus ◽  
Wild Type ◽  
Treatment Groups ◽  
Estrogenic Effects ◽  
Low Levels ◽  
The Brain ◽  
All Treatment

The phytoestrogen coumestrol has estrogenic actions on peripheral reproductive tissues. Yet in the brain this compound has both estrogenic and anti-estrogenic effects. We used estrogen receptor α knockout mice (ERαKO) to determine whether coumestrol has estrogenic actions in mice and also if these effects are mediated by the classic ERα. Female wild-type (WT) and ERαKO mice were ovariectomized and treated with estradiol (E2), dietary coumestrol, both, or neither compound. Ten days later the animals were sacrificed, blood was collected, and brain tissues were perfused. Fixed brains were sectioned and immunocytochemistry was employed to quantify progesterone receptors (PR) in the medial preoptic (POA) and ventromedial nucleus of the hypothalamus (VMN). Plasma was assayed for luteinizing hormone (LH). Estrogen treatment induced PR immunoreactivity in both regions in brains of WT females. In ERαKO mice, lower levels of PR were induced. The stimulatory effects of E2 on PR were attenuated in the POA by cotreatment with coumestrol, and the same trend was noted in the VMN. WT ovariectomized females treated with E2 had low levels of LH, while LH was high in untreated females and even higher in ovariectomized females treated with coumestrol. ERαKO females in all treatment groups had high levels of LH. Taken together, the results show that coumestrol has anti-estrogenic actions in the brain and pituitary and that ERα mediates these effects.

Estrogen Receptor-Independent Catechol Estrogen Binding Activity:  Protein Binding Studies in Wild-Type, Estrogen Receptor-α KO, and Aromatase KO Mice Tissues†

Biochemistry ◽  
2004 ◽  
Vol 43 (21) ◽  
pp. 6698-6708 ◽  
Author(s):  
Brian J. Philips ◽  
Pete J. Ansell ◽  
Leslie G. Newton ◽  
Nobuhiro Harada ◽  
Shin-Ichiro Honda ◽  
...  
Keyword(s):  
Estrogen Receptor ◽  
Protein Binding ◽  
Estrogen Receptor Α ◽  
Binding Activity ◽  
Wild Type ◽  
Binding Studies ◽  
Catechol Estrogen ◽  
Estrogen Binding

scholarly journals Association of Cryptorchidism with a Specific Haplotype of the Estrogen Receptor α Gene: Implication for the Susceptibility to Estrogenic Environmental Endocrine Disruptors

2005 ◽  
Vol 90 (8) ◽  
pp. 4716-4721 ◽  
Author(s):  
Rie Yoshida ◽  
Maki Fukami ◽  
Isoji Sasagawa ◽  
Tomonobu Hasegawa ◽  
Naoyuki Kamatani ◽  
...  
Keyword(s):  
Estrogen Receptor ◽  
Endocrine Disruptors ◽  
Outcome Measure ◽  
Estrogen Receptor Α ◽  
Nucleotide Polymorphisms ◽  
Single Nucleotide ◽  
Main Outcome Measure ◽  
Environmental Endocrine Disruptors ◽  
Estrogenic Effects ◽  
Specific Haplotype

Context: The prevalence of cryptorchidism (CO) has increased during the past few decades in several countries, and this event has primarily been ascribed to the estrogenic effects of environmental endocrine disruptors (EEDs). Little is known, however, about the role of genetic susceptibility to EEDs in this phenomenon. Objective: The objective of this study was to determine whether CO is associated with a specific haplotype of the gene for estrogen receptor α (ESR1) that mediates the estrogenic effects of EEDs. Design: This was a case-control study. Setting: The study was performed at the National Research Institute and University Hospitals. Subjects: Sixty-three cryptorchid males, aged 1–13 yr, and 47 control males, aged 4–12 yr, were studied. Intervention: After genotyping 15 single nucleotide polymorphisms widely distributed in the greater than 300-kb genomic sequences of ESR1, haplotype analysis was performed. Main Outcome Measure: Identification of a specific ESR1 haplotype associated with CO was the main outcome measure. Results: A haplotype block was identified for an approximately 50-kb region encompassing single nucleotide polymorphisms 10–14 in the 3′ region of ESR1 in both groups. The frequency of the estimated AGATA haplotype within the block was higher in the patients than in the control males (34.0% vs. 21.3%; P = 0.037), and the association of this haplotype with CO phenotype was significant in a recessive mode (P = 0.0060). The homozygosity for this haplotype was identified only in the patients, and the frequency of the homozygotes was significantly different between the two groups (10 of 63 vs. zero of 47; P = 0.0042). Conclusions: The association of CO with homozygosity for the specific ESR1 haplotype suggests the relevance of genetic susceptibility to EEDs in the development of CO.

scholarly journals Nuclear Activation Function 2 Estrogen Receptor α Attenuates Arterial and Renal Alterations Due to Aging and Hypertension in Female Mice

2020 ◽  
Vol 9 (5) ◽  
Author(s):  
Emmanuel Guivarc'h ◽  
Julie Favre ◽  
Anne‐Laure Guihot ◽  
Emilie Vessières ◽  
Linda Grimaud ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Estrogen Receptor ◽  
Angiotensin Ii ◽  
Systolic Blood Pressure ◽  
Vascular Reactivity ◽  
Nuclear Gene ◽  
Estrogen Receptor Α ◽  
Protective Effects ◽  
Wild Type ◽  
Female Mice

Background The cardiovascular protective effects of estrogens in premenopausal women depend mainly on estrogen receptor α (ERα). ERα activates nuclear gene transcription regulation and membrane‐initiated signaling. The latter plays a key role in estrogen‐dependent activation of endothelial NO synthase. The goal of the present work was to determine the respective roles of the 2 ERα activities in endothelial function and cardiac and kidney damage in young and old female mice with hypertension, which is a major risk factor in postmenopausal women. Methods and Results Five‐ and 18‐month‐old female mice lacking either ERα (ERα −/− ), the nuclear activating function AF2 of ERα (AF2°), or membrane‐located ERα (C451A) were treated with angiotensin II (0.5 mg/kg per day) for 1 month. Systolic blood pressure, left ventricle weight, vascular reactivity, and kidney function were then assessed. Angiotensin II increased systolic blood pressure, ventricle weight, and vascular contractility in ERα −/− and AF2° mice more than in wild‐type and C451A mice, independent of age. In both the aorta and mesenteric resistance arteries, angiotensin II and aging reduced endothelium‐dependent relaxation in all groups, but this effect was more pronounced in ERα −/− and AF2° than in the wild‐type and C451A mice. Kidney inflammation and oxidative stress, as well as blood urea and creatinine levels, were also more pronounced in old hypertensive ERα −/− and AF2° than in old hypertensive wild‐type and C451A mice. Conclusions The nuclear ERα‐AF2 dependent function attenuates angiotensin II–dependent hypertension and protects target organs in aging mice, whereas membrane ERα signaling does not seem to play a role.

scholarly journals Ins1-Cre and Ins1-CreER Gene Replacement Alleles Are Susceptible To Silencing By DNA Hypermethylation

Endocrinology ◽  
2020 ◽  
Vol 161 (8) ◽  
Author(s):  
Elham Mosleh ◽  
Kristy Ou ◽  
Matthew W Haemmerle ◽  
Teguru Tembo ◽  
Andrew Yuhas ◽  
...  
Keyword(s):  
Beta Cell ◽  
Endocrine Cells ◽  
Target Genes ◽  
Cell Function ◽  
Gene Replacement ◽  
Wild Type ◽  
Dna Hypermethylation ◽  
Gene Ablation ◽  
Low Levels ◽  
The Brain

Abstract Targeted gene ablation studies of the endocrine pancreas have long suffered from suboptimal Cre deleter strains. In many cases, Cre lines purportedly specific for beta cells also displayed expression in other islet endocrine cells or in a subset of neurons in the brain. Several pancreas and endocrine Cre lines have experienced silencing or mosaicism over time. In addition, many Cre transgenic constructs were designed to include the hGH mini-gene, which by itself increases beta-cell replication and decreases beta-cell function. More recently, driver lines with Cre or CreER inserted into the Ins1 locus were generated, with the intent of producing β cell-specific Cre lines with faithful recapitulation of insulin expression. These lines were bred in multiple labs to several different mouse lines harboring various lox alleles. In our hands, the ability of the Ins1-Cre and Ins1-CreER lines to delete target genes varied from that originally reported, with both alleles displaying low levels of expression, increased levels of methylation compared to the wild-type allele, and ultimately inefficient or absent target deletion. Thus, caution is warranted in the interpretation of results obtained with these genetic tools, and Cre expression and activity should be monitored regularly when using these lines.

Effect of anti-PMSG on distribution of estrogen receptor alpha and progesterone receptor in mouse ovary, oviduct and uterus

Zygote ◽  
2014 ◽  
Vol 23 (5) ◽  
pp. 695-703 ◽  
Author(s):  
Zi Li Lin ◽  
He Min Ni ◽  
Yun Hai Liu ◽  
Xi Hui Sheng ◽  
Xiang Shun Cui ◽  
...  
Keyword(s):  
Estrogen Receptor ◽  
Progesterone Receptor ◽  
Estrogen Receptor Alpha ◽  
Negative Impact ◽  
Embryo Implantation ◽  
Estrogen Receptor Α ◽  
Endogenous Hormones ◽  
Treatment Groups ◽  
Cycle Dependent ◽  
Implantation Period

SummaryIt is well established that estrogen and progesterone are critical endogenous hormones that are essential for implantation and pregnancy in females. However, the distribution of estrogen receptor α (ERα) and progesterone receptor (PR) in female reproductive tracts is elusive. Herein, we report that after serial treatments with pregnant mare's serum gonadotrophin (PMSG) with or without anti-PMSG (AP), mice could regulate the distribution of ERα and PR in the murine ovary, oviduct and uterus and the level of estradiol in serum. ERα and PR regulation by PMSG and anti-PMSG was estrous cycle-dependent and critical for promoting the embryo-implantation period. Furthermore, our results suggested that AP-42 h treatment is more effective than the other treatments. In contrast, other treatment groups also affected the distribution of ERα and PR in mouse reproductive tracts. Thus, we found that anti-PMSG has the potential to restore the distribution of ERα and PR, which could effectively reduce the negative impact of residual estrogen caused by the normal superovulation effect of PMSG in mice.

scholarly journals Effects of histone deacetylase inhibitors on estradiol-induced proliferation and hyperplasia formation in the mouse uterus

2005 ◽  
Vol 185 (3) ◽  
pp. 539-549 ◽  
Author(s):  
Andrei G Gunin ◽  
Irina N Kapitova ◽  
Nina V Suslonova
Keyword(s):  
Estrogen Receptor ◽  
Histone Acetylation ◽  
Histone Deacetylase ◽  
Sodium Butyrate ◽  
Histone Deacetylase Inhibitors ◽  
Trichostatin A ◽  
Progesterone Receptors ◽  
Estrogen Receptor Α ◽  
Mouse Uterus ◽  
Myometrial Cells

It is suggested that estrogen hormones recruit mechanisms controlling histone acetylation to bring about their effects in the uterus. However, it is not known how the level of histone acetylation affects estrogen-dependent processes in the uterus, especially proliferation and morphogenetic changes. Therefore, this study examined the effects of histone deacetylase blockers, trichostatin A and sodium butyrate, on proliferative and morphogenetic reactions in the uterus under long-term estrogen treatment. Ovari-ectomized mice were treated with estradiol dipropionate (4 μg per 100 g; s.c., once a week) or vehicle and trichostatin A (0.008 mg per 100 g; s.c., once a day) or sodium butyrate (1% in drinking water), or with no additional treatments for a month. In animals treated with estradiol and trichostatin A or sodium butyrate, uterine mass was increased, and abnormal uterine glands and atypical endometrial hyperplasia were found more often. Both histone deacetylase inhibitors produced an increase in the numbers of mitotic and bromodeoxyuridine-labelled cells in luminal and glandular epithelia, in stromal and myometrial cells. Levels of estrogen receptor-α and progesterone receptors in uterine epithelia, stromal and myometrial cells were decreased in mice treated with estradiol and trichostatin A or sodium butyrate. Expression of β-catenin in luminal and glandular epithelia was attenuated in mice treated with estradiol with trichostatin A or sodium butyrate. Both histone deacetylase inhibitors have similar unilateral effects; however the action of trichostatin A was more expressed than that of sodium butyrate. Thus, histone deacetylase inhibitors exert proliferative and morphogenetic effects of estradiol. The effects of trichostatin A and sodium butyrate are associated with changes in expression of estrogen receptor-α, progesterone receptors and β-catenin in the uterus.

scholarly journals Estrogen receptor-α mediates estrogen-inducible abnormalities in the developing penis

Reproduction ◽  
2007 ◽  
Vol 133 (5) ◽  
pp. 1057-1067 ◽  
Author(s):  
H O Goyal ◽  
T D Braden ◽  
P S Cooke ◽  
M A Szewczykowski ◽  
C S Williams ◽  
...  
Keyword(s):  
Estrogen Receptor ◽  
Levator Ani ◽  
Estrogen Receptor Α ◽  
Control Group ◽  
Wild Type ◽  
Penile Length ◽  
In The Wild ◽  
Os Penis ◽  
Harmful Effects ◽  
Wild Type Control

Previously, we reported an association between estrogen receptor-α (ERα) upregulation and detrimental effects of neonatal diethylstilbestrol (DES) exposure in the rat penis. The objective of this study was to employ the ERα knockout (ERαKO) mouse model to test the hypothesis that ERα mediates DES effects in the developing penis. ERαKO and wild-type C57BL/6 mice received oil or DES at a dose of 0.2 μg/pup per day (0.1 mg/kg) on alternate days from postnatal days 2 to 12. Fertility was tested at 80–240 days of age and tissues were examined at 96–255 days of age. DES caused malformation of the os penis, significant reductions in penile length, diameter, and weight, accumulation of fat cells in the corpora cavernosa penis, and significant reductions in weight of the bulbospongiosus and levator ani muscles in wild-type mice. Conversely, ERαKO mice treated with DES developed none of the above abnormalities. While nine out of ten male mice sired pups in the wild-type/control group, none did in the wild-type/DES group. ERαKO mice, despite normal penile development, are inherently infertile. Both plasma and intratesticular testosterone levels were unaltered in the DES-treated wild-type or DES-treated ERαKO mice when compared with controls, although testosterone concentration was much higher in the ERαKO mice. Hence, the resistance of ERαKO mice to developing penile abnormalities provides unequivocal evidence of an obligatory role for ERα in mediating the harmful effects of neonatal DES exposure in the developing penis.

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