RESUMEN
Applying sewage sludge or animal manure onto agricultural land can result in estrogen pollution, which increases the risk of human exposure to steroid estrogens (SEs) via the food chain. However, the uptake and accumulation mechanism of SEs by plants is still unclear. In this study, the uptake, accumulation, and translocation of 17ß-E2, a representative SE, were investigated through a series of wheat hydroponic experiments. Various inhibitors were applied to explore the uptake pathways of 17ß-E2 by wheat. In addition, the effects of exposure concentrations, coexisting 17α-ethynylestradiol (EE2) and plant properties on the uptake of 17ß-E2 were examined. The results indicated that the accumulation of 17ß-E2 in wheat roots mainly resulted from adsorption and active uptake that involved aquaporins and anion channels transport. The chlorophyll and protein contents of plants were positively correlated with the uptake of 17ß-E2, whereas competitive inhibition occurred when 17ß-E2 and EE2 coexisted in the same solution. Nevertheless, the results of a split-root experiment showed that 17ß-E2 absorbed by wheat could further migrate in plant via long-distance transport and ultimately was discharged from plants, suggesting that 17ß-E2 was still at risk of being released even though it had been absorbed by plants. These results could provide valuable insights into the risk assessment and risk control of the uptake of SEs by plants.
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Estradiol , Estrógenos , Plantas , Contaminantes del Suelo , Adsorción , Estradiol/farmacocinética , Estrógenos/farmacocinética , Etinilestradiol/farmacocinética , Humanos , Aguas del Alcantarillado , Contaminantes del Suelo/farmacocinéticaRESUMEN
Every woman, if she lives long enough, will transition into menopause, and as the US population ages, women will be spending more time in a postmenopausal state than before. For postmenopausal women, the decision to initiate menopausal hormone therapy should be individualized. A thorough evaluation of the patient's cardiovascular, venous thromboembolic, cancer, and fracture risk should be considered along with the woman's quality of life. Hormone therapy exerts its therapeutic effects on vasomotor symptoms, the skeleton, and the genitourinary system independent of age since menopause and these benefits are lost once hormone therapy is stopped. Here we review the pharmacologic properties dose, formulation, mode of administration, timing of initiation, and duration of hormonal therapies in regard to optimizing benefit and minimizing risk to the patient. This discussion will focus on the effects of common hormonal therapies including estrogen (local and systemic), progesterone, estrogen receptor agonist/antagonist, and local dehydroepiandrosterone and include a brief review of compounded bioidentical hormone therapy.
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Terapia de Reemplazo de Estrógeno/métodos , Menopausia/efectos de los fármacos , Deshidroepiandrosterona/administración & dosificación , Estrógenos/administración & dosificación , Estrógenos/efectos adversos , Estrógenos/metabolismo , Estrógenos/farmacocinética , Femenino , Enfermedades Urogenitales Femeninas/tratamiento farmacológico , Humanos , Progestinas/administración & dosificación , Progestinas/efectos adversos , Progestinas/metabolismo , Progestinas/farmacocinética , Receptores de Estrógenos/efectos de los fármacos , Testosterona/administración & dosificaciónRESUMEN
One of the concerns when using grain ingredients in feed formulation for livestock and poultry diets is mycotoxin contamination. Aflatoxin, fumonisin, ochratoxin, trichothecene (deoxynivalenol, T-2 and HT-2) and zearalenone (ZEN) are mycotoxins that have been frequently reported in animal feed. ZEN, which has raised additional concern due to its estrogenic response in animals, is mainly produced by Fusariumgraminearum (F.graminearum), F.culmorum, F.cerealis, F.equiseti, F.crookwellense and F.semitectums, and often co-occurs with deoxynivalenol in grains. The commonly elaborated derivatives of ZEN are -zearalenol, -zearalenol, zearalanone, -zearalanol, and -zearalanol. Other modified and masked forms of ZEN (including the extractable conjugated and non-extractable bound derivatives of ZEN) have also been quantified. In this review, common dose of ZEN in animal feed was summarized. The absorption rate, distribution ("carry-over"), major metabolites, toxicity and estrogenicity of ZEN related to poultry, swine and ruminants are discussed.
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Alimentación Animal/microbiología , Estrógenos/toxicidad , Microbiología de Alimentos , Hongos/metabolismo , Zearalenona/toxicidad , Crianza de Animales Domésticos , Animales , Relación Dosis-Respuesta a Droga , Estrógenos/farmacocinética , Cadena Alimentaria , Aves de Corral , Medición de Riesgo , Rumiantes , Sus scrofa , Toxicocinética , Zearalenona/farmacocinéticaRESUMEN
BACKGROUND AND AIMS: Intestinal calcium absorption from the diet plays important role in maintaining calcium homeostasis in the body. Estrogen exerts wide physiological and pathological effects in the human. Previous studies have shown that estrogen is involved in the intestinal calcium absorption. In this study, we made investigation on the mechanism of estrogen action on duodenal calcium absorption. METHODS: The experiments were performed in mice, human, and human duodenal epithelial cells, SCBN cells. Murine duodenal calcium absorption was measured by using single pass perfusion of the duodenum in vivo. The calcium absorption of SCBN cells was evaluated by calcium imaging system. The expression of calcium transport proteins, transient receptor potential cation channel (TRPV6) and plasma membrane calcium pump (PMCA1b), in the duodenum or SCBN cells were analyzed by western blot. RESULTS: The duodenal calcium absorption in ovariectomized mice was significantly decreased, compared with control female mice, which returned to control level after 17ß-estradiol replacement treatment. Estrogen regulated the expressions of TRPV6 and PMCA1b in murine and human duodenal mucosae and SCBN cells. The further results from SCBN cells showed that 17ß-estradiol regulated calcium influx through the respective effects of estrogen receptor (ER) É and ß on TRPV6 and PMCA1b. CONCLUSION: Estrogen regulates duodenal calcium absorption through differential role of ERÉ and ERß on duodenal epithelial cellular TRPV6 and PMCA1b. The study further elucidates the mechanism of estrogen on the regulation of intestinal calcium absorption.
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Canales de Calcio/metabolismo , Calcio/metabolismo , Duodeno/fisiología , Estradiol/farmacocinética , Mucosa Intestinal/metabolismo , ATPasas Transportadoras de Calcio de la Membrana Plasmática/metabolismo , Receptores de Estrógenos/metabolismo , Canales Catiónicos TRPV/metabolismo , Animales , Transporte Biológico Activo/efectos de los fármacos , Transporte Biológico Activo/fisiología , Células Cultivadas , Estrógenos/farmacocinética , Humanos , Absorción Intestinal/efectos de los fármacos , Absorción Intestinal/fisiología , RatonesRESUMEN
The encapsulation into liposomes of several types of molecules presents the advantages to protect the activity of these molecules and to target specific tissues. Nevertheless, a major obstacle remains the incomplete understanding of nano-bio interactions. Specifically, the impact that inclusion of drug into liposomes or of drug-in-cyclodextrin-in liposomes (DCL) could have on the molecular and cellular mechanism of drug action is largely unknown. As a proof of concept, we evaluated the impact of 17ß-estradiol (E2) included into liposomes or DCL on estrogen receptor (ER)α signaling pathways. Indeed, ERα relays the pleiotropic actions of E2 in physiology and pathophysiology through two major pathways: (1) the genomic/nuclear effects associated to the transcriptional activity of the ERα and (2) the rapid/nongenomic/membrane-initiated steroid signaling (MISS) effects related to the induction of fast signaling pathways occurring when ERα is anchored to the plasma membrane. We evidenced that the inclusion of E2 into liposomes (Lipo-E2) or into DCL (DCL-E2) prevented the activation of the rapid/nongenomic/extranuclear/MISS pathway of ERα, while the activation of the genomic/nuclear pathway was maintained. These results support that Lipo-E2 and DCL-E2 could be a useful tool to delineate the complex molecular mechanisms associated to ERα. In conclusion, this study supports the notion that inclusion of drugs into liposomes or DCL could modify some specific pathways of their molecular and cellular mechanisms of action. These results emphasized that attention should be paid to nano-bio interactions induced by the use of nanovectors in medicine.
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Membrana Celular/efectos de los fármacos , Composición de Medicamentos/métodos , Estradiol/administración & dosificación , Estrógenos/administración & dosificación , Transducción de Señal/efectos de los fármacos , Animales , Disponibilidad Biológica , Membrana Celular/metabolismo , Ciclodextrinas/química , Modelos Animales de Enfermedad , Estradiol/química , Estradiol/farmacocinética , Receptor alfa de Estrógeno/metabolismo , Estrógenos/química , Estrógenos/farmacocinética , Femenino , Terapia de Reemplazo de Hormonas/métodos , Sofocos/tratamiento farmacológico , Sofocos/etiología , Humanos , Liposomas , Células MCF-7 , Menopausia/efectos de los fármacos , Menopausia/fisiología , Ratones , Microscopía Electrónica de Transmisión , Nanopartículas/química , Nanopartículas/ultraestructura , Ovariectomía/efectos adversos , Tamaño de la Partícula , Prueba de Estudio Conceptual , Transducción de Señal/fisiología , SolubilidadRESUMEN
2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD), commonly referred to simply as "dioxin", is a persistent environmental pollutant. Because of its high environmental persistence and biological accumulation, humans and animals are often exposed to TCDD. Therefore, the harmful effects on humans and animals is a major concern. Although studies have elucidated the adverse estrogenic and anti-estrogenic effects of TCDD, it is unclear in which tissues TCDD exerts these effects in vivo. To investigate the estrogen-related effects of TCDD in various tissues, we generated an improved estrogen-responsive reporter transgenic mouse in which the luciferase gene luc2 is expressed in response to estrogenic signals. Using these mice, we clarified that TCDD inhibits estrogenic signaling in liver and kidney but enhances estrogenic signaling in the pituitary gland in the same individual. Expression of aryl hydrocarbon receptor, aryl hydrocarbon receptor nuclear translocator, and estrogen receptor alpha mRNA was detected in liver, kidney, and pituitary gland, suggesting that the effects of TCDD on estrogenic signaling in these organs is independent of the expression pattern of these receptors. Thus, our results indicate that TCDD exerts both estrogenic and anti-estrogenic tissue-specific effects within the same individual.
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Contaminantes Ambientales/toxicidad , Moduladores de los Receptores de Estrógeno/toxicidad , Estrógenos/toxicidad , Dibenzodioxinas Policloradas/toxicidad , Animales , Línea Celular Tumoral , Contaminantes Ambientales/farmacocinética , Moduladores de los Receptores de Estrógeno/farmacocinética , Estrógenos/farmacocinética , Femenino , Expresión Génica/efectos de los fármacos , Humanos , Luciferasas/genética , Ratones Transgénicos , Dibenzodioxinas Policloradas/farmacocinética , Transducción de Señal/efectos de los fármacos , Distribución TisularRESUMEN
INTRODUCTION: Oral HIV Pre-Exposure Prophylaxis (PrEP) with tenofovir (TFV) disoproxil fumarate (TDF)/emtricitabine (FTC) is highly effective. Transgender women (TGW) have increased HIV risk, but have been underrepresented in trials. For TGW on oestrogens for gender-affirming hormone treatment (GAHT), TDF/FTC-oestrogen interactions may negatively affect HIV prevention or gender-affirming goals. Our aim was to evaluate any pharmacokinetic drug-drug interaction between GAHT and TDF/FTC. METHODS: We performed a pharmacokinetic study, in an urban outpatient setting in 2016 to 2018, of the effects of GAHT on TFV, FTC and the active forms TFV diphosphate (TFV-DP) and FTC triphosphate (FTC-TP) in eight TGW and eight cisgender men (CGM). At screening, participants were HIV negative. TGW were to maintain their GAHT regimens and have plasma oestradiol concentrations >100 pg/mL. Under direct observation, participants took oral TDF/FTC daily for seven days. At the last dose, blood was collected pre-dose, one, two, four, six, eight and twenty-four hours, and colon biopsies were collected at 24 hours to measure drug concentration. TGW versus CGM concentration comparisons used non-parametric tests. Blood and colon tissue were also obtained to assess kinase expression. RESULTS: Plasma TFV and FTC C24 (trough) concentrations in TGW were lower by 32% (p = 0.010) and 32% (p = 0.038) respectively, when compared to CGM. Plasma TFV and FTC 24-hr area under the concentration-time curve in TGW trended toward and was significantly lower by 27% (p = 0.065) and 24% (p = 0.028) respectively. Peak plasma TFV and FTC concentrations, as well as all other pharmacokinetic measures, were not statistically significant when comparing TGW to CGM. Oestradiol concentrations were not different comparing before and after TDF/FTC dosing. Plasma oestrogen concentration, renal function (estimated creatinine clearance and glomerular filtration rate), and TFV and FTC plasma concentrations (trough and area under the concentration-time curve) were all correlated. CONCLUSIONS: GAHT modestly reduces both TFV and FTC plasma concentrations. In TGW taking GAHT, it is unknown if this reduction will impact the HIV protective efficacy of a daily PrEP regimen. However, the combination of an on demand (2 + 1 + 1) PrEP regimen and GAHT may result in concentrations too low for reliable prevention of HIV infection.
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Emtricitabina/sangre , Estrógenos/farmacocinética , Infecciones por VIH/prevención & control , Profilaxis Pre-Exposición , Tenofovir/sangre , Personas Transgénero , Adulto , Fármacos Anti-VIH/administración & dosificación , Fármacos Anti-VIH/sangre , Fármacos Anti-VIH/farmacología , Interacciones Farmacológicas , Emtricitabina/administración & dosificación , Emtricitabina/farmacología , Estrógenos/administración & dosificación , Estrógenos/farmacología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Tenofovir/administración & dosificación , Tenofovir/farmacología , Adulto JovenRESUMEN
Genistein is an isoflavone derived from soy-rich products, which is known to exhibit several beneficial biological effects, such as anti-tumor activity, improvement of glucose metabolism, and reduction of the frequency of peri-menopausal hot flashes, and thus has potential for clinical application. Certain limitations and side effects, such as low bioavailability, biological estrogenic activity, and detrimental effects on thyroid function, have restricted its clinical applications to some extent. Recently, it has been reported that fermentation, use of micromicelles, and modification of its chemical structure can enhance the bioavailability of genistein. Moreover, the modification of its molecular structure may also eliminate its biological estrogenic activity and adverse effects on thyroid function. In this review, we summarize the clinical application prospects and limitations of genistein, as well as the plausible solutions to overcome its low bioavailability, phytoestrogenic activity, and adverse effects on thyroid function.
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Antineoplásicos Fitogénicos , Estrógenos , Genisteína , Sofocos/tratamiento farmacológico , Menopausia/metabolismo , Glándula Tiroides/metabolismo , Antineoplásicos Fitogénicos/farmacocinética , Antineoplásicos Fitogénicos/farmacología , Estrógenos/farmacocinética , Estrógenos/uso terapéutico , Femenino , Genisteína/farmacocinética , Genisteína/uso terapéutico , Sofocos/metabolismo , Sofocos/patología , Humanos , MicelasRESUMEN
The goal of the present study was to obtain an in vivo relevant prioritization method for the endocrine potencies of different polycarbonate monomers, by combining in vitro bioassay data with physiologically based kinetic (PBK) modelling. PBK models were developed for a selection of monomers, including bisphenol A (BPA), two bisphenol F (BPF) isomers and four different bisphenol A diglycidyl ethers (BADGEs), using in vitro input data. With these models, the plasma concentrations of the compounds were simulated, providing means to estimate the dose levels at which the in vitro endocrine effect concentrations are reached. The results revealed that, whereas the in vitro relative potencies of different BADGEs (predominantly anti-androgenic effects) can be up to fourfold higher than BPA, the estimated in vivo potencies based on the oral equivalent doses are one to two orders of magnitude lower than BPA because of fast detoxification of the BADGEs. In contrast, the relative potencies of 2,2-BPF and 4,4-BPF increase when accounting for the in vivo availability. 4,4-BPF is estimated to be fivefold more potent than BPA in humans in vivo in inducing estrogenic effects and both 2,2-BPF and 4,4-BPF are estimated to be, respectively, 7 and 11-fold more potent in inducing anti-androgenic effects. These relative potencies were considered to be first-tier estimates, particularly given that the potential influence of intestinal metabolism on the in vivo availability was not accounted for. Overall, it can be concluded that both 2,2-BPF and 4,4-BPF are priority compounds.
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Compuestos de Bencidrilo/administración & dosificación , Compuestos Epoxi/administración & dosificación , Modelos Biológicos , Fenoles/administración & dosificación , Antagonistas de Andrógenos/administración & dosificación , Antagonistas de Andrógenos/farmacocinética , Antagonistas de Andrógenos/toxicidad , Compuestos de Bencidrilo/farmacocinética , Compuestos de Bencidrilo/toxicidad , Células CACO-2 , Línea Celular , Relación Dosis-Respuesta a Droga , Compuestos Epoxi/farmacocinética , Compuestos Epoxi/toxicidad , Estrógenos/administración & dosificación , Estrógenos/farmacocinética , Estrógenos/toxicidad , Humanos , Fenoles/farmacocinética , Fenoles/toxicidadRESUMEN
This study reports the preparation, in vitro release, pharmacokinetics, and local tolerability of novel ethylene-vinyl acetate intravaginal rings (IVRs) delivering 17ß-estradiol (E2) and progesterone (P), in drug-naïve ovariectomized female Dorset crossbred sheep. After preparation and assessment of in vitro release of E2 and P, animals were randomized to treatment groups 1 or 2 (comparator rings releasing 50 or 100 µg/d E2, respectively), groups 3 or 4 (ethylene-vinyl acetate IVRs, 160 µg/d E2 with 4 [160/4 IVR] or 8 mg/d P [160/8 IVR], respectively), or group 5 (160 µg E2 and 10 mg P administered intravenously). IVRs were placed on day 1 and remained in place through day 29. Animals underwent daily examinations to confirm ring placement, and vaginal irritation was scored from 0 (none) to 4 (severe). Blood samples were taken at scheduled times for pharmacokinetic analysis. Postmortem examinations performed on groups 1-4 were macroscopic and microscopic evaluations, including irritation scoring and histopathology. IVRs were retained over 28 days in all but 1 animal (group 4). In all animal groups, clinical observations showed no significant abnormal findings. Pharmacokinetic analysis in the animals showed sustained release of E2 and P over a 28-day period. Irritation scores and microscopic assessments were consistent with foreign object placement. A novel 2-drug IVR delivery system was well tolerated in a sheep model and pharmacokinetic release was as expected over a 28-day release period. These results will guide future human clinical studies.
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Estradiol/farmacocinética , Estrógenos/farmacocinética , Progesterona/farmacocinética , Progestinas/farmacocinética , Administración Intravaginal , Animales , Sistemas de Liberación de Medicamentos/efectos adversos , Sistemas de Liberación de Medicamentos/métodos , Estradiol/administración & dosificación , Estrógenos/administración & dosificación , Etilenos/química , Femenino , Progesterona/administración & dosificación , Progestinas/administración & dosificación , Ovinos , Compuestos de Vinilo/químicaRESUMEN
Low birth weight is associated with a greater prevalence of hypertension and an earlier age at menopause in women in later life. Yet, the association between birth weight and blood pressure (BP) in women as they age is not well defined. In a rodent model of low birth weight induced by placental insufficiency, intrauterine growth restriction programs a significant increase in BP by 12 months of age in female growth-restricted offspring that is associated with early reproductive senescence, increased testosterone, and a shift in the hormonal milieu. Thus, this study tested the hypothesis that increased BP in female growth-restricted offspring is abolished by chronic estradiol supplementation. Placebo or 17ß-estradiol valerate mini pellets (1.5 mg for 60-day release) were administered at 12 months of age for 6 weeks. BP, measured in conscious catheterized rats, was significantly increased in placebo-treated growth-restricted relative to placebo-treated control. However, BP was not elevated in estradiol-treated growth-restricted relative to placebo-treated growth-restricted. Estradiol mediates its effects on BP via its receptors and the renin-angiotensin system. BP was decreased in growth-restricted offspring treated with a G-protein coupled receptor agonist, G1 (400 mg/kg for 2 weeks). Renal AT1aR (angiotensin type 1a receptor) and AT1bR (angiotensin type 1b receptor) and renal AR (androgen receptor) mRNA expression were elevated in vehicle-treated growth-restricted offspring, but not in G1-treated growth-restricted. Therefore, these data suggest that chronic estradiol supplementation prevents the increase in BP that develops in female growth-restricted offspring via actions that may involve its G-protein coupled receptor and the renin-angiotensin system.
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Presión Sanguínea/efectos de los fármacos , Estradiol/administración & dosificación , Retardo del Crecimiento Fetal/prevención & control , Preñez , Animales , Suplementos Dietéticos , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Estradiol/farmacocinética , Estrógenos/administración & dosificación , Estrógenos/farmacocinética , Femenino , Retardo del Crecimiento Fetal/metabolismo , Retardo del Crecimiento Fetal/fisiopatología , Masculino , Embarazo , RatasRESUMEN
An inverse agonist of estrogen-related receptor-γ (ERRγ), an orphan nuclear receptor encoded by E srrg, enhances sodium iodide symporter-mediated radioiodine uptake in anaplastic thyroid cancer (ATC) cells, thereby facilitating responsiveness to radioiodine therapy in vitro. We synthesized potent, selective, and orally bioavailable ERRγ-inverse agonists and evaluated their activity by analyzing in vitro pharmacology and absorption, distribution, metabolism, excretion, and toxicity profiles. X-ray crystallographic analysis of the ligand and ERRγ complex showed that 35 completely binds to the target protein (PDB 6A6K ). Our results showed improved radioiodine avidity in ATC cells through compound 35-mediated upregulation of iodide-handling genes, leading to enhanced responsiveness to radioiodine therapy in vitro. Importantly, in vivo 124I-positron emission tomography/computed tomography imaging revealed that 35 increases radioiodine avidity in CAL62 tumors. Collectively, these results demonstrated that 35 can be developed as a promising treatment for ERRγ-related cancer in the future.
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Receptores de Estrógenos/metabolismo , Simportadores/metabolismo , Tamoxifeno/análogos & derivados , Tamoxifeno/uso terapéutico , Carcinoma Anaplásico de Tiroides/tratamiento farmacológico , Neoplasias de la Tiroides/tratamiento farmacológico , Animales , Antineoplásicos/síntesis química , Antineoplásicos/farmacocinética , Antineoplásicos/uso terapéutico , Línea Celular Tumoral , Descubrimiento de Drogas , Agonismo Inverso de Drogas , Estrógenos/agonistas , Estrógenos/síntesis química , Estrógenos/farmacocinética , Estrógenos/uso terapéutico , Femenino , Expresión Génica/efectos de los fármacos , Humanos , Radioisótopos de Yodo/metabolismo , Ratones Endogámicos BALB C , Estructura Molecular , Relación Estructura-Actividad , Tamoxifeno/agonistas , Tamoxifeno/farmacocinética , Carcinoma Anaplásico de Tiroides/metabolismo , Neoplasias de la Tiroides/metabolismoRESUMEN
Many women suffer from the genitourinary syndrome of the menopause (GSM), in particular pathological changes that occur in the vagina due to the reduction in their production of estrogens. TherapeuticsMD has developed Imvexxy, small softgel capsules that contain solubilized estradiol and that are inserted vaginally by women twice a week, every 3 to 4 days. These vaginal inserts have been found to readily supply estradiol to the vagina and to result in significant improvement in the GSM signs and symptoms these women had been experiencing. At the same time, pharmacokinetic studies have demonstrated that the small doses of estradiol used do not increase systemic blood levels of estrogens above baseline values, thus greatly reducing the likelihood of unwanted systemic effects of estradiol. The placebo used in clinical trials, which only contained the 'inactive' ingredients in Imvexxy, had partial efficacy, the result either of a placebo effect or of the use of MIGLYOL 812 N to keep the estradiol in solution.
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Estradiol/administración & dosificación , Estrógenos/administración & dosificación , Enfermedades Urogenitales Femeninas/tratamiento farmacológico , Terapia de Reemplazo de Hormonas/métodos , Menopausia , Vagina/efectos de los fármacos , Administración Intravaginal , Atrofia , Cápsulas , Composición de Medicamentos , Estradiol/efectos adversos , Estradiol/química , Estradiol/farmacocinética , Estrógenos/efectos adversos , Estrógenos/química , Estrógenos/farmacocinética , Femenino , Enfermedades Urogenitales Femeninas/sangre , Enfermedades Urogenitales Femeninas/diagnóstico , Enfermedades Urogenitales Femeninas/fisiopatología , Geles , Terapia de Reemplazo de Hormonas/efectos adversos , Humanos , Síndrome , Resultado del Tratamiento , Vagina/metabolismo , Vagina/patología , Vagina/fisiopatologíaRESUMEN
Uterotrophic effect of 17α-estradiol, the C17 epimer of the main human estrogen 17ß-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 10ß,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.
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Encéfalo/metabolismo , Estradiol/farmacocinética , Estrógenos/farmacocinética , Profármacos/farmacocinética , Útero/metabolismo , Animales , Cromatografía Liquida , Estradiol/metabolismo , Antagonistas del Receptor de Estrógeno/farmacología , Receptor alfa de Estrógeno/metabolismo , Receptor beta de Estrógeno/metabolismo , Femenino , Fulvestrant/farmacología , Ratones , Ovariectomía , Espectrometría de Masas en TándemRESUMEN
Bisphenols, anthropogenic pollutants, leach from consumer products and have potential to be ingested and are excreted in waste. The endocrine disrupting effects of highly manufactured bisphenols (BPA, BPS, and BPF) are known, however the activities of others are not. Here, the estrogenic and androgenic activities of a series of 4,4'-bisphenols that vary at the inter-connecting bisphenol bridge were determined (BPA, BPB, BPBP, BPC2, BPE, BPF, BPS, and BPZ) and compared to in silico binding to estrogen receptor-alpha and the androgen receptor. Bioassay results showed the order of estrogenicity (BPC2 (strongest) > BPBP > BPB > BPZ > BPE > BPF > BPA > BPS, r2 = 0.995) and anti-androgenicity (BPC2 (strongest) > BPE, BPB, BPA, BPF, and BPS, r2 = 0.996) correlated to nuclear receptor binding affinities. Like testosterone and the anti-androgen hydroxyflutamide, bisphenol fit in the ligand-binding domain through hydrogen-bonding at residues Thr877 and Asn705, but also interacted at either Cys784/Ser778 or Gln711 through the other phenol ring. This suggests the 4,4'-bisphenols, like hydroxyflutamide, are androgen receptor antagonists. Hydrogen-bond trends between ERα and the 4,4'-bisphenols were limited to residue Glu353, which interacted with the -OH of one phenol and the -OH of the A ring of 17ß-estradiol; hydrogen-bonding varied at the -OH of ring D of 17ß-estradiol and the second phenol -OH group. While both estrogen and androgen bioassays correlated to in silico results, conservation of hydrogen-bonding residues in the androgen receptor provides a convincing picture of direct antagonist binding by 4,4'-bisphenols.
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Antagonistas de Andrógenos/farmacocinética , Compuestos de Bencidrilo/farmacocinética , Disruptores Endocrinos/farmacocinética , Estrógenos/farmacocinética , Fenoles/farmacocinética , Antagonistas de Andrógenos/química , Compuestos de Bencidrilo/química , Evaluación Preclínica de Medicamentos/métodos , Disruptores Endocrinos/química , Disruptores Endocrinos/aislamiento & purificación , Estradiol/análogos & derivados , Estradiol/química , Estrógenos/química , Técnicas In Vitro , Simulación del Acoplamiento Molecular , Fenoles/química , Unión Proteica , Relación Estructura-Actividad Cuantitativa , Receptores Androgénicos/química , Receptores Androgénicos/metabolismo , Receptores de Estrógenos/química , Receptores de Estrógenos/metabolismo , LevadurasRESUMEN
Xenoestrogenic mycotoxins may contaminate food and feed posing a public health issue. Besides the zearalenone group, the Alternaria toxin alternariol (AOH) has been described as a potential mycoestrogen. However, the estrogenicity of Alternaria toxins is still largely overlooked and further data are needed to better describe the group toxicity. In the frame of risk assessment, mixed in silico/in vitro approaches already proved to be effective first-line analytical tools. An integrated in silico/in vitro approach was used to investigate the effects of metabolic and chemical modifications on the estrogenicity of AOH. Among the considered modifications, methylation was found critical for enhancing estrogenicity (as seen for alternariol monomethyl ether (AME)) while hydroxylation and glucuronidation had the opposite effect (as seen for 4-hydroxy AOH and 4-hydroxy AME). The structure-activity relationship analysis provided the structural rationale. Our results provide insights to design more efficient risk assessment studies expanding knowledge over the group toxicity.
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Alternaria/química , Micotoxinas/metabolismo , Micotoxinas/toxicidad , Simulación por Computador , Estrógenos/química , Estrógenos/farmacocinética , Estrógenos/toxicidad , Humanos , Hidroxilación , Lactonas/química , Lactonas/farmacocinética , Lactonas/toxicidad , Metilación , Micotoxinas/química , Receptores de Estrógenos/química , Receptores de Estrógenos/metabolismo , Medición de Riesgo , Relación Estructura-Actividad , Xenobióticos/química , Xenobióticos/farmacocinética , Xenobióticos/toxicidadRESUMEN
STUDY OBJECTIVE: To demonstrate how a novel laparoscopic approach allows the development of a mouse model for endometriosis after seeding menstrual endometrium from donor mice into the abdominal cavity of syngeneic recipient mice. DESIGN: A step-by-step video description of the techniques used to adapt the estrous cycle of mice towards a menstrual cycle and to subsequently induce endometriosis via laparoscopic seeding of menstrual endometrium. SETTING: University research institute. ETHICS: All animal experiments were ethically approved by KU Leuven, Belgium (ethical approval number: P031/2013). INTERVENTIONS, MEASUREMENTS, AND MAIN RESULTS: Oophorectomized female C57BL/6JRj mice received a series of estrogen injections. Next, a progesterone pellet was administered, together with a second series of estrogen injections. In addition, decidualization of the endometrium was induced with an intrauterine sesame oil stimulus. Four days later the progesterone pellet was removed and menstruation started [1]. Five hours after the progesterone pellet was removal the uterus was harvested, and the menstrual endometrium was dissected and seeded into the abdominal cavity of syngeneic recipient mice to induce endometriosis [2] using a laparoscopic approach [3]. Uterus and lesions were removed from the recipient mice 1 week after induction, and tissues were immunohistochemically stained for H&E, vimentin, and cytokeratin. CONCLUSION: In this video we show a novel methodology to induce endometriosis in mice using laparoscopic inoculation of syngeneic menstrual endometrium, mimicking Sampson's theory of retrograde menstruation [4]. Compared with currently available rodent models, our model offers a less invasive and more physiologic way for fundamental and preclinical endometriosis research, with a high endometriosis incidence and lesion take rate.
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Endometriosis/cirugía , Laparoscopía/métodos , Animales , Modelos Animales de Enfermedad , Endometrio/patología , Estrógenos/farmacocinética , Femenino , Humanos , Ciclo Menstrual/fisiología , Menstruación/fisiología , Ratones Endogámicos C57BL , Progesterona/farmacología , Progestinas/farmacologíaRESUMEN
INTRODUCTION: The increased maternal estradiol (E2) concentrations induced by assisted reproductive technology (ART) result in lower birth weight of offspring, which is associated with increased risk of adult diseases. However, the exact mechanism remains unknown. The present study investigated the effect of high E2 exposure on the expression of imprinted genes CDKN1C and IGF2 in human placentas and the DNA methylation status of their differential methylation regions (DMRs). METHODS: The mRNA expression of CDKN1C and IGF2 in human placentas and the human trophoblast cells (HTR8) treated with E2 were investigated by reverse transcription-real time polymerase chain reaction (PCR). The DNA methylation of their DMRs were investigated by sodium bisulfite sequencing. RESULTS: CDKN1C and IGF2 were significantly up-regulated in ART conceived placentas. The mean birth weight of ART singletons was significantly lower than that of naturally conceived (NC) ones, with the increased percentage of small-for-gestational-age (SGA) birth. The DNA methylation was significantly down-regulated in the DMR of CDKN1C (KvDMR1) and up-regulated in the DMR of IGF2 (H19 DMR) in ART placentas. The treatment of E2 altered the expression of the two genes and the DNA methylation of their DMRs in HTR8 to a similar tendency as in vivo. DISCUSSION: The maternal high E2 levels after ART up-regulate the expression of imprinted genes in human placentas through epigenetic modifications, which influences the growth potential of the offspring. Further studies are needed to follow up the growth and development of the ART offspring.
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Inhibidor p57 de las Quinasas Dependientes de la Ciclina/agonistas , Metilación de ADN/efectos de los fármacos , Estradiol/efectos adversos , Regulación del Desarrollo de la Expresión Génica/efectos de los fármacos , Factor II del Crecimiento Similar a la Insulina/agonistas , Inducción de la Ovulación/efectos adversos , Placenta/efectos de los fármacos , Adulto , Línea Celular , China/epidemiología , Inhibidor p57 de las Quinasas Dependientes de la Ciclina/química , Inhibidor p57 de las Quinasas Dependientes de la Ciclina/genética , Inhibidor p57 de las Quinasas Dependientes de la Ciclina/metabolismo , Transferencia de Embrión/efectos adversos , Estradiol/sangre , Estradiol/farmacocinética , Estradiol/farmacología , Estrógenos/efectos adversos , Estrógenos/sangre , Estrógenos/farmacocinética , Estrógenos/farmacología , Femenino , Fármacos para la Fertilidad Femenina/efectos adversos , Fármacos para la Fertilidad Femenina/sangre , Fármacos para la Fertilidad Femenina/farmacocinética , Fármacos para la Fertilidad Femenina/farmacología , Desarrollo Fetal/efectos de los fármacos , Retardo del Crecimiento Fetal/inducido químicamente , Retardo del Crecimiento Fetal/epidemiología , Retardo del Crecimiento Fetal/etiología , Humanos , Infertilidad Femenina/sangre , Infertilidad Femenina/metabolismo , Infertilidad Femenina/terapia , Factor II del Crecimiento Similar a la Insulina/química , Factor II del Crecimiento Similar a la Insulina/genética , Factor II del Crecimiento Similar a la Insulina/metabolismo , Placenta/metabolismo , Embarazo , Riesgo , Trofoblastos/efectos de los fármacos , Trofoblastos/metabolismoRESUMEN
Tamoxifen, a standard therapy for breast cancer, is metabolized to compounds with anti-estrogenic as well as estrogen-like action at the estrogen receptor. Little is known about the formation of estrogen-like metabolites and their biological impact. Thus, we characterized the estrogen-like metabolites tamoxifen bisphenol and metabolite E for their metabolic pathway and their influence on cytochrome P450 activity and ADME gene expression. The formation of tamoxifen bisphenol and metabolite E was studied in human liver microsomes and Supersomes™. Cellular metabolism and impact on CYP enzymes was analyzed in upcyte® hepatocytes. The influence of 5 µM of tamoxifen, anti-estrogenic and estrogen-like metabolites on CYP activity was measured by HPLC MS/MS and on ADME gene expression using RT-PCR analyses. Metabolite E was formed from tamoxifen by CYP2C19, 3A and 1A2 and from desmethyltamoxifen by CYP2D6, 1A2 and 3A. Tamoxifen bisphenol was mainly formed from (E)- and (Z)-metabolite E by CYP2B6 and CYP2C19, respectively. Regarding phase II metabolism, UGT2B7, 1A8 and 1A3 showed highest activity in glucuronidation of tamoxifen bisphenol and metabolite E. Anti-estrogenic metabolites (Z)-4-hydroxytamoxifen, (Z)-endoxifen and (Z)-norendoxifen inhibited the activity of CYP2C enzymes while tamoxifen bisphenol consistently induced CYPs similar to rifampicin and phenobarbital. On the transcript level, highest induction up to 5.6-fold was observed for CYP3A4 by tamoxifen, (Z)-4-hydroxytamoxifen, tamoxifen bisphenol and (E)-metabolite E. Estrogen-like tamoxifen metabolites are formed in CYP-dependent reactions and are further metabolized by glucuronidation. The induction of CYP activity by tamoxifen bisphenol and the inhibition of CYP2C enzymes by anti-estrogenic metabolites may lead to drug-drug-interactions.
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Sistema Enzimático del Citocromo P-450/genética , Sistema Enzimático del Citocromo P-450/metabolismo , Tamoxifeno/farmacocinética , Alquenos/farmacocinética , Línea Celular , Estrógenos/farmacocinética , Regulación Enzimológica de la Expresión Génica/efectos de los fármacos , Glucurónidos/metabolismo , Glucuronosiltransferasa/metabolismo , Hepatocitos/efectos de los fármacos , Hepatocitos/metabolismo , Humanos , Microsomas Hepáticos/efectos de los fármacos , Microsomas Hepáticos/metabolismo , Fenoles/farmacocinética , Tamoxifeno/análogos & derivados , Tamoxifeno/metabolismoRESUMEN
BACKGROUND: Estrogen is a vital hormone that regulates many biological functions within the body. These include roles in the development of the secondary sexual organs in both sexes, plus uterine angiogenesis and proliferation during the menstrual cycle and pregnancy in women. The varied biological roles of estrogens in human health also make them a therapeutic target for contraception, mitigation of the adverse effects of the menopause, and treatment of estrogen-responsive tumours. In addition, endogenous (e.g. genetic variation) and external (e.g. exposure to estrogen-like chemicals) factors are known to impact estrogen biology. To understand how these multiple factors interact to determine an individual's response to therapy is complex, and may be best approached through a systems approach. METHODS: We present a physiologically-based pharmacokinetic model (PBPK) of estradiol, and validate it against plasma kinetics in humans following intravenous and oral exposure. We extend this model by replacing the intrinsic clearance term with: a detailed kinetic model of estrogen metabolism in the liver; or, a genome-scale model of liver metabolism. Both models were validated by their ability to reproduce clinical data on estradiol exposure. We hypothesise that the enhanced mechanistic information contained within these models will lead to more robust predictions of the biological phenotype that emerges from the complex interactions between estrogens and the body. RESULTS: To demonstrate the utility of these models we examine the known drug-drug interactions between phenytoin and oral estradiol. We are able to reproduce the approximate 50% reduction in area under the concentration-time curve for estradiol associated with this interaction. Importantly, the inclusion of a genome-scale metabolic model allows the prediction of this interaction without directly specifying it within the model. In addition, we predict that PXR activation by drugs results in an enhanced ability of the liver to excrete glucose. This has important implications for the relationship between drug treatment and metabolic syndrome. CONCLUSIONS: We demonstrate how the novel coupling of PBPK models with genome-scale metabolic networks has the potential to aid prediction of drug action, including both drug-drug interactions and changes to the metabolic landscape that may predispose an individual to disease development.