Development of ER-α and ER-β expression in the developing ovine brain and pituitary

Schaub, C; Gersting, Jason A.; Keller‐Wood, Maureen; Wood, Charles E.

doi:10.1016/j.gep.2008.03.001

Cited by 24 publications

(33 citation statements)

References 36 publications

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“…The apparent upregulation of both HIF1A and ARNT2 by E 2 S in the present experiment suggests that during the last stage of gestation before spontaneous parturition, the fetal hypothalamus increases the expression of hypoxic-related genes in response to increased hypothalamic E 2 and E 2 S concentrations or increased abundance of ER␣ (34), even when the fetus in not undergoing clinical hypoxia. Given that the genes of the bHLH-PAS family can interact with ER, the mediator of this effect might be E 2 through ER␣ binding.…”

Section: Mediators Of Vascularization and Hypoxia Responsementioning

confidence: 50%

“…The fetal hypothalamus expresses STS, and the ratio of STS to STF (the enzyme that catalyzes the reverse reaction) is high in the fetal hypothalamus (31,43). The fetal hypothalamus also expresses both estrogen receptor alpha and beta (ER␣ and ER␤) throughout the latter half of gestation (34). Because E 2 S cannot bind ER directly and must be converted to E 2 by STS, we have proposed that it functions as a precursor hormone.…”

Section: Discussionmentioning

confidence: 99%

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Genomics of estradiol-3-sulfate action in the ovine fetal hypothalamus

Rabaglino

Richards

Denslow

et al. 2012

Physiological Genomics

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In fetal sheep during late gestation sulfoconjugated estrogens in plasma reach a concentration 40 -100 times greater than unconjugated estrogens. The objective of the present study was to determine the genomics of estradiol-3-sulfate (E2S) action in the ovine fetal brain. The hypothesis was that E2S stimulates genes involved in the neuroendocrine pathways that direct or facilitate fetal development at the end of gestation. Four sets of chronically catheterized ovine twin fetuses were studied (gestational age: 120 -127 days gestation) with one infused with E 2S intracerebroventricularly (1 mg/day) and the other remaining untreated (control). After euthanasia, mRNA samples were extracted from fetal brains. Only hypothalamic samples were employed for this study given the important function of this brain region in the control of the hypothalamus-pituitary-adrenal axis. Microarray analysis was performed following the Agilent protocol for one-color 8 ϫ 15 microarrays, designed for Ovis aries. A total of 363 known genes were significantly upregulated by the E 2S treatment (P Ͻ 0.05). Network and enrichment analyses were performed using the Cytoscape/Bingo software, and the results validated by quantitative realtime PCR. The main overrepresented biological processes resulting from this analysis were feeding behavior, hypoxia response, and transforming growth factor signaling. Notably, the genes involved in the feeding behavior (neuropeptide Y and agouti-related protein) were the most strongly induced by the E2S treatment. In conclusion, E2S may be an important component of the mechanism for activating orexigenic, hypoxia responsiveness and neuroprotective pathways in the lamb as it approaches postnatal life. heart rate; estradiol; hypoxia; estrogen receptor; neuropeptides; neurosteroid IN FETAL SHEEP and pregnant ewes, sulfoconjugated estrogens are far more abundant than unconjugated estrogens (9,41,46). High concentrations of estrone sulfate in uterine vein plasma (compared to peripheral vein plasma) of pregnant sheep suggested a high secretion rate for this steroid by placenta in late gestation (15). Plasma concentrations of estradiol-3-sulfate (E 2 S) are ϳ40 -100 times those of estradiol (E 2 ) in the lategestation fetal sheep. E 2 S is taken up by the fetal brain and stimulates responses that are both similar to and distinct from the responses to E 2 (43, 46). Sulfoconjugation increases the half-life in the blood (33) and supplies a ready source of E 2 in tissues (e.g., hypothalamus) that express steroid sulfatase (STS) (31, 43). E 2 S can bind estrogen receptor only after deconjugation by STS. We have proposed that, while the function of the sulfoconjugated estrogens in fetal and maternal sheep is unknown, deconjugation can increase estrogen action in specific tissues that express STS and estrogen receptor (43,44,46). The fetal brain expresses both STS and estrogen sulfotransferase (STF), allowing for the bidirectional interconversion of E 2 and E 2 S (31, 32), although the ratio of expression for these enzymes fa...

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Section: Mediators Of Vascularization and Hypoxia Responsementioning

confidence: 50%

Section: Discussionmentioning

confidence: 99%

Genomics of estradiol-3-sulfate action in the ovine fetal hypothalamus

Rabaglino

Richards

Denslow

et al. 2012

Physiological Genomics

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“…Most interestingly, the response to E2 did not substantially overlap with genes known to be directly controlled by ESR1 (estrogen receptor alpha), and prediction of putative TF binding by WebGestalt did not predict a major role for E2 through the ESR1. We have reported that the fetal hypothalamus expresses ER␣ and that the abundance of the receptor is ontogenetically regulated (25).…”

Section: ϫ16mentioning

confidence: 99%

“…What that mechanism might be is unknown, and it is not possible to discern specific mechanisms from the present study. Possibilities include binding to G protein estrogen receptor 1 (GPER1), which is highly expressed in fetal brain (2), or binding to ESR2, which is also abundant in fetal brain (25) but whose action could be more related to alterations in mitochondrial function (27).…”

Section: ϫ16mentioning

confidence: 99%

Transcriptomics of the fetal hypothalamic response to brachiocephalic occlusion and estradiol treatment

Wood

Rabaglino

Richards

et al. 2014

Physiological Genomics

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Wood CE, Rabaglino MB, Richards E, Denslow N, Zarate MA, Chang EI, Keller-Wood M. Transcriptomics of the fetal hypothalamic response to brachiocephalic occlusion and estradiol treatment. Physiol Genomics 46: 523-532, 2014. First published May 13, 2014 doi:10.1152 doi:10. /physiolgenomics.00186.2013 is a wellknown modulator of fetal neuroendocrine activity and has been proposed as a critical endocrine signal readying the fetus for birth and postnatal life. To investigate the modulatory role of E2 on fetal stress responsiveness and the response of the fetal brain to asphyxic stress, we subjected chronically catheterized fetal sheep to a transient (10 min) brachiocephalic artery occlusion (BCO) or sham occlusion. Half of the fetuses received subcutaneous pellets that increased plasma E2 concentrations within the physiological range. Hypothalamic mRNA was analyzed using the Agilent 8x15k ovine array (019921), processed and annotated as previously reported by our laboratory. Analysis of the data by ANOVA revealed that E2 differentially regulated (DR) 561 genes, and BCO DR 894 genes compared with control and E2ϩBCO DR 1,153 genes compared with BCO alone (all P Ͻ 0.05). E2 upregulated epigenetic pathways and downregulated local steroid biosynthesis but did not significantly involve genes known to directly respond to the estrogen receptor. Brachiocephalic occlusion upregulated kinase pathways as well as genes associated with lymphocyte infiltration into the brain and downregulated neuropeptide synthesis. E2 upregulated immune-and apoptosis-related pathways after BCO and reduced kinase and epigenetic pathway responses to the BCO. Responses to BCO are different from responses to hypoxic hypoxia suggesting that mechanisms of responses to these two forms of brain hypoxia are distinct. We conclude that cerebral ischemia caused by BCO might stimulate lymphocyte infiltration into the brain and that this response appears to be modified by estradiol. cortisol; fetal heart; mitochondria; metabolism; late gestation DURING THE TRANSITION FROM intra-to extrauterine life, birth asphyxia is a common cause of cerebral ischemia (29), commonly resulting in the need for resuscitation of the neonate. Disturbances in cerebral blood flow can result from various manipulations in the neonatal intensive care unit, including hypocarbia secondary to mechanical ventilation (18), continuous positive airway pressure (16, 42), and extracorporeal membrane oxygenation (7). Reduction of cerebral blood flow in the neonate compromises oxygen delivery or, if severe, produces ischemia/reperfusion injury (10) and results in morbidity, including intraventricular hemorrhage (6) and long-term cognitive deficit (14).We have investigated the cardiovascular and endocrine responses to cerebral hypoperfusion in late-gestation chronically catheterized fetal sheep (31,38,39), in this animal model of late fetal development. This model allows us to investigate responses to stress in utero and better understand the native homeostatic mechanisms that promote survival af...

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“…The abundance of ERb in different tissues varies during development, via unknown regulatory mechanisms, suggesting an important role of ERb-mediated estrogen action in the maturation of fetal and postnatal tissues [136][137][138].…”

Section: Circadian Regulation Of Erb Expressionmentioning

confidence: 99%

Regulation of estrogen receptor beta activity and implications in health and disease

Swedenborg

Power

Wen

et al. 2009

Cell. Mol. Life Sci.

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Together with the estrogen receptor (ER) alpha, estrogen receptor beta (ER beta ) mediates many of the physiological effects of estrogens. As ER beta is crucially involved in a variety of important physiological processes, its activity should be tightly regulated. ER beta regulation is achieved by hormone binding as well as by posttranslational modifications of the receptor. Furthermore, ER beta expression levels are under circadian control and can be regulated by DNA methylation of the ER beta promoter region. There are also a number of factors that can interfere with ER beta activity, such as phytoestrogens, endocrine disruptive chemicals, and growth factors. In this article, we outline different mechanisms of ER beta regulation and how they are implicated in various diseases. We also discuss how these insights might help to specifically target ER beta in drug design.

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Development of ER-α and ER-β expression in the developing ovine brain and pituitary

Cited by 24 publications

References 36 publications

Genomics of estradiol-3-sulfate action in the ovine fetal hypothalamus

Genomics of estradiol-3-sulfate action in the ovine fetal hypothalamus

Transcriptomics of the fetal hypothalamic response to brachiocephalic occlusion and estradiol treatment

Regulation of estrogen receptor beta activity and implications in health and disease

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