Search

The Caenorhabditis Intervention Testing Program (CITP) is an NIH-funded research consortium of investigators who conduct analyses at three independent sites to identify chemical interventions that reproducibly promote health and lifespan in a robust manner. The founding principle of the CITP is that compounds with positive effects across a genetically diverse panel of Caenorhabditis species and strains are likely engaging conserved biochemical pathways to exert their effects. As such, interventions that are broadly efficacious might be considered prominent compounds for translation for pre-clinical research and human clinical applications. Here, we report results generated using a recently streamlined pipeline approach for the evaluation of the effects of chemical compounds on lifespan and health. We studied five compounds previously shown to extend C. elegans lifespan or thought to promote mammalian health: 17α-estradiol, acarbose, green tea extract, nordihydroguaiaretic acid, and rapamycin. We found that green tea extract and nordihydroguaiaretic acid extend Caenorhabditis lifespan in a species-specific manner. Additionally, these two antioxidants conferred assay-specific effects in some studies—for example, decreasing survival for certain genetic backgrounds in manual survival assays in contrast with extended lifespan as assayed using automated C. elegans Lifespan Machines. We also observed that GTE and NDGA impact on older adult mobility capacity is dependent on genetic background, and that GTE reduces oxidative stress resistance in some Caenorhabditis strains. Overall, our analysis of the five compounds supports the general idea that genetic background and assay type can influence lifespan and health effects of compounds, and underscores that lifespan and health can be uncoupled by chemical interventions. [ABSTRACT FROM AUTHOR]

HIV-1 Tat continues to play an important role in the development of HIV-associated neurocognitive disorders (HAND), which persist in 15–55% of people living with HIV even with virological control. In the brain, Tat is present on neurons, where Tat exerts direct neuronal damaging effects by, at least in part, disrupting endolysosome functions, a pathological feature present in HAND. In this study, we determined the protective effects of 17α-estradiol (17αE2), the predominant form of estrogen in the brain, against Tat-induced endolysosome dysfunction and dendritic impairment in primary cultured hippocampal neurons. We demonstrated that pre-treatment with 17αE2 protected against Tat-induced endolysosome dysfunction and reduction in dendritic spine density. Estrogen receptor alpha (ERα) knockdown impairs the ability of 17αE2 to protect against Tat-induced endolysosome dysfunction and reduction in dendritic spine density. Furthermore, over-expressing an ERα mutant that fails to localize on endolysosomes impairs 17αE2′s protective effects against Tat-induced endolysosome dysfunction and reduction in dendritic spine density. Our findings demonstrate that 17αE2 protects against Tat-induced neuronal injury via a novel ERα-mediated and endolysosome-dependent pathway, and such a finding might lead to the development of novel adjunct therapeutics against HAND. [ABSTRACT FROM AUTHOR]

17α-Estradiol (αE2) is a natural diastereoisomer of 17β-estradiol (E2). It is well known that αE2 can bind to estrogen receptors. However, its biological activity is less than that of E2 and is species and tissue specific. The goal of our study was to propose the mechanism of αE2 hormonal response in rat sperm during their capacitation in vitro and compare it with a previously studied mouse model. Concentration changes in externally added αE2 during capacitation of rat sperm were monitored by the high-performance liquid chromatographic method with tandem mass spectrometric detection (HPLC-MS/MS). The calculated values of relative concentrations Bt were subjected to kinetic analysis. The findings indicated that αE2 in rat sperm did not trigger autocatalytic reaction, in contrast to the mouse sperm, and that the initiation of the hormone penetration through the sperm plasma membrane was substantially faster in rats. [ABSTRACT FROM AUTHOR]

Recently, estrogen has attracted widespread concern because it is increasing being detected in wastewater treatment plants. While techniques for estrogen removal have been reported, these have mostly focused on exploring the effect on removal using simple single-factor experiments, rather than applying more complex multifactor mathematical models to wastewater treatment. In this study, reduced graphene oxide-based iron nanoparticles (rGO@Fe NPs) were used for 17α-estradiol (αE2) removal based on adsorption and Fenton oxidation. A response surface methodology, based on a Box-Behnken design, was used to determine the relationships between critical operation factors (pH, temperature, αE2 concentration, rGOOFe NPs dose and H2O2 concentration) and removal efficiency to establish the optimal conditions for 1 mg L-1 αE2 removal. Under the determined optimal reaction condition of pH 6.0, temperature 40 °C, 0.08 g L-1 rGO@Fe NPs dose and 6 mM H2O2, a maximum removal efficiency of 99.9% was obtained. Subsequently, the presence of coexisting anions (Cl-, SO42- and NO3-) significantly decreased the removal efficiency of αE2. However, αE2 removal from domestic wastewater could be increased by 38.0% when applying RS M results. Moreover, αE2 removal by rGO@Fe NPs remained stable over five reuse cycles indicating that rGO@Fe NPs would be an efficient and practical advanced materials for αE2 removal. [ABSTRACT FROM AUTHOR]

Recently, estrogen has attracted widespread concern because it is increasing being detected in wastewater treatment plants. While techniques for estrogen removal have been reported, these have mostly focused on exploring the effect on removal using simple single-factor experiments, rather than applying more complex multifactor mathematical models to wastewater treatment. In this study, reduced graphene oxide-based iron nanoparticles (rGO@Fe NPs) were used for 17α-estradiol (αE 2) removal based on adsorption and Fenton oxidation. A response surface methodology, based on a Box-Behnken design, was used to determine the relationships between critical operation factors (pH, temperature, αE 2 concentration, rGO@Fe NPs dose and H 2 O 2 concentration) and removal efficiency to establish the optimal conditions for 1 mg L−1 αE 2 removal. Under the determined optimal reaction condition of pH 6.0, temperature 40 °C, 0.08 g L−1 rGO@Fe NPs dose and 6 mM H 2 O 2 , a maximum removal efficiency of 99.9% was obtained. Subsequently, the presence of co-existing anions (Cl−, SO 4 2− and NO 3 −) significantly decreased the removal efficiency of αE 2. However, αE 2 removal from domestic wastewater could be increased by 38.0% when applying RSM results. Moreover, αE 2 removal by rGO@Fe NPs remained stable over five reuse cycles indicating that rGO@Fe NPs would be an efficient and practical advanced materials for αE 2 removal. [ABSTRACT FROM AUTHOR]

HIV-1 Tat continues to play an important role in the development of HIV-associated neurocognitive disorders (HAND), which persist in 15–55% of people living with HIV even with virological control. In the brain, Tat is present on neurons, where Tat exerts direct neuronal damaging effects by, at least in part, disrupting endolysosome functions, a pathological feature present in HAND. In this study, we determined the protective effects of 17α-estradiol (17αE2), the predominant form of estrogen in the brain, against Tat-induced endolysosome dysfunction and dendritic impairment in primary cultured hippocampal neurons. We demonstrated that pre-treatment with 17αE2 protected against Tat-induced endolysosome dysfunction and reduction in dendritic spine density. Estrogen receptor alpha (ERα) knockdown impairs the ability of 17αE2 to protect against Tat-induced endolysosome dysfunction and reduction in dendritic spine density. Furthermore, over-expressing an ERα mutant that fails to localize on endolysosomes impairs 17αE2′s protective effects against Tat-induced endolysosome dysfunction and reduction in dendritic spine density. Our findings demonstrate that 17αE2 protects against Tat-induced neuronal injury via a novel ERα-mediated and endolysosome-dependent pathway, and such a finding might lead to the development of novel adjunct therapeutics against HAND.

We hypothesized that rapamycin (Rapa), acarbose (ACA), which both increase mouse lifespan, and 17α‐estradiol, which increases lifespan in males (17aE2) all share common intracellular signaling pathways with long‐lived Snell dwarf, PAPPA‐KO, and Ghr−/− mice. The long‐lived mutant mice exhibit reduction in mTORC1 activity, declines in cap‐dependent mRNA translation, and increases in cap‐independent translation (CIT). Here, we report that Rapa and ACA prevent age‐related declines in CIT target proteins in both sexes, while 17aE2 has the same effect only in males, suggesting increases in CIT. mTORC1 activity showed the reciprocal pattern, with age‐related increases blocked by Rapa, ACA, and 17aE2 (in males only). METTL3, required for addition of 6‐methyl‐adenosine to mRNA and thus a trigger for CIT, also showed an age‐dependent increase blunted by Rapa, ACA, and 17aE2 (in males). Diminution of mTORC1 activity and increases in CIT‐dependent proteins may represent a shared pathway for both long‐lived‐mutant mice and drug‐induced lifespan extension in mice. [ABSTRACT FROM AUTHOR]

Aging is the greatest risk factor for most chronic diseases. The somatotropic axis is one of the most conserved biological pathways that regulates aging across species. 17α-Estradiol (17α-E2), a diastereomer of 17β-estradiol (17β-E2), was recently found to elicit health benefits, including improved insulin sensitivity and extend longevity exclusively in male mice. Given that 17β-E2 is known to modulate somatotropic signaling in females through actions in the pituitary and liver, we hypothesized that 17α-E2 may be modulating the somatotropic axis in males, thereby contributing to health benefits. Herein, we demonstrate that 17α-E2 increases hepatic insulin-like growth factor 1 (IGF1) production in male mice without inducing any changes in pulsatile growth hormone (GH) secretion. Using growth hormone receptor knockout (GHRKO) mice, we subsequently determined that the induction of hepatic IGF1 by 17α-E2 is dependent upon GH signaling in male mice, and that 17α-E2 elicits no effects on IGF1 production in female mice. We also determined that 17α-E2 failed to feminize the hepatic transcriptional profile in normal (N) male mice, as evidenced by a clear divergence between the sexes, regardless of treatment. Conversely, significant overlap in transcriptional profiles was observed between sexes in GHRKO mice, and this was unaffected by 17α-E2 treatment. Based on these findings, we propose that 17α-E2 acts as a pleiotropic pathway modulator in male mice by uncoupling IGF1 production from insulin sensitivity. In summary, 17α-E2 treatment upregulates IGF1 production in wild-type (and N) male mice in what appears to be a GH-dependent fashion, while no effects in female IGF1 production are observed following 17α-E2 treatment. [ABSTRACT FROM AUTHOR]

17α-Estradiol (αE2) is a natural diastereoisomer of 17β-estradiol (E2). It is well known that αE2 can bind to estrogen receptors. However, its biological activity is less than that of E2 and is species and tissue specific. The goal of our study was to propose the mechanism of αE2 hormonal response in rat sperm during their capacitation in vitro and compare it with a previously studied mouse model. Concentration changes in externally added αE2 during capacitation of rat sperm were monitored by the high-performance liquid chromatographic method with tandem mass spectrometric detection (HPLC-MS/MS). The calculated values of relative concentrations Bt were subjected to kinetic analysis. The findings indicated that αE2 in rat sperm did not trigger autocatalytic reaction, in contrast to the mouse sperm, and that the initiation of the hormone penetration through the sperm plasma membrane was substantially faster in rats.

Metabolic dysfunction underlies several chronic diseases, many of which are exacerbated by obesity. Dietary interventions can reverse metabolic declines and slow aging, although compliance issues remain paramount. 17α-estradiol treatment improves metabolic parameters and slows aging in male mice. The mechanisms by which 17α-estradiol elicits these benefits remain unresolved. Herein, we show that 17α-estradiol elicits similar genomic binding and transcriptional activation through estrogen receptor α (ERα) to that of 17β-estradiol. In addition, we show that the ablation of ERα completely attenuates the beneficial metabolic effects of 17α-E2 in male mice. Our findings suggest that 17α-E2 may act through the liver and hypothalamus to improve metabolic parameters in male mice. Lastly, we also determined that 17α-E2 improves metabolic parameters in male rats, thereby proving that the beneficial effects of 17α-E2 are not limited to mice. Collectively, these studies suggest ERα may be a drug target for mitigating chronic diseases in male mammals.

Summary: Weight loss is an effective intervention for diminishing disease burden in obese older adults. Pharmacological interventions that reduce food intake and thereby promote weight loss may offer effective strategies to reduce age‐related disease. We previously reported that 17α‐estradiol (17α‐E2) administration elicits beneficial effects on metabolism and inflammation in old male mice. These observations were associated with reduced calorie intake. Here, we demonstrate that 17α‐E2 acts through pro‐opiomelanocortin (Pomc) expression in the arcuate nucleus (ARC) to reduce food intake and body mass in mouse models of obesity. These results confirm that 17α‐E2 modulates appetite through selective interactions within hypothalamic anorexigenic pathways. Interestingly, some peripheral markers of metabolic homeostasis were also improved in animals with near complete loss of ARC Pomc transcription. This suggests that 17α‐E2 might have central and peripheral actions that can beneficially affect metabolism cooperatively or independently. [ABSTRACT FROM AUTHOR]

Estrogen receptor α (ERα) and estrogen receptor β (ERβ) play important roles in cardiovascular disease (CVD) prevention. Recently, these estrogen receptors were reconsidered as an important treatment target of obesity leading to CVD. In this study, 17β-estradiol (17β-E) replacement therapy applied to high-fat diet-induced obese C57B male mice and ovariectomized (OVX) rats were evaluated, and the protective effects against high-fat diet-induced obesity were assessed in C57B mouse hearts. The results showed that 17β-E treatment activated both ERα and ERβ, and ERβ levels increased in a dose-dependent manner in high-fat diet C57B mouse cardiomyocytes following 17β-E treatment. Notably, an almost 16% reduction in body weight was observed in the 17β-E-treated (12 μg/kg/day for 60 days) high-fat diet-induced obese C57B male mice. These results suggested that 17β-E supplements may reduce CVD risk due to obesity. [ABSTRACT FROM AUTHOR]

Aging is associated with visceral adiposity, metabolic disorders, and chronic low-grade inflammation. 17α-estradiol (17α-E2), a naturally occurring enantiomer of 17β-estradiol (17β-E2), extends life span in male mice through unresolved mechanisms. We tested whether 17α-E2 could alleviate age-related metabolic dysfunction and inflammation. 17α-E2 reduced body mass, visceral adiposity, and ectopic lipid deposition without decreasing lean mass. These declines were associated with reductions in energy intake due to the activation of hypothalamic anorexigenic pathways and direct effects of 17α-E2 on nutrient-sensing pathways in visceral adipose tissue. 17α-E2 did not alter energy expenditure or excretion. Fasting glucose, insulin, and glycosylated hemoglobin were also reduced by 17α-E2, and hyperinsulinemic-euglycemic clamps revealed improvements in peripheral glucose disposal and hepatic glucose production. Inflammatory mediators in visceral adipose tissue and the circulation were reduced by 17α-E2. 17α-E2 increased AMPKα and reduced mTOR complex 1 activity in visceral adipose tissue but not in liver or quadriceps muscle, which is in contrast to the generalized systemic effects of caloric restriction. These beneficial phenotypic changes occurred in the absence of feminization or cardiac dysfunction, two commonly observed deleterious effects of exogenous estrogen administration. Thus, 17α-E2 holds potential as a novel therapeutic for alleviating age-related metabolic dysfunction through tissue-specific effects. [ABSTRACT FROM AUTHOR]

Estrogen has demonstrated neuroprotective properties, which may underlie the observed preventive effect of estrogen-based hormone therapy (HT) against the development of neurodegenerative disorders such as Alzheimer's disease. Deleterious side effects of HT have increased efforts to develop safer compounds that selectively reproduce beneficial estrogen actions. Recently, 4-estren-3α,17β-diol (estren) was identified as having estrogen agonist properties in bone, without significantly stimulating growth of reproductive tissues. Here, we examined whether estren parallels the neuroprotective actions of estrogen against β-amyloid (Aβ) in cultured cerebrocortical neurons. Estren increased neuronal viability to a similar extent to that observed with 17β-estradiol (E2) and 17α-estradiol. As we previously reported for E2, estren rapidly increased PKC activity, and PKC inhibition prevented estren neuroprotection. In contrast, the estrogen receptor antagonist ICI 182,780 blocked E2, but not estren neuroprotection. Our results indicate that estren-induced activation of rapid cell signaling pathways protects cultured neurons from Aβ toxicity.

Estrogen receptor alpha (ERα) plays a crucial role in reproductive function in both sexes. It also mediates cellular responses to estrogens in multiple nonreproductive organ systems, many of which regulate systemic metabolic homeostasis and inflammatory processes in mammals. The loss of estrogens and/or ERα agonism during aging is associated with the emergence of several comorbid conditions, particularly in females undergoing the menopausal transition. Emerging data also suggests that male mammals likely benefit from ERα agonism if done in a way that circumvents feminizing characteristics. This has led us, and others, to speculate that tissue-specific ERα agonism may hold therapeutic potential for curtailing aging and chronic disease burden in males and females that are at high-risk of cancer and/or cardiovascular events with traditional estrogen replacement therapies. In this mini-review, we emphasize the role of ERα in the brain and liver, summarizing recent evidence that indicates these two organs systems mediate the beneficial effects of estrogens on metabolism and inflammation during aging. We also discuss how 17α-estradiol administration elicits health benefits in an ERα-dependent manner, which provides proof-of-concept that ERα may be a druggable target for attenuating aging and age-related disease burden., Competing Interests: CONFLICTS OF INTEREST The authors declare no conflicts of interest.

A valid approach to treating frontal fibrosing alopecia (FFA), a scarring alopecia, does not yet exist. The aim of this study is to evaluate the efficacy of a topical application composed of minoxidil, hydrocortisone butyrate, 17α-estradiol, ciclosilicone pentamer, and alcohol in women affected by FFA. Forty women affected by FFA were treated with 2 ml of a topical lotion composed of 2% minoxidil base, 0.08% hydrocortisone butyrate, 0.05% 17α-estradiol, 16% ciclosilicone pentamer, 96° alcohol, applied once a day on the scalp. A score index, based on the comparison of the photos, taken at the beginning (T0) and after 36 months (T36), was used. The topical lotion led to an improvement in 20 patients, stabilization in 15 patients and worsening of the clinical condition in 5 women. This topical lotion induces a considerable improvement or stabilization of frontal fibrosing alopecia. [ABSTRACT FROM AUTHOR]

Abstract: In Jurkat T cell clone (JT/Neo), G2/M arrest, apoptotic sub-G1 peak, mitochondrial membrane potential (Δψm) loss, and TUNEL-positive DNA fragmentation were induced following exposure to 17α-estradiol (17α-E2), whereas none of these events (except for G2/M arrest) were induced in Jurkat cells overexpressing Bcl-2 (JT/Bcl-2). Under these conditions, phosphorylation at Thr161 and dephosphorylation at Tyr15 of Cdk1, upregulation of cyclin B1 level, histone H1 phosphorylation, Cdc25C phosphorylation at Thr-48, Bcl-2 phosphorylation at Thr-56 and Ser-70, Mcl-1 phosphorylation, and Bim phosphorylation were detected in the presence of Bcl-2 overexpression. However, the 17α-E2-induced upregulation of Bak levels, activation of Bak, activation of caspase-3, and PARP degradation were abrogated by Bcl-2 overexpression. In the presence of the G1/S blocking agent hydroxyurea, 17α-E2 failed to induce G2/M arrest and all apoptotic events including Cdk1 activation and phosphorylation of Bcl-2, Mcl-1 and Bim. The 17α-E2-induced phosphorylation of Bcl-2 family proteins and mitochondrial apoptotic events were suppressed by a Cdk1 inhibitor but not by aurora A and aurora B kinase inhibitors. Immunofluorescence microscopic analysis showed that an aberrant bipolar microtubule array, incomplete chromosome congression at the metaphase plate, and prometaphase arrest, which was reversible, were the underlying factors for 17α-E2-induced mitotic arrest. The in vitro microtubule polymerization assay showed that 17α-E2 could directly inhibit microtubule formation. These results show that the apoptogenic activity of 17α-E2 was due to the impaired mitotic spindle assembly causing prometaphase arrest and prolonged Cdk1 activation, the phosphorylation of Bcl-2, Mcl-1 and Bim, and the activation of Bak and mitochondria-dependent caspase cascade. [Copyright &y& Elsevier]

Abstract: Considerable research has focused on the fate of 17β-estradiol (17β-E2) given its high estrogenic potency and frequent detection in the environment; however, little is known about the fate behavior of 17α-estradiol (17α-E2) although it often dominates in some animal feces, and recently has been shown to have similar impacts as the β-isomer. In this study, the aerobic biotransformation rates of 17α-E2 and 17β-E2 applied at 50μgkg−1 soil and metabolite trends were quantified in batch microcosms at ∼21°C and 70–85% field capacity using two soils with different taxonomic properties. Soils were extracted at designated times over a 3-week period and analyzed over time using negative electrospray ionization tandem mass spectrometry. For a given soil type, the two isomers degraded at the same rate with half lives across soils ranging between 4 and 12h. Estrone (E1) was the only metabolite detected and in all cases subsequent dissipation patterns of E1 are statistically different between isomers. Autoclaved-sterilized controls support that E2 dissipation is dominated by microbial processes. A first order exponential decay model that assumed sorption did not limit bioavailability was not able to accurately predict hormone residuals at later times, which indicates caution is required when trying to model fate and transport of hormones in the environment. [Copyright &y& Elsevier]

Herein, we report the effects of six different room temperature ionic liquids (RTILs) on fluorescence spectra of 17α-estradiol (EE1) and 17β-estradiol (E2). The selected RTILs belonged to the compound classes of 1-alkyl-3-methylimidazolium tetrafluoroborate ([CMIM]BF) and 1-alkyl-3-methyl imidazolium hexafluorophosphate ([CMIM]PF). RTILs had a gradual quenching effect on fluorescence intensity (FI) of EE1 and E2, and the quenching process followed the well-known Stern-Volmer theory. The quenching mechanism of EE1 and E2 by RTILs was demonstrated to be dynamic quenching. Additionally, the overall quenching efficiency by [CMIM]BF was higher than [CMIM]PF. The increased carbon chain length of RTILs did not lead to obvious differences in FI for EE1 and E2. The quenching efficiency showed irregular trend at three different temperatures (25, 35 and 45 °C). RTILs such as [CMIM]PF had the different fluorescent effects on organic chemicals with different fluorophores. The enhancing effects of [CMIM]PF were observed on strong fluorescence chemicals (dansyl chloride, rhrodamine B, 1,10-phenanthroline, norfloxacin), while quenching effect on weak fluorescence chemicals (EE1 and E2). In theory, these results provide a theoretical foundation for deep insight into their interaction mechanism between RTILs and estradiol. [ABSTRACT FROM AUTHOR]

Abstract: Estrogens exert sustained, genomically mediated effects on memory throughout the female life cycle, but here we review new studies documenting rapid effects of estradiol on memory, which are exerted through membrane-mediated mechanisms. Use of recognition memory tasks in rats shows that estrogens enhance memory consolidation within 1h. 17α-Estradiol is more potent than 17β-estradiol, and the dose response relationship between estrogens and memory is an inverted U shape. Use of specific estrogen receptor (ER) agonists suggests mediation by an ERβ-like membrane receptor. Enhanced memory is associated with increased spine density and altered noradrenergic activity in the medial prefrontal cortex and hippocampus within 30min of administration. The environmental chemical, bisphenol-A, rapidly antagonizes enhancements in memory in both sexes possibly through actions on spines. Thus, estradiol and related compounds exert rapid alterations in cognition through non-genomic mechanisms, a finding which may provide a basis for better understanding and treating memory impairments. [Copyright &y& Elsevier]

Abstract: Although controversial, estrogen replacement therapy has been implicated as a possible therapeutic agent for ameliorating age-related cognitive decline in postmenopausal women. We have shown previously that different types of estrogen promote hippocampal neurogenesis in a dose-dependent manner in young adult female rats. However, previous studies have not found a beneficial effect of 17β-estradiol in middle-aged female rats. The aim of the present study was to determine the acute effects of 17β-estradiol, 17α-estradiol, and estrone on hippocampal cell proliferation in middle-aged ovariectomized female rats and to determine whether effects are dependent on previous reproductive experience. Middle-aged multiparous female rats or age-matched virgin female rats were injected subcutaneously with vehicle or 10μg dose of 17β-estradiol, 17α-estradiol, or estrone, and then given BrdU 30min later and perfused 24h later to assess cell proliferation. All estrogens significantly upregulated cell proliferation in the hippocampus in middle-aged multiparous females but none of the estrogens upregulated cell proliferation in the middle-aged virgins. Therefore, previous reproductive experience may make the older brain more responsive to estrogens later in life. We also found that 17α-estradiol upregulated cell proliferation to a greater degree than the other estrogens in the multiparous females. Together these findings may lead to the development of new therapeutic advances in the treatment of symptoms associated with menopause in women. [Copyright &y& Elsevier]

Abstract: 17β-Estradiol is the most potent natural estrogen commonly found in anthropogenically altered environments and has been the focus of many toxicological laboratory studies. However, fewer aquatic toxicological data on the effects of 17α-estradiol, a diastereoisomer of 17β-estradiol, exists in the literature even though it has been found in the aquatic environment, sometimes at higher concentrations than 17β-estradiol. The central objective of this study was to determine how the anatomical, physiological, and behavioral effects of exposure to 17α-estradiol compare to the well-documented effects of 17β-estradiol exposures in aquatic vertebrates. A 21-day flow-through exposure of mature male and female fathead minnows to three concentrations each of 17α- and 17β-estradiol (averaged measured concentrations 27, 72, and 150ng/L for 17α-estradiol, and 9, 20, and 44ng/L for β-estradiol, respectively) yielded significant, concentration-dependent differences in plasma vitellogenin concentrations among estradiol-exposed males when compared to fish from an ethanol carrier control. Interstitial cell prominence in the testis of fish was elevated in all estradiol treatments. Aggressiveness of male fish to defend nest sites appeared depressed in many of the higher concentration estradiol treatments (albeit not significantly). No clear effects were observed in female fish. Based on plasma vitellogenin data, it appears that 17β-estradiol is 8–9 times more potent than 17α-estradiol and that the lowest observable effect concentration (LOEC) for 17α-estradiol in fathead minnows is greater than 25ng/L and may be less than 75ng/L. [Copyright &y& Elsevier]

Abstract: Background: Estrogens modulate the morphology and function of the hippocampus. Recent studies have focused on the effects of different types of estrogens on neuroplasticity in the hippocampus and cognition. There are three main forms of estrogens found in mammals: estradiol, estrone, and estriol. The vast majority of studies have used estradiol to investigate the effects of estrogens on the brain. Scope of review: This review focuses on the effects of different estrogens on adult hippocampal neurogenesis, synaptic plasticity in the hippocampus, and cognition in female rats. Major conclusions: Different forms of estrogens modulate neuroplasticity and cognition in complex and intriguing ways. Specifically, estrogens upregulate adult hippocampal neurogenesis (via cell proliferation) and synaptic protein levels in the hippocampus in a time- and dose-dependent manner. Low levels of estradiol facilitate spatial working memory and contextual fear conditioning while high levels of estradiol impair spatial working, spatial reference memory and contextual fear conditioning. In addition, estrone impairs contextual fear conditioning. General significance: Advances in our knowledge of how estrogens exert their effects on the brain may ultimately lead to refinements in targeted therapies for cognitive impairments at all stages of life. However caution should be taken in interpreting current research and in conducting future studies as estrogens likely work differently in males than in females. [ABSTRACT FROM AUTHOR]

Abstract: Acute effects of estrogens on mnemonic processes were examined at the behavioral and neurochemical levels. 17β-estradiol and 17α-estradiol influences on memory consolidation were assessed using object placement (OP) and object recognition (OR) tasks. Subjects received treatment immediately after a sample trial (exploring two novel objects), and memory of objects (OR memory) or location of objects (OP memory) was tested 4h later. Both isomers of estradiol enhanced memory. For spatial memory, 15 and 20µg/kg of 17β-estradiol facilitated OP, while lower and higher doses were ineffective. 17α-estradiol had a similar pattern, but a lower dose was effective. When treatment was delayed until 45min after a sample trial, memory was not enhanced. For non-spatial memory, OR was facilitated at 5µg/kg of 17β-estradiol and at 1 and 2µg/kg of 17α-estradiol and, similar to OP, lower and higher doses were ineffective. These data demonstrate that beneficial effects of estrogens are dose, time and task dependent, and the dose–response pattern is an inverted U. Because monoamines are known to have contributions to memory, brains were removed 30min after treatment for measurements of dopamine (DA), norepinephrine (NE), serotonin (5-HT), and metabolites. Estrogen elevated 5HT, NE metabolite MHPG, turnover ratio of NE to MHPG, and DA metabolite DOPAC levels in the prefrontal cortex, while NE and MHPG were decreased in the hippocampus. Thus, acute estrogens exert rapid effects on memory consolidation and neural function, which suggests that its mnemonic effects may involve activation of membrane associated estrogen receptors and subsequent signaling cascades, and that monoamines may contribute to this process. [ABSTRACT FROM AUTHOR]

Abstract: The conformational structures of the hormone 17β-estradiol (E2) and the epimeric 17α-estradiol determined by solution NMR spectroscopy and restrained molecular dynamics calculations found a single low energy conformation. [Copyright &y& Elsevier]

Estrogens are known to exert significant structural and functional effects in the hippocampus of adult rodents. In particular, 17β-estradiol can improve, impair, or have no effect on hippocampus-dependent learning and memory depending on dose and time of administration. The effects of other forms of estrogen, such as estrone and 17α-estradiol, on hippocampus-dependent learning have not been as thoroughly investigated. Therefore, the purpose of this study was to investigate the effects of 17β-estradiol, estrone, and 17α-estradiol at three different doses on two different tasks: hippocampus-dependent contextual fear conditioning and hippocampus-independent cued fear conditioning. Adult ovariectomized female rats were injected with one of the estrogens at one of the three doses 30 mins before conditioning to assess the rapid effects of these estrogens on acquisition. Twenty-four hours later memory for the context was examined and 1 h later memory for the cue (tone) was assessed. Levels of synaptophysin were examined in the dorsal hippocampus of rats to identify a potential synaptic correlate of hormonal effects on contextual fear conditioning. Low 17β-estradiol and 17α-estradiol enhanced, whereas high 17β-estradiol and 17α-estradiol impaired, contextual fear conditioning. Only the middle dose of estrone severely impaired contextual fear conditioning. Estrogens did not alter performance in the hippocampus-independent cued task. Synaptophysin expression was increased by estrone (at a middle and high dose) and 17β-estradiol (at a middle dose) in the CA3 region of the hippocampus and was not correlated with cognition. The results of this study indicate that estradiol can positively or negatively influence hippocampus-dependent learning and memory, whereas estrone impairs hippocampus-dependent learning and memory in a dose-dependent manner. These results have important therapeutic implications, as estrone, a main component of a widely used hormone replacement therapy, was shown to have either a negative effect or no effect on learning and memory. It may be possible to use 17α-estradiol and lower doses of estrogens as potential alternatives in hormone replacement therapies. [ABSTRACT FROM AUTHOR]

• A new functional based on FeNPs/rGO was biosynthesized. • Adsorption and Fenton-like oxidation enhanced 17α-estradiol removal. • The removal mechanism of αE 2 by FeNPs/rGO was proposed. • Degradation products were identified by HPLC-MS. Wastewater from sewage treatment plants containing 17α-estradiol (αE 2) has a high potential to cause environmental and human toxicity. Integration of adsorption and Fenton-like oxidation is one of the potential approaches to enhance αE 2 removal. In this study, one-step biosynthesized iron nanoparticles/reduced graphene oxide (FeNPs/rGO) by tea extract was successfully used for αE 2 removal. The results showed that the removal of αE 2 by FeNPs/rGO increased to 56.1%, being only 25.4% and 45.4% for rGO and FeNPs, respectively, indicating that both adsorption and Fenton-like oxidation enhanced the removal of αE 2 , where was confirmed by HPLC-UV. To understand the removal mechanism, characterizations, including ESR, SEM, EDS, FTIR and XPS were used to elucidate the specific roles of rGO and FeNPs in the adsorption and oxidation of αE 2 , and results showed that αE 2 was adsorbed as a monolayer on the surface of rGO via π–π bond interactions and that FeNPs underwent reactions with H 2 O 2 to generate ·OH for αE 2 degradation. Thereafter, a αE 2 degradation pathway was proposed via identification of degradation products (e.g., C 18 H 22 O 3) by HPLC-MS. Moreover, the removal of αE 2 by FeNPs/rGO conformed to the Langmuir isotherm with pseudo-first-order adsorption kinetics and pseudo-second-order degradation kinetics. Based on these evidences, the removal of αE 2 by FeNPs/rGO was presented. [ABSTRACT FROM AUTHOR]

Abstract: We report the results of a recent survey of the concentration of natural estrogens (17β-estradiol, 17α-estradiol, estrone, estriol) and the synthetic estrogen, 17α-ethynylestradiol in representative animal wastes and sewage treatment plant (STP) effluents in the Waikato region of New Zealand. Dairy farm effluent samples showed high levels of estradiol (19–1360 ng/L) and its breakdown product estrone (41–3123 ng/L) compared with piggery or goat farm effluents. The combined load for these estrogens (excluding β epimer) varied from 60 to >4000 ng/L. The piggery effluent provided the lowest total estrogen load (46 ng/L), with estrone accounting for nearly 60% of the measured estrogens in this sample. The synthetic analogue, 17α-ethynylestradiol was detected only in one wastewater treatment plant sample, albeit at trace level. An estrogen receptor competitive binding assay was used to test the biological activity of the samples and confirmed that most agricultural waste samples contain high levels of estrogenic compounds. The potential of these wastes to cause endocrine disruption in the receiving ecosystem is unknown at present. [Copyright &y& Elsevier]

The brain of both sexes is a major target of estradiol and a site of estrogen synthesis during development and in the adult. In addition to the classical intranuclear estrogen receptors (ERs) ER-α and ER-β, we have recently identified a novel, plasma membrane-associated ER that is neither ER-α nor ER-β in the brain and uterus, which we have designated "ER-X". ER-X is a developmentally regulated estrogen-binding protein that is present in wild-type, ER-α gene-disrupted (αERKO) and ER-α-null mice. ER-X is re-expressed after ischemic brain injury and in adult transgenic mice with Alzheimer's disease. Although ER-X shares some homology with the C-terminal region of ER-α, it is not an alternative splicing variant of ER-α and may be a new gene. ER-X mediates 17α- estradiol and 17β-estradiol activation of MAPK/ERK. In contrast, ER-α does not elicit ERK activation but, surprisingly, is inhibitory. The potential importance of 17α-estradiol, the preferred ligand of ER-X, for the brain is underscored by our findings by liquid chromatography/tandem mass spectrometry that the endogenous levels of 17α-estradiol are significantly elevated in the postnatal day-7 and adult mouse neocortex and hippocampus, as compared with 17β-estradiol. That there is so much more 17α-estradiol than 17β-estradiol in the brain suggests that this enantiomer would be readily available to the brain. In considering estrogens for postmenopausal treatment, one should consider all the ERs present in the brain, not just ER-β and ER-β, but ER-X as well, and focus on ligands such as 17α- estradiol that may be more selective for this ER. [ABSTRACT FROM AUTHOR]

Abstract: Estrogen has demonstrated neuroprotective properties, which may underlie the observed preventive effect of estrogen-based hormone therapy (HT) against the development of neurodegenerative disorders such as Alzheimer''s disease. Deleterious side effects of HT have increased efforts to develop safer compounds that selectively reproduce beneficial estrogen actions. Recently, 4-estren-3α,17β-diol (estren) was identified as having estrogen agonist properties in bone, without significantly stimulating growth of reproductive tissues. Here, we examined whether estren parallels the neuroprotective actions of estrogen against β-amyloid (Aβ) in cultured cerebrocortical neurons. Estren increased neuronal viability to a similar extent to that observed with 17β-estradiol (E2) and 17α-estradiol. As we previously reported for E2, estren rapidly increased PKC activity, and PKC inhibition prevented estren neuroprotection. In contrast, the estrogen receptor antagonist ICI 182,780 blocked E2, but not estren neuroprotection. Our results indicate that estren-induced activation of rapid cell signaling pathways protects cultured neurons from Aβ toxicity. [Copyright &y& Elsevier]

Abstract: To investigate the role of the estrogen receptor (ER) in mediating neuroprotection, the neuroprotective profiles of selective ER agonists for ERα and ERβ, propylpyrazole triol (PPT) and 2,3-bis(4-hydroxyphenyl) proprionitrile (DPN), respectively, were compared to that of 17β-estradiol and 17α-estradiol in primary neuron cultures challenged by β-amyloid toxicity. All compounds were found to be neuroprotective in an ER-dependent manner. However, protein kinase C (PKC) inhibition completely blocked the protective effects of 17β-estradiol and 17α-estradiol and significantly attenuated PPT but not DPN neuroprotection. These data indicate that estrogen-mediated neuroprotection likely involves a variety of mechanisms and that protection due to PKC activation is more likely due to ERα compared to ERβ. [Copyright &y& Elsevier]

1.Previous studies demonstrated that estrogens, specifically 17β-estradiol, the potent, naturally occurring estrogen, are neuroprotective in a variety of models including glutamate toxicity. The aim of the present study is twofold: (1) to assess the requirement for glutamate receptors in neuronal cell death associated with anoxia–reoxygenation in three cell types, SK-N-SH and HT-22 neuronal cell lines and primary rat cortical neuronal cultures, and (2) to evaluate the neuroprotective activity of both 17β-estradiol and its weaker isomer, 17α-estradiol, in both anoxia-reoxygenation and glutamate toxicity. 2.SK-N-SH and HT-22 cell lines, both of which lack NMDA receptors as assessed by MK-801 binding assays, were resistant to both anoxia–reoxygenation and glutamate-induced cell death. In contrast, primary rat cortical neurons, which exhibit both NMDA and AMPA receptors, were sensitive to brief periods of exposure to anoxia–reoxygenation or glutamate. As such, there appears to be an obligatory requirement for NMDA and/or AMPA receptors in neuronal cell death resulting from brief periods of anoxia followed by reoxygenation. 3.Using primary rat cortical neuronal cultures, we evaluated the neuroprotective activity of 17β-estradiol (1.3 or 133 n M) and 17α-estradiol (133 n M) in both anoxia–reoxygenation and excitotoxicity models of cell death. We found that the 133 n M but not the 1.3 n M dose of the potent estrogen, 17β-estradiol, protected 58.0, 57.5, and 85.3% of the primary rat cortical neurons from anoxia–reoxygenation, glutamate, or AMPA toxicity, respectively, and the 133 n M dose of the weak estrogen, 17α-estradiol, protected 74.6, 81.7, and 85.8% of cells from anoxia–reoxygenation, glutamate, or AMPA toxicity, respectively. These data demonstrate that pretreatment with estrogens can attenuate glutamate excitotoxicity and that this protection is independent of the ability of the steroid to bind the estrogen receptor. [ABSTRACT FROM AUTHOR]

17α-estradiol (αE2), an endogenous stereoisomer of the hormone 17β-estradiol (E2), is capable of binding to estrogen receptors (ER). We aimed to mathematically describe, using experimental data, the possible interactions between αE2 and sperm ER during the process of sperm capacitation and to develop a kinetic model. The goal was to compare the suggested kinetic model with previously published results of ER interactions with E2 and 17α-ethynylestradiol (EE2). The HPLC-MS/MS method was developed to monitor the changes of αE2 concentration during capacitation. The calculated relative concentrations Bt were used for kinetic analysis. Rate constants k and molar ratio n were optimized and used for the construction of theoretical B(t) curves. Modifications in αE2–ER interactions were discovered during comparison with models for E2 and EE2. These new interactions displayed autocatalytic formation of an unstable adduct between the hormone and the cytoplasmic receptors. αE2 accumulates between the plasma membrane lipid bilayer with increasing potential, and when the critical level is reached, αE2 penetrates through the inner layer of the plasma membrane into the cytoplasm. It then rapidly reacts with the ER and creates an unstable adduct. The revealed dynamics of αE2–ER action may contribute to understanding tissue rejuvenation and the cancer-related physiology of αE2 signaling. [ABSTRACT FROM AUTHOR]

Menopause is a natural physiological process in older women that is associated with reduced estrogen production and results in increased risk for obesity, diabetes, and osteoporosis. 17α-estradiol (17α-E2) treatment in males, but not females, reverses several metabolic conditions associated with advancing age, highlighting sexually dimorphic actions on age-related pathologies. In this study we sought to determine if 17α-E2 could prevent ovariectomy (OVX)-mediated detriments on adiposity and bone parameters in females. Eight-week-old female C57BL/6J mice were subjected to SHAM or OVX surgery and received dietary 17α-E2 during a six-week intervention period. We observed that 17α-E2 prevented OVX-induced increases in body weight and adiposity. Similarly, uterine weight and luminal cell thickness were decreased by OVX and prevented by 17α-E2 treatment. Interestingly, 17α-E2 prevented OVX-induced declines in tibial metaphysis cancellous bone. And similarly, 17α-E2 improved bone density parameters in both tibia and femur cancellous bone, primarily in OVX mice. In contrast, to the effects on cancellous bone, cortical bone parameters were largely unaffected by OVX or 17α-E2. In the non-weight bearing lumbar vertebrae, OVX reduced trabecular thickness but not spacing, while 17α-E2 increased trabecular thickness and reduced spacing. Despite this, 17α-E2 did improve bone volume/tissue volume in lumbar vertebrae. Overall, we found that 17α-E2 prevented OVX-induced increases in adiposity and changes in bone mass and architecture, with minimal effects in SHAM-operated mice. We also observed that 17α-E2 rescued uterine tissue mass and lining morphology to control levels without inducing hypertrophy, suggesting that 17α-E2 could be considered as an adjunct to traditional hormone replacement therapies. • 17α-E2 prevents OVX-related obesity. • 17α-E2 beneficially modulates OVX-mediated cancellous bone loss. • 17α-E2 prevents OVX-mediated uterine atrophy. [ABSTRACT FROM AUTHOR]

• The spatio-temporal trend for E2 isomers migration was similar in soil. • The transport of E2 isomers may be affected by sorption and isomeric transformation. • Estrogenic activity was investigated to evaluate potential environmental impacts. The environmental behaviors of steroid estrogens (SEs) associated with land irrigation and application are of critical concern worldwide. Understanding the spatio-temporal distribution and transformation process of these estrogenic compounds in soil is greatly significant. In this study, laboratory soil column experiments were conducted to investigate and explore the migration and abiotic transformation of 17α-estradiol (17α-E2) and 17β-estradiol (17β-E2) over spatial and time scales. Results indicated that the migration tendency of 17α-E2 and 17β-E2 was similar. Discrepancies in transport for different SEs groups might be due to the competitive sorption and isomeric transformation in the binary-solute system. 17α-E2 and 17β-E2 can also undergo the abiotic transformation during soil column transport. The soil with naturally abundant mineral substances (e.g., iron and manganese oxides) indicated that E2 isomers tended to mineral-promoted racemization, oxidation, reduction, and radical coupling reactions. Some possible transformation products (e.g., SE 239 , E2 378 , and SE dimer 476) were identified and proposed in soil samples. Compared to the single compound tests, the estimated 17β-estradiol equivalency (EEQ) values of E2 mixture were higher during SEs migration process. [ABSTRACT FROM AUTHOR]

Metabolic dysfunction underlies several chronic diseases, many of which are exacerbated by obesity. Dietary interventions can reverse metabolic declines and slow aging, although compliance issues remain paramount. 17α-estradiol treatment improves metabolic parameters and slows aging in male mice. The mechanisms by which 17α-estradiol elicits these benefits remain unresolved. Herein, we show that 17α-estradiol elicits similar genomic binding and transcriptional activation through estrogen receptor α (ERα) to that of 17β-estradiol. In addition, we show that the ablation of ERα completely attenuates the beneficial metabolic effects of 17α-E2 in male mice. Our findings suggest that 17α-E2 may act through the liver and hypothalamus to improve metabolic parameters in male mice. Lastly, we also determined that 17α-E2 improves metabolic parameters in male rats, thereby proving that the beneficial effects of 17α-E2 are not limited to mice. Collectively, these studies suggest ERα may be a drug target for mitigating chronic diseases in male mammals., Competing Interests: SM, NH, MN, AR, RS, SA, MA, AU, MS, JH, DH, WF, MS No competing interests declared, (© 2020, Mann et al.)

Uterotrophic effect of 17α-estradiol, the C17 epimer of the main human estrogen 17β-estradiol, was shown to manifest in animal models at doses lower than those necessary for central outcome raising concerns about its potential to treat maladies of the central nervous system. We introduce here 10β,17α-dihydroxyestra-1,4-dien-3-one (α-DHED) that acts as a bioprecursor prodrug producing 17α-estradiol with remarkable selectivity to the brain and, therefore, without appreciable exposure of the periphery to the parent steroid. This distinguishing feature of α-DHED is shown by using an estrogen-responsive mouse model with complementary LC-MS/MS measurement of drug contents in target tissues. Our data warrant further research to fully establish the potential of α-DHED for a safe and efficacious 17α-estradiol-based neurotherapy.

Bisphenol-A (BPA) possesses estrogenic properties both in vitro and in vivo as an endocrine disrupting chemical. Humans experience a long-term and cumulative exposure to BPA. BPA was detectable in 97.3% of 1904 urine specimens from Korean adults. We investigated urinary estrogen concentrations in subjects with low and high BPA concentrations and its possible association with estrogen metabolism. Urine samples were collected from a high BPA concentration group (BPA-H; n=100, 11.05 ± 20.47 μg/g creatinine) and a low BPA concentration group (BPA-L; n=100, 0.70 ± 0.22 μg/g creatinine) from Korea Biomonitoring Program of Hazardous Materials Survey 2009-2010. Urinary estrogens were enzymatically hydrolyzed, extracted, and then derivatized for quantitative analysis by gas chromatography-mass spectrometry. Estrogen levels were higher in the BPA-H group than in the BPA-L group. Concentrations of estrone, 17β-estradiol, and their hydroxylated metabolites in both men and women were significantly higher in the BPA-H group than in the BPA-L group (p<0.04). Furthermore, in the BPA-H group, estrogen metabolism to 4-hydroxy-estrone and 4-hydroxy-17β-estradiol was more active than that to 2-hydroxy-estrone and 2-hydroxy-17β-estradiol. Although single measurement and/or single spot urine samples limit the measurement of long-term exposure to BPA, we found significant differences of estrogen metabolism in the BPA-H and the BPA-L groups. The increase of hydroxyestrogens, especially 4-hydroxyestrogens, can be an important factor resulting negative effects of prolonged exposure to BPA., (© 2013.)

Background: There are several commercially available agents to treat female pattern hair loss (FPHL), including minoxidil solution, anti-androgen agents and mineral supplements. However, these treatments are not always satisfactory. We report the results of a clinical trial of 17α-estradiol (Ell-Cranell® alpha 0.025%) solution to Korean female patients with FPHL., Objective: This study was designed to examine the efficacy and safety of Ell-Cranell® alpha 0.025% solution in Korean female patients with FPHL., Methods: A total of 53 women, 18 to 55 years old, applied topical Ell-Cranell® alpha 0.025% solution once daily for 8 months. Efficacy was evaluated by the change of hair counts and diameter, subjective assessment, and photographic assessment by investigators., Results: Hair counts and diameter from baseline to 4 and 8 months after treatment increased in treated patients and these changes were statistically significant (p<0.0001). 17α-estradiol (Ell-Cranell® alpha 0.025%) solution showed significant improvement by subjective self-assessment and by investigator photographic assessment. Ell-Cranell® alpha 0.025% solution was well tolerated over 8-months period., Conclusion: This study showed that Ell-Cranell® alpha 0.025% solution is a safe and effective agent for Korean women with FPHL.